@article{breeyear_hellwege_schroeder_house_poisner_mitchell_charest_khakharia_basnet_halladay_et al._2024, title={Adaptive selection at G6PD and disparities in diabetes complications}, url={https://doi.org/10.1038/s41591-024-03089-1}, DOI={10.1038/s41591-024-03089-1}, journal={Nature Medicine}, author={Breeyear, Joseph H. and Hellwege, Jacklyn N. and Schroeder, Philip H. and House, John S. and Poisner, Hannah M. and Mitchell, Sabrina L. and Charest, Brian and Khakharia, Anjali and Basnet, Til B. and Halladay, Christopher W. and et al.}, year={2024}, month={Jun} }
 @article{chung_house_akhtari_makris_langston_islam_holmes_chadeau-hyam_smirnov_du_et al._2024, title={Decoding the exposome: data science methodologies and implications in exposome-wide association studies (ExWASs)}, url={https://doi.org/10.1093/exposome/osae001}, DOI={10.1093/exposome/osae001}, abstractNote={Abstract}, journal={Exposome}, author={Chung, Ming Kei and House, John S and Akhtari, Farida S and Makris, Konstantinos C and Langston, Michael A and Islam, Khandaker Talat and Holmes, Philip and Chadeau-Hyam, Marc and Smirnov, Alex I and Du, Xiuxia and et al.}, year={2024}, month={Feb} }
 @article{fleming_house_chappel_motsinger-reif_reif_2024, title={Guided optimization of ToxPi model weights using a Semi-Automated approach}, volume={29}, ISSN={["2468-1113"]}, DOI={10.1016/j.comtox.2023.100294}, abstractNote={The Toxicological Prioritization Index (ToxPi) is a visual analysis and decision support tool for dimension reduction and visualization of high throughput, multi-dimensional feature data. ToxPi was originally developed for assessing the relative toxicity of multiple chemicals or stressors by synthesizing complex toxicological data to provide a single comprehensive view of the potential health effects. It continues to be used for profiling chemicals and has since been applied to other types of "sample" entities, including geospatial (e.g. county-level Covid-19 risk and sites of historical PFAS exposure) and other profiling applications. For any set of features (data collected on a set of sample entities), ToxPi integrates the data into a set of weighted slices that provide a visual profile and a score metric for comparison. This scoring system is highly dependent on user-provided feature weights, yet users often lack knowledge of how to define these feature weights. Common methods for predicting feature weights are generally unusable due to inappropriate statistical assumptions and lack of global distributional expectation. However, users often have an inherent understanding of expected results for a small subset of samples. For example, in chemical toxicity, prior knowledge can often place subsets of chemicals into categories of low, moderate or high toxicity (reference chemicals). Ordinal regression can be used to predict weights based on these response levels that are applicable to the entire feature set, analogous to using positive and negative controls to contextualize an empirical distribution. We propose a semi-supervised method utilizing ordinal regression to predict a set of feature weights that produces the best fit for the known response ("reference") data and subsequently fine-tunes the weights via a customized genetic algorithm. We conduct a simulation study to show when this method can improve the results of ordinal regression, allowing for accurate feature weight prediction and sample ranking in scenarios with minimal response data. To ground-truth the guided weight optimization, we test this method on published data to build a ToxPi model for comparison against expert-knowledge-driven weight assignments.}, journal={COMPUTATIONAL TOXICOLOGY}, author={Fleming, Jonathon F. and House, John S. and Chappel, Jessie R. and Motsinger-Reif, Alison A. and Reif, David M.}, year={2024}, month={Mar} }
 @article{lloyd_house_akhtari_schmitt_fargo_scholl_phillips_choksi_shah_hall_et al._2024, title={Interactive data sharing for multiple questionnaire-based exposome-wide association studies and exposome correlations in the Personalized Environment and Genes Study}, url={https://doi.org/10.1093/exposome/osae003}, DOI={10.1093/exposome/osae003}, abstractNote={Abstract}, journal={Exposome}, author={Lloyd, Dillon and House, John S and Akhtari, Farida S and Schmitt, Charles P and Fargo, David C and Scholl, Elizabeth H and Phillips, Jason and Choksi, Shail and Shah, Ruchir and Hall, Janet E and et al.}, year={2024}, month={Feb} }
 @article{lloyd_house_akhtari_schmitt_fargo_scholl_phillips_choksi_shah_hall_et al._2024, title={Questionnaire-based exposome-wide association studies for common diseases in the Personalized Environment and Genes Study}, url={https://doi.org/10.1093/exposome/osae002}, DOI={10.1093/exposome/osae002}, abstractNote={Abstract}, journal={Exposome}, author={Lloyd, Dillon and House, John S and Akhtari, Farida S and Schmitt, Charles P and Fargo, David C and Scholl, Elizabeth H and Phillips, Jason and Choksi, Shail and Shah, Ruchir and Hall, Janet E and et al.}, year={2024}, month={Feb} }
 @article{tsai_house_wright_chiu_rusyn_2023, title={A tiered testing strategy based on in vitro phenotypic and transcriptomic data for selecting representative petroleum UVCBs for toxicity evaluation in vivo}, ISSN={["1096-0929"]}, url={https://doi.org/10.1093/toxsci/kfad041}, DOI={10.1093/toxsci/kfad041}, abstractNote={Abstract}, journal={TOXICOLOGICAL SCIENCES}, author={Tsai, Han-Hsuan Doris and House, John S. and Wright, Fred A. and Chiu, Weihsueh A. and Rusyn, Ivan}, year={2023}, month={Apr} }
 @article{house_gray_owen_jima_smart_hall_2023, title={C/EBP beta deficiency enhances the keratinocyte innate immune response to direct activators of cytosolic pattern recognition receptors}, volume={29}, ISSN={["1753-4267"]}, DOI={10.1177/17534259231162192}, abstractNote={ The skin is the first line of defense to cutaneous microbes and viruses, and epidermal keratinocytes play a critical role in preventing infection by viruses and pathogens through activation of the type I interferon (IFN) response. Using RNAseq analysis, here we report that the conditional deletion of C/EBPβ transcription factor in mouse epidermis (CKOβ mice) resulted in the upregulation of IFNβ and numerous keratinocyte interferon-stimulated genes (ISGs). The expression of cytosolic pattern recognition receptors (cPRRs), that recognize viral RNA and DNA, were significantly increased, and enriched in the RNAseq data set. cPRRs stimulate a type I IFN response that can trigger cell death to eliminate infected cells. To determine if the observed increases in cPRRs had functional consequences, we transfected CKOβ primary keratinocytes with the pathogen and viral mimics poly(I:C) (dsRNA) or poly(dA:dT) (synthetic B-DNA) that directly activate PRRs. Transfected CKOβ primary keratinocytes displayed an amplified type I IFN response which was accompanied by increased activation of IRF3, enhanced ISG expression, enhanced activation of caspase-8, caspase-3 and increased apoptosis. Our results identify C/EBPβ as a critical repressor of the keratinocyte type I IFN response, and demonstrates that the loss of C/EBPβ primes keratinocytes to the activation of cytosolic PRRs by pathogen RNA and DNA to induce cell death mediated by caspase-8 and caspase-3. }, number={1-2}, journal={INNATE IMMUNITY}, author={House, John S. and Gray, Sophia and Owen, Jennifer R. and Jima, Dereje D. and Smart, Robert C. and Hall, Jonathan R.}, year={2023}, month={Jan}, pages={14–24} }
 @article{choudhary_monasso_karhunen_ronkainen_mancano_howe_niu_zeng_guan_dou_et al._2023, title={Maternal educational attainment in pregnancy and epigenome-wide DNA methylation changes in the offspring from birth until adolescence}, volume={12}, ISSN={["1476-5578"]}, DOI={10.1038/s41380-023-02331-5}, abstractNote={Abstract}, journal={MOLECULAR PSYCHIATRY}, author={Choudhary, Priyanka and Monasso, Giulietta S. and Karhunen, Ville and Ronkainen, Justiina and Mancano, Giulia and Howe, Caitlin G. and Niu, Zhongzheng and Zeng, Xuehuo and Guan, Weihua and Dou, John and et al.}, year={2023}, month={Dec} }
 @article{jackson_house_henriquez_schladweiler_jackson_fisher_snow_alewel_motsinger-reif_kodavanti_2023, title={Multi-tissue transcriptomic and serum metabolomic assessment reveals systemic implications of acute ozone-induced stress response in male Wistar Kyoto rats}, url={https://doi.org/10.1007/s11306-023-02043-5}, DOI={10.1007/s11306-023-02043-5}, journal={Metabolomics}, author={Jackson, Thomas W. and House, John S. and Henriquez, Andres R. and Schladweiler, Mette C. and Jackson, Kimberly MP and Fisher, Anna A. and Snow, Sam J. and Alewel, Devin I. and Motsinger-Reif, Allison A. and Kodavanti, Urmila P.}, year={2023}, month={Sep} }
 @article{wheeler_lim_house_shockley_john bailer_fostel_yang_talley_raghuraman_gift_et al._2023, title={ToxicR: A computational platform in R for computational toxicology and dose–response analyses}, volume={25}, ISSN={2468-1113}, url={http://dx.doi.org/10.1016/j.comtox.2022.100259}, DOI={10.1016/j.comtox.2022.100259}, abstractNote={The need to analyze the complex relationships observed in high-throughput toxicogenomic and other omic platforms has resulted in an explosion of methodological advances in computational toxicology. However, advancements in the literature often outpace the development of software researchers can implement in their pipelines, and existing software is frequently based on pre-specified workflows built from well-vetted assumptions that may not be optimal for novel research questions. Accordingly, there is a need for a stable platform and open-source codebase attached to a programming language that allows users to program new algorithms. To fill this gap, the Biostatistics and Computational Biology Branch of the National Institute of Environmental Health Sciences, in cooperation with the National Toxicology Program (NTP) and US Environmental Protection Agency (EPA), developed ToxicR, an open-source R programming package. The ToxicR platform implements many of the standard analyses used by the NTP and EPA, including dose–response analyses for continuous and dichotomous data that employ Bayesian, maximum likelihood, and model averaging methods, as well as many standard tests the NTP uses in rodent toxicology and carcinogenicity studies, such as the poly-K and Jonckheere trend tests. ToxicR is built on the same codebase as current versions of the EPA's Benchmark Dose software and NTP's BMDExpress software but has increased flexibility because it directly accesses this software. To demonstrate ToxicR, we developed a custom workflow to illustrate its capabilities for analyzing toxicogenomic data. The unique features of ToxicR will allow researchers in other fields to add modules, increasing its functionality in the future.}, journal={Computational Toxicology}, publisher={Elsevier BV}, author={Wheeler, Matthew W. and Lim, Sooyeong and House, John S. and Shockley, Keith R. and John Bailer, A. and Fostel, Jennifer and Yang, Longlong and Talley, Dawan and Raghuraman, Ashwin and Gift, Jeffery S. and et al.}, year={2023}, month={Feb}, pages={100259} }
 @article{house_rotroff_fonseca_hempe_mychaleckyj_doria_buse_motsinger reif_2022, title={143-OR: Mapping Genetic Determinants of Blood Glucose Control in the Action to Control Cardiovascular Risk in Diabetes Study Group (ACCORD)}, volume={71}, ISSN={0012-1797}, url={http://dx.doi.org/10.2337/db22-143-OR}, DOI={10.2337/db22-143-OR}, abstractNote={The hemoglobin glycation index (HGI) is the difference between observed HbA1c and predicted HbA1c from FPG using linear regression. HGI is an important biomarker of clinical management/drug treatment outcomes and can identify individuals at high risk for multiple adverse events and outcomes before the appearance of clinical symptoms. Here, we sought to test if variation in HGI has genetic determinants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial using a genome-wide association approach (N = 7913) . We subsequently replicated the top hits (P < 1e-5) in the Atherosclerosis Risk in Communities Study (ARIC; N = 3741) . An intergenic SNP rs73407935 (7q11.22) was associated with HGI (P = 5.8e-10) with the locus replicating in ARIC. Further, multiple variants at suggestive genome-wide significance in discovery (P < 5e-6) replicated in ARIC including variants near or in ASAH1 (P = 2.4e-6) , a region previously associated with risk of CAD in T2D, LRRC4C (P = 2.4e-6) , SHLD1 (P = 3.7e-6) and FAM22B (P = 2.5e-6) . The top 2 replicated SNPs in FAM22B are characterized eQTLs for expression of multiple genes in cells from pancreas, brain, and the immune system, including TRAF4, PROCA1, and RPL23A. Many SNPs associated with HGI were distinct from those associated with FPG or HbA1c. In ACCORD, sex-specific HGI associations with SNPs in or near GALNT11 in females (P = 5e-9) and HECW2 (P = 1.5e-8) in males were observed. Further, analysis of 544 Hispanics revealed associations of a strong eQTL variant near USF1 (rs2516837; P = 1.5e-09) and SNPs near NXNL2/SPIN1 (rs141006133; P = 6.9e-9) with HGI. This work represents the first evaluation of the genetic etiology of HGI. We identified and replicated variants that merit further study in the development of precision medicine for treatment of T2D. The results of the stratified analyses highlight the potential importance of heterogeneity in these efforts.}, number={Supplement_1}, journal={Diabetes}, publisher={American Diabetes Association}, author={House, John S. and Rotroff, Daniel M. and Fonseca, Vivian and Hempe, James M. and Mychaleckyj, Josyf and Doria, Alessandro and Buse, John B. and Motsinger Reif, Alison}, year={2022}, month={Jun} }
 @article{shive_house_ferguson_jima_selmek_lloyd_2022, title={Abstract PR011: Characterization of the precancerous and cancer microenvironment in a zebrafish sarcoma model}, volume={28}, ISSN={1557-3265}, url={http://dx.doi.org/10.1158/1557-3265.SARCOMAS22-PR011}, DOI={10.1158/1557-3265.SARCOMAS22-PR011}, abstractNote={Abstract}, number={18_Supplement}, journal={Clinical Cancer Research}, publisher={American Association for Cancer Research (AACR)}, author={Shive, Heather R. and House, John S. and Ferguson, Jordan L. and Jima, Dereje D. and Selmek, Aubrie A. and Lloyd, Dillon T.}, year={2022}, month={Sep}, pages={PR011–PR011} }
 @article{jackson_henriquez_snow_schladweiler_fisher_alewel_house_kodavanti_2022, title={Adrenal Stress Hormone Regulation of Hepatic Homeostatic Function After an Acute Ozone Exposure in Wistar-Kyoto Male Rats}, volume={189}, ISSN={1096-6080 1096-0929}, url={http://dx.doi.org/10.1093/toxsci/kfac065}, DOI={10.1093/toxsci/kfac065}, abstractNote={Abstract}, number={1}, journal={Toxicological Sciences}, publisher={Oxford University Press (OUP)}, author={Jackson, Thomas W and Henriquez, Andres R and Snow, Samantha J and Schladweiler, Mette C and Fisher, Anna A and Alewel, Devin I and House, John S and Kodavanti, Urmila P}, year={2022}, month={Jun}, pages={73–90} }
 @article{lloyd_skinner_maguire_murphy_motsinger-reif_hoyo_house_2022, title={Clomifene and Assisted Reproductive Technology in Humans Are Associated with Sex-Specific Offspring Epigenetic Alterations in Imprinted Control Regions}, volume={23}, ISSN={["1422-0067"]}, url={https://doi.org/10.3390/ijms231810450}, DOI={10.3390/ijms231810450}, abstractNote={Children conceived with assisted reproductive technology (ART) have an increased risk of adverse outcomes, including congenital malformations and imprinted gene disorders. In a retrospective North Carolina-based-birth-cohort, we examined the effect of ovulation drugs and ART on CpG methylation in differentially methylated CpGs in known imprint control regions (ICRs). Nine ICRs containing 48 CpGs were assessed for methylation status by pyrosequencing in mixed leukocytes from cord blood. After restricting to non-smoking, college-educated participants who agreed to follow-up, ART-exposed (n = 27), clomifene-only-exposed (n = 22), and non-exposed (n = 516) groups were defined. Associations of clomifene and ART with ICR CpG methylation were assessed with linear regression and stratifying by offspring sex. In males, ART was associated with hypomethylation of the PEG3 ICR [β(95% CI) = −1.46 (−2.81, −0.12)] and hypermethylation of the MEG3 ICR [3.71 (0.01, 7.40)]; clomifene-only was associated with hypomethylation of the NNAT ICR [−5.25 (−10.12, −0.38)]. In female offspring, ART was associated with hypomethylation of the IGF2 ICR [−3.67 (−6.79, −0.55)]. Aberrant methylation of these ICRs has been associated with cardiovascular disease and metabolic and behavioral outcomes in children. The results suggest that the increased risk of adverse outcomes in offspring conceived through ART may be due in part to altered methylation of ICRs. Larger studies utilizing epigenome-wide interrogation are warranted.}, number={18}, journal={INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, author={Lloyd, Dillon T. and Skinner, Harlyn G. and Maguire, Rachel and Murphy, Susan K. and Motsinger-Reif, Alison A. and Hoyo, Cathrine and House, John S.}, year={2022}, month={Sep} }
 @article{wolkin_collier_house_reif_motsinger-reif_duca_sharpe_2022, title={Comparison of National Vulnerability Indices Used by the Centers for Disease Control and Prevention for the COVID-19 Response}, volume={137}, ISSN={0033-3549 1468-2877}, url={http://dx.doi.org/10.1177/00333549221090262}, DOI={10.1177/00333549221090262}, abstractNote={Objective: Vulnerability indices use quantitative indicators and geospatial data to examine the level of vulnerability to morbidity in a community. The Centers for Disease Control and Prevention (CDC) uses 3 indices for the COVID-19 response: the CDC Social Vulnerability Index (CDC-SVI), the US COVID-19 Community Vulnerability Index (CCVI), and the Pandemic Vulnerability Index (PVI). The objective of this review was to describe these tools and explain the similarities and differences between them. }, number={4}, journal={Public Health Reports}, publisher={SAGE Publications}, author={Wolkin, Amy and Collier, Sarah and House, John S. and Reif, David and Motsinger-Reif, Alison and Duca, Lindsey and Sharpe, J. Danielle}, year={2022}, month={May}, pages={803–812} }
 @article{jima_skaar_planchart_motsinger-reif_cevik_park_cowley_wright_house_liu_et al._2022, title={Genomic map of candidate human imprint control regions: the imprintome}, volume={6}, ISSN={["1559-2308"]}, url={https://doi.org/10.1080/15592294.2022.2091815}, DOI={10.1080/15592294.2022.2091815}, abstractNote={ABSTRACT Imprinted genes – critical for growth, metabolism, and neuronal function – are expressed from one parental allele. Parent-of-origin-dependent CpG methylation regulates this expression at imprint control regions (ICRs). Since ICRs are established before tissue specification, these methylation marks are similar across cell types. Thus, they are attractive for investigating the developmental origins of adult diseases using accessible tissues, but remain unknown. We determined genome-wide candidate ICRs in humans by performing whole-genome bisulphite sequencing (WGBS) of DNA derived from the three germ layers and from gametes. We identified 1,488 hemi-methylated candidate ICRs, including 19 of 25 previously characterized ICRs (https://humanicr.org/). Gamete methylation approached 0% or 100% in 332 ICRs (178 paternally and 154 maternally methylated), supporting parent-of-origin-specific methylation, and 65% were in well-described CTCF-binding or DNaseI hypersensitive regions. This draft of the human imprintome will allow for the systematic determination of the role of early-acquired imprinting dysregulation in the pathogenesis of human diseases and developmental and behavioural disorders.}, journal={EPIGENETICS}, author={Jima, Dereje D. and Skaar, David A. and Planchart, Antonio and Motsinger-Reif, Alison and Cevik, Sebnem E. and Park, Sarah S. and Cowley, Michael and Wright, Fred and House, John and Liu, Andy and et al.}, year={2022}, month={Jun} }
 @article{house_grimm_klaren_dalzell_kuchi_zhang_lenz_boogaard_ketelslegers_gant_et al._2022, title={Grouping of UVCB Substances with Dose-Response Transcriptomics Data from Human Cell-Based Assays}, volume={39}, ISSN={["1868-8551"]}, DOI={10.14573/altex.2107051}, abstractNote={The application of in vitro biological assays as new approach methodologies (NAMs) to support grouping of UVCB (unknown or variable composition, complex reaction products, and biological materials) substances has recently been demonstrated. In addition to cell-based phenotyping as NAMs, in vitro transcriptomic profiling is used to gain deeper mechanistic understanding of biological responses to chemicals and to support grouping and read-across. However, the value of gene expression profiling for characterizing complex substances like UVCBs has not been explored. Using 141 petroleum substance extracts, we performed dose-response transcriptomic profiling in human induced pluripotent stem cell (iPSC)-derived hepatocytes, cardiomyocytes, neurons, and endothelial cells, as well as cell lines MCF7 and A375. The goal was to determine whether transcriptomic data can be used to group these UVCBs and to further characterize the molecular basis for in vitro biological responses. We found distinct transcriptional responses for petroleum substances by manufacturing class. Pathway enrichment informed interpretation of effects of substances and UVCB petroleum-class. Transcriptional activity was strongly correlated with concentration of polycyclic aromatic compounds (PAC), especially in iPSC-derived hepatocytes. Supervised analysis using transcriptomics, alone or in combination with bioactivity data collected on these same substances/cells, suggest that transcriptomics data provide useful mechanistic information, but only modest additional value for grouping. Overall, these results further demonstrate the value of NAMs for grouping of UVCBs, identify informative cell lines, and provide data that could be used for justifying selection of substances for further testing that may be required for registration.}, number={3}, journal={ALTEX-ALTERNATIVES TO ANIMAL EXPERIMENTATION}, author={House, John S. and Grimm, Fabian A. and Klaren, William D. and Dalzell, Abigail and Kuchi, Srikeerthana and Zhang, Shu-Dong and Lenz, Klaus and Boogaard, Peter J. and Ketelslegers, Hans B. and Gant, Timothy W. and et al.}, year={2022}, pages={388–404} }
 @article{brown_shekhar_delaney_burkholder_plummer_mericq_merino_quinton_lewis_shaw_et al._2022, title={LBMON114 Enrichment Of Rare Sequence Variants In Genes That Communicate Metabolic Signals To The GnRH System In Hypothalamic Amenorrhea}, volume={6}, ISSN={2472-1972}, url={http://dx.doi.org/10.1210/jendso/bvac150.970}, DOI={10.1210/jendso/bvac150.970}, abstractNote={Abstract}, number={Supplement_1}, journal={Journal of the Endocrine Society}, publisher={The Endocrine Society}, author={Brown, Ethan and Shekhar, Skand and Delaney, Angela and Burkholder, Adam B and Plummer, Lacey and Mericq, Veronica and Merino, Paulina M and Quinton, Richard and Lewis, Katie L and Shaw, Natalie D and et al.}, year={2022}, month={Nov}, pages={A466–A467} }
 @article{mcgee_shi_house_drude_gonzalez_martin_chen_rogers_njunge_hodge_et al._2022, title={Longitudinal Serological Surveillance for COVID-19 Antibodies after Infection and Vaccination}, volume={10}, ISSN={2165-0497}, url={http://dx.doi.org/10.1128/spectrum.02026-22}, DOI={10.1128/spectrum.02026-22}, abstractNote={The COVID-19 pandemic continues to impact societies and health care systems worldwide and is continuously evolving. Immunity via vaccination or prior infection is the first and most important line of defense against COVID-19.}, number={5}, journal={Microbiology Spectrum}, publisher={American Society for Microbiology}, author={McGee, Christopher and Shi, Min and House, John and Drude, Anna and Gonzalez, Gladys and Martin, Negin and Chen, Shih-Heng and Rogers, Heidi and Njunge, Alex and Hodge, Xiomara and et al.}, editor={Laeyendecker, OliverEditor}, year={2022}, month={Oct} }
 @article{gonzalez-nahm_marchesoni_maity_maguire_house_tucker_atkinson_murphy_hoyo_2022, title={Maternal Mediterranean Diet Adherence and Its Associations with Maternal Prenatal Stressors and Child Growth}, volume={6}, ISSN={["2475-2991"]}, DOI={10.1093/cdn/nzac146}, abstractNote={ABSTRACT Background Psychosocial and physiologic stressors, such as depression and obesity, during pregnancy can have negative consequences, such as increased systemic inflammation, contributing to chronic disease for both mothers and their unborn children. These conditions disproportionately affect racial/ethnic minorities. The effects of recommended dietary patterns in mitigating the effects of these stressors remain understudied. Objectives We aimed to evaluate the relations between maternal Mediterranean diet adherence (MDA) and maternal and offspring outcomes during the first decade of life in African Americans, Hispanics, and Whites. Methods This study included 929 mother–child dyads from the NEST (Newborn Epigenetics STudy), a prospective cohort study. FFQs were used to estimate MDA in pregnant women. Weight and height were measured in children between birth and age 8 y. Multivariable linear regression models were used to examine associations between maternal MDA, inflammatory cytokines, and pregnancy and postnatal outcomes. Results More than 55% of White women reported high MDA during the periconceptional period compared with 22% of Hispanic and 18% of African American women (P < 0.05). Higher MDA was associated with lower likelihood of depressive mood (β = −0.45; 95% CI: −0.90, −0.18; P = 0.02) and prepregnancy obesity (β = −0.29; 95% CI: −0.57, −0.0002; P = 0.05). Higher MDA was also associated with lower body size at birth, which was maintained to ages 3–5 and 6–8 y—this association was most apparent in White children (3–5 y: β = −2.9, P = 0.02; 6–8 y: β = −3.99, P = 0.01). Conclusions If replicated in larger studies, our data suggest that MDA provides a potent avenue by which effects of prenatal stressors on maternal and fetal outcomes can be mitigated to reduce ethnic disparities in childhood obesity.}, number={11}, journal={CURRENT DEVELOPMENTS IN NUTRITION}, author={Gonzalez-Nahm, Sarah and Marchesoni, Joddy and Maity, Arnab and Maguire, Rachel L. and House, John S. and Tucker, Rachel and Atkinson, Tamara and Murphy, Susan K. and Hoyo, Cathrine}, year={2022}, month={Nov} }
 @article{gonzalez-nahm_marchesoni_maity_maguire_house_tucker_atkinson_murphy_hoyo_2022, title={Maternal Periconceptional Stressors, Mediterranean Diet Adherence, and Child Outcomes}, volume={6}, ISSN={2475-2991}, url={http://dx.doi.org/10.1093/cdn/nzac061.034}, DOI={10.1093/cdn/nzac061.034}, abstractNote={Abstract Objectives To evaluate the relationships between maternal periconceptional Mediterranean diet adherence and 1) maternal periconceptional BMI, 2) subsequent maternal depression during pregnancy, 3) prenatal inflammatory cytokine IL-17A, 4) child birthweight, and 5) child weight-for-height at ages 0–8 years in African American, Hispanic and White mother-child dyads from the Newborn Epigenetics STudy (NEST). Methods Food frequency questionnaires were used to estimate periconceptional Mediterranean diet adherence in mothers. Maternal depression during pregnancy was assessed using the Centers for Epidemiological Studies Depression scale. Weight and height were measured in children between birth and age 8 years. Linear and logistic regression models were used to examine associations between maternal adherence to a Mediterranean diet, inflammatory cytokines and pregnancy and postnatal outcomes, adjusted for education, maternal age at delivery, maternal smoking, gestational age, age and sex of child, breastfeeding, parity, maternal BMI. Results Adherence to a Mediterranean diet varied widely by ethnicity with > 55% of White mothers reporting high adherence during the periconceptional period, compared to 22% of Hispanic mothers, and 18% of African American mothers (P < 0.05). Higher adherence to this diet was associated with lower risk of depressive mood (β = −0.45, p = 0.02) and pre-pregnancy obesity (β = −0.29, p = 0.05). Higher maternal adherence to this diet pattern was also associated with lower body weight at birth, that was maintained to ages 3–5 and 6–8 years—these associations were most apparent in White children (3–5 years: β = −2.9, p = 0.02; 6–8 years: β = −3.99, p = 0.01). Higher diet adherence was associated with lower levels of prenatal IL-17A levels in African American mother-child dyads (β = 0.21, p = 0.03). Conclusions Our data suggest that maternal Mediterranean diet adherence provides a potent avenue by which effects of prenatal stressors on maternal and fetal outcomes can be mitigated to reduce ethnic disparities in childhood obesity. Funding Sources This research was funded by grants from the National Institute of Minority Health and Health Disparities and the National Institute of Environmental Health Sciences, and supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences.}, journal={Current Developments in Nutrition}, publisher={Elsevier BV}, author={Gonzalez-Nahm, Sarah and Marchesoni, Joddy and Maity, Arnab and Maguire, Rachel and House, John and Tucker, Rachel and Atkinson, Tamara and Murphy, Susan and Hoyo, Cathrine}, year={2022}, month={Jun}, pages={650} }
 @article{akhtari_lloyd_burkholder_tong_house_lee_buse_schurman_fargo_schmitt_et al._2022, title={Questionnaire-Based Polyexposure Assessment Outperforms Polygenic Scores for Classification of Type 2 Diabetes in a Multiancestry Cohort}, volume={11}, ISSN={0149-5992 1935-5548}, url={http://dx.doi.org/10.2337/dc22-0295}, DOI={10.2337/dc22-0295}, abstractNote={
                  OBJECTIVE
                  Environmental exposures may have greater predictive power for type 2 diabetes than polygenic scores (PGS). Studies examining environmental risk factors, however, have included only individuals with European ancestry, limiting the applicability of results. We conducted an exposome-wide association study in the multiancestry Personalized Environment and Genes Study to assess the effects of environmental factors on type 2 diabetes.
               }, journal={Diabetes Care}, publisher={American Diabetes Association}, author={Akhtari, Farida S. and Lloyd, Dillon and Burkholder, Adam and Tong, Xiaoran and House, John S. and Lee, Eunice Y. and Buse, John and Schurman, Shepherd H. and Fargo, David C. and Schmitt, Charles P. and et al.}, year={2022}, month={Nov}, pages={dc220295} }
 @article{lee_akhtari_house_simpson_schmitt_fargo_schurman_hall_motsinger-reif_2022, title={Questionnaire-based exposome-wide association studies (ExWAS) reveal expected and novel risk factors associated with cardiovascular outcomes in the Personalized Environment and Genes Study}, volume={212}, ISSN={0013-9351}, url={http://dx.doi.org/10.1016/j.envres.2022.113463}, DOI={10.1016/j.envres.2022.113463}, abstractNote={While multiple factors are associated with cardiovascular disease (CVD), many environmental exposures that may contribute to CVD have not been examined. To understand environmental effects on cardiovascular health, we performed an exposome-wide association study (ExWAS), a hypothesis-free approach, using survey data on endogenous and exogenous exposures at home and work and data from health and medical histories from the North Carolina-based Personalized Environment and Genes Study (PEGS) (n = 5015). We performed ExWAS analyses separately on six cardiovascular outcomes (cardiac arrhythmia, congestive heart failure, coronary artery disease, heart attack, stroke, and a combined atherogenic-related outcome comprising angina, angioplasty, atherosclerosis, coronary artery disease, heart attack, and stroke) using logistic regression and a false discovery rate of 5%. For each CVD outcome, we tested 502 single exposures and built multi-exposure models using the deletion-substitution-addition (DSA) algorithm. To evaluate complex nonlinear relationships, we employed the knockoff boosted tree (KOBT) algorithm. We adjusted all analyses for age, sex, race, BMI, and annual household income. ExWAS analyses revealed novel associations that include blood type A (Rh-) with heart attack (OR[95%CI] = 8.2[2.2:29.7]); paint exposures with stroke (paint related chemicals: 6.1[2.2:16.0], acrylic paint: 8.1[2.6:22.9], primer: 6.7[2.2:18.6]); biohazardous materials exposure with arrhythmia (1.8[1.5:2.3]); and higher paternal education level with reduced risk of multiple CVD outcomes (stroke, heart attack, coronary artery disease, and combined atherogenic outcome). In multi-exposure models, trouble sleeping and smoking remained important risk factors. KOBT identified significant nonlinear effects of sleep disorder, regular intake of grapefruit, and a family history of blood clotting problems for multiple CVD outcomes (combined atherogenic outcome, congestive heart failure, and coronary artery disease). In conclusion, using statistics and machine learning, these findings identify novel potential risk factors for CVD, enable hypothesis generation, provide insights into the complex relationships between risk factors and CVD, and highlight the importance of considering multiple exposures when examining CVD outcomes.}, journal={Environmental Research}, publisher={Elsevier BV}, author={Lee, Eunice Y. and Akhtari, Farida and House, John S. and Simpson, Ross J., Jr. and Schmitt, Charles P. and Fargo, David C. and Schurman, Shepherd H. and Hall, Janet E. and Motsinger-Reif, Alison A.}, year={2022}, month={Sep}, pages={113463} }
 @article{henriquez_snow_jackson_house_alewel_schladweiler_valdez_freeborn_miller_grindstaff_et al._2022, title={Social isolation exacerbates acute ozone inhalation induced pulmonary and systemic health outcomes}, volume={457}, ISSN={0041-008X}, url={http://dx.doi.org/10.1016/j.taap.2022.116295}, DOI={10.1016/j.taap.2022.116295}, abstractNote={Psychosocially-stressed individuals might have exacerbated responses to air pollution exposure. Acute ozone exposure activates the neuroendocrine stress response leading to systemic metabolic and lung inflammatory changes. We hypothesized chronic mild stress (CS) and/or social isolation (SI) would cause neuroendocrine, inflammatory, and metabolic phenotypes that would be exacerbated by an acute ozone exposure. Male 5-week-old Wistar-Kyoto rats were randomly assigned into 3 groups: no stress (NS) (pair-housed, regular-handling); SI (single-housed, minimal-handling); CS (single-housed, subjected to mild unpredicted-randomized stressors [restraint-1 h, tilted cage-1 h, shaking-1 h, intermittent noise-6 h, and predator odor-1 h], 1-stressor/day*5-days/week*8-weeks. All animals then 13-week-old were subsequently exposed to filtered-air or ozone (0.8-ppm) for 4 h and immediately necropsied. CS, but not SI animals had increased adrenal weights. However, relative to NS, both CS and SI had lower circulating luteinizing hormone, prolactin, and follicle-stimulating hormone regardless of exposure (SI > CS), and only CS demonstrated lower thyroid-stimulating hormone levels. SI caused more severe systemic inflammation than CS, as evidenced by higher circulating cytokines and cholesterol. Ozone exposure increased urine corticosterone and catecholamine metabolites with no significant stressor effect. Ozone-induced lung injury, and increases in lavage-fluid neutrophils and IL-6, were exacerbated by SI. Ozone severely lowered circulating thyroid-stimulating hormone, prolactin, and luteinizing hormone in all groups and exacerbated systemic inflammation in SI. Ozone-induced increases in serum glucose, leptin, and triglycerides were consistent across stressors; however, increases in cholesterol were exacerbated by SI. Collectively, psychosocial stressors, especially SI, affected the neuroendocrine system and induced adverse metabolic and inflammatory effects that were exacerbated by ozone exposure.}, journal={Toxicology and Applied Pharmacology}, publisher={Elsevier BV}, author={Henriquez, Andres R. and Snow, Samantha J. and Jackson, Thomas W. and House, John S. and Alewel, Devin I. and Schladweiler, Mette C. and Valdez, Matthew C. and Freeborn, Danielle L. and Miller, Colette N. and Grindstaff, Rachel and et al.}, year={2022}, month={Dec}, pages={116295} }
 @article{henriquez_snow_jackson_house_motsinger-reif_ward-caviness_schladweiler_alewel_miller_farraj_et al._2022, title={Stress Drivers of Glucose Dynamics during Ozone Exposure Measured Using Radiotelemetry in Rats}, volume={130}, ISSN={0091-6765 1552-9924}, url={http://dx.doi.org/10.1289/EHP11088}, DOI={10.1289/EHP11088}, abstractNote={Background: Inhaled irritant air pollutants may trigger stress-related metabolic dysfunction associated with altered circulating adrenal-derived hormones. Objectives: We used implantable telemetry in rats to assess real-time changes in circulating glucose during and after exposure to ozone and mechanistically linked responses to neuroendocrine stress hormones. Methods: First, using a cross-over design, we monitored glucose during ozone exposures (0.0, 0.2, 0.4, and 0.8 ppm) and nonexposure periods in male Wistar Kyoto rats implanted with glucose telemeters. A second cohort of unimplanted rats was exposed to ozone (0.0, 0.4 or 0.8 ppm) for 30 min, 1 h, 2 h, or 4 h with hormones measured immediately post exposure. We assessed glucose metabolism in sham and adrenalectomized rats, with or without supplementation of adrenergic/glucocorticoid receptor agonists, and in a separate cohort, antagonists. Results: Ozone (0.8 ppm) was associated with significantly higher blood glucose and lower core body temperature beginning 90 min into exposure, with reversal of effects 4–6 h post exposure. Glucose monitoring during four daily 4-h ozone exposures revealed duration of glucose increases, adaptation, and diurnal variations. Ozone-induced glucose changes were preceded by higher levels of adrenocorticotropic hormone, corticosterone, and epinephrine but lower levels of thyroid-stimulating hormone, prolactin, and luteinizing hormones. Higher glucose and glucose intolerance were inhibited in rats that were adrenalectomized or treated with adrenergic plus glucocorticoid receptor antagonists but exacerbated by agonists. Discussion: We demonstrated the temporality of neuroendocrine-stress–mediated biological sequalae responsible for ozone-induced glucose metabolic dysfunction and mechanism in a rodent model. Stress hormones assessment with real-time glucose monitoring may be useful in identifying interactions among irritant pollutants and stress-related illnesses. https://doi.org/10.1289/EHP11088}, number={12}, journal={Environmental Health Perspectives}, publisher={Environmental Health Perspectives}, author={Henriquez, Andres R. and Snow, Samantha J. and Jackson, Thomas W. and House, John S. and Motsinger-Reif, Alison A. and Ward-Caviness, Cavin K. and Schladweiler, Mette C. and Alewel, Devin I. and Miller, Colette N. and Farraj, Aimen K. and et al.}, year={2022}, month={Dec} }
 @article{mcdonough_warren_jack_motsinger‐reif_armstrong_bis_house_singh_el rouby_gong_et al._2021, title={Adverse Cardiovascular Outcomes and Antihypertensive Treatment: A Genome‐Wide Interaction Meta‐Analysis in the International Consortium for Antihypertensive Pharmacogenomics Studies}, volume={110}, ISSN={0009-9236 1532-6535}, url={http://dx.doi.org/10.1002/cpt.2355}, DOI={10.1002/cpt.2355}, abstractNote={We sought to identify genome‐wide variants influencing antihypertensive drug response and adverse cardiovascular outcomes, utilizing data from four randomized controlled trials in the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS). Genome‐wide antihypertensive drug‐single nucleotide polymorphism (SNP) interaction tests for four drug classes (β‐blockers, n = 9,195; calcium channel blockers (CCBs), n = 10,511; thiazide/thiazide‐like diuretics, n = 3,516; ACE‐inhibitors/ARBs, n = 2,559) and cardiovascular outcomes (incident myocardial infarction, stroke, or death) were analyzed among patients with hypertension of European ancestry. Top SNPs from the meta‐analyses were tested for replication of cardiovascular outcomes in an independent Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) study (n = 21,267), blood pressure (BP) response in independent ICAPS studies (n = 1,552), and ethnic validation in African Americans from the Genetics of Hypertension Associated Treatment study (GenHAT; n = 5,115). One signal reached genome‐wide significance in the β‐blocker‐SNP interaction analysis (rs139945292, Interaction P = 1.56 × 10−8). rs139945292 was validated through BP response to β‐blockers, with the T‐allele associated with less BP reduction (systolic BP response P = 6 × 10−4, Beta = 3.09, diastolic BP response P = 5 × 10−3, Beta = 1.53). The T‐allele was also associated with increased adverse cardiovascular risk within the β‐blocker treated patients’ subgroup (P = 2.35 × 10−4, odds ratio = 1.57, 95% confidence interval = 1.23–1.99). The locus showed nominal replication in CHARGE, and consistent directional trends in β‐blocker treated African Americans. rs139945292 is an expression quantitative trait locus for the 50 kb upstream gene NTM (neurotrimin). No SNPs attained genome‐wide significance for any other drugs classes. Top SNPs were located near CALB1 (CCB), FLJ367777 (ACE‐inhibitor), and CES5AP1 (thiazide). The NTM region is associated with increased risk for adverse cardiovascular outcomes and less BP reduction in β‐blocker treated patients. Further investigation into this region is warranted.}, number={3}, journal={Clinical Pharmacology & Therapeutics}, publisher={Wiley}, author={McDonough, Caitrin W. and Warren, Helen R. and Jack, John R. and Motsinger‐Reif, Alison A. and Armstrong, Nicole D. and Bis, Joshua C. and House, John S. and Singh, Sonal and El Rouby, Nihal M. and Gong, Yan and et al.}, year={2021}, month={Aug}, pages={723–732} }
 @article{maguire_house_lloyd_skinner_allen_raffi_skaar_park_mccullough_kollins_et al._2021, title={Associations between maternal obesity, gestational cytokine levels and child obesity in the NEST cohort}, volume={16}, ISSN={["2047-6302"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85098446153&partnerID=MN8TOARS}, DOI={10.1111/ijpo.12763}, abstractNote={Summary}, number={7}, journal={PEDIATRIC OBESITY}, author={Maguire, Rachel L. and House, John S. and Lloyd, Dillon T. and Skinner, Harlyn G. and Allen, Terrence K. and Raffi, Asifa Mohamed and Skaar, David A. and Park, Sarah S. and McCullough, Lauren E. and Kollins, Scott H. and et al.}, year={2021}, month={Jul} }
 @article{henriquez_snow_jackson_house_motsinger-reif_ward-caviness_schladweiler_alewel_miller_farraj_et al._2021, title={Glucose dynamics during ozone exposure measured using radiotelemetry: Stress drivers}, volume={12}, url={https://doi.org/10.1101/2021.12.09.471963}, DOI={10.1101/2021.12.09.471963}, abstractNote={Abstract}, publisher={Cold Spring Harbor Laboratory}, author={Henriquez, Andres R. and Snow, Samantha J. and Jackson, Thomas W. and House, John S. and Motsinger-Reif, Alison A. and Ward-Caviness, Cavin K. and Schladweiler, Mette C. and Alewel, Devin I. and Miller, Colette N. and Farraj, Aimen K. and et al.}, year={2021}, month={Dec} }
 @article{house_grimm_klaren_dalzell_kuchi_zhang_lenz_boogaard_ketelslegers_gant_et al._2021, title={Grouping of UVCB Substances with New Approach Methodologies (NAMs) Data}, volume={38}, ISSN={["1868-8551"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85100279673&partnerID=MN8TOARS}, DOI={10.14573/altex.2006262}, abstractNote={One of the most challenging areas in regulatory science is assessment of the substances known as UVCB (unknown or variable composition, complex reaction products and biological materials). Because the inherent complexity and variability of UVCBs present considerable challenges for establishing sufficient substance similarity based on chemical characteristics or other data, we hypothesized that new approach methodologies (NAMs), including in vitro test-derived biological activity signatures to characterize substance similarity, could be used to support grouping of UVCBs. We tested 141 petroleum substances as representative UVCBs in a compendium of 15 human cell types representing a variety of tissues. Petroleum substances were assayed in dilution series to derive point of departure estimates for each cell type and phenotype. Extensive quality control measures were taken to ensure that only high-confidence in vitro data were used to determine whether current groupings of these petroleum substances, based largely on the manufacturing process and physico-chemical properties, are justifiable. We found that bioactivity data-based groupings of petroleum substances were generally consistent with the manufacturing class-based categories. We also showed that these data, especially bioactivity from human induced pluripotent stem cell (iPSC)-derived and primary cells, can be used to rank substances in a manner highly concordant with their expected in vivo hazard potential based on their chemical compositional profile. Overall, this study demonstrates that NAMs can be used to inform groupings of UVCBs, to assist in identification of representative substances in each group for testing when needed, and to fill data gaps by read-across.}, number={1}, journal={ALTEX-ALTERNATIVES TO ANIMAL EXPERIMENTATION}, author={House, John S. and Grimm, Fabian A. and Klaren, William D. and Dalzell, Abigail and Kuchi, Srikeerthana and Zhang, Shu-Dong and Lenz, Klaus and Boogaard, Peter J. and Ketelslegers, Hans B. and Gant, Timothy W. and et al.}, year={2021}, pages={123–137} }
 @article{akhtari_green_small_havener_house_roell_reif_mcleod_wiltshire_motsinger-reif_2021, title={High-throughput screening and genome-wide analyses of 44 anticancer drugs in the 1000 Genomes cell lines reveals an association of the NQO1 gene with the response of multiple anticancer drugs}, volume={17}, ISSN={["1553-7404"]}, url={https://doi.org/10.1371/journal.pgen.1009732}, DOI={10.1371/journal.pgen.1009732}, abstractNote={Cancer patients exhibit a broad range of inter-individual variability in response and toxicity to widely used anticancer drugs, and genetic variation is a major contributor to this variability. To identify new genes that influence the response of 44 FDA-approved anticancer drug treatments widely used to treat various types of cancer, we conducted high-throughput screening and genome-wide association mapping using 680 lymphoblastoid cell lines from the 1000 Genomes Project. The drug treatments considered in this study represent nine drug classes widely used in the treatment of cancer in addition to the paclitaxel + epirubicin combination therapy commonly used for breast cancer patients. Our genome-wide association study (GWAS) found several significant and suggestive associations. We prioritized consistent associations for functional follow-up using gene-expression analyses. The NAD(P)H quinone dehydrogenase 1 (NQO1) gene was found to be associated with the dose-response of arsenic trioxide, erlotinib, trametinib, and a combination treatment of paclitaxel + epirubicin. NQO1 has previously been shown as a biomarker of epirubicin response, but our results reveal novel associations with these additional treatments. Baseline gene expression of NQO1 was positively correlated with response for 43 of the 44 treatments surveyed. By interrogating the functional mechanisms of this association, the results demonstrate differences in both baseline and drug-exposed induction.}, number={8}, journal={PLOS GENETICS}, publisher={Public Library of Science (PLoS)}, author={Akhtari, Farida S. and Green, Adrian J. and Small, George W. and Havener, Tammy M. and House, John S. and Roell, Kyle R. and Reif, David M. and McLeod, Howard L. and Wiltshire, Timothy and Motsinger-Reif, Alison A.}, editor={Vazquez, FranciscaEditor}, year={2021}, month={Aug} }
 @article{nichols_house_li_ward_wyss_williams_deterding_bradbury_miller_zeldin_et al._2021, title={Lrp1 regulation of pulmonary function follow-up of human GWAS in mice}, volume={64}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85101877952&partnerID=MN8TOARS}, DOI={10.1165/rcmb.2019-0444OC}, abstractNote={Human genome-wide association studies (GWAS) have identified over 270 loci associated with pulmonary function; however, follow-up studies to determine causal genes at these loci are few. Single nucleotide polymorphisms (SNPs) in low-density lipoprotein receptor-related protein 1 (LRP1) are associated with human pulmonary function in GWAS. Using murine models, we investigated the effect of genetic disruption of the Lrp1 gene in smooth muscle cells on pulmonary function in naïve animals and after exposure to bacterial lipopolysaccharide (LPS) or house dust mite extract (HDME). Disruption of Lrp1 in smooth muscle cells leads to an increase in tissue resistance, elastance, and tissue elastance at baseline. Further, disruption of Lrp1 in smooth muscle increases airway responsiveness as measured by increased total lung resistance and airway resistance after methacholine. Immune cell counts in bronchoalveolar lavage fluid were increased in animals with Lrp1 disruption. The difference in airway responsiveness by genotype observed in naïve animals was not observed following LPS or HDME exposure. To further explore the mechanisms contributing to changes in pulmonary function, we identified several ligands dysregulated with Lrp1 disruption in smooth muscle cells. These data suggest that dysregulation of LRP1 in smooth muscle cells affects baseline pulmonary function and airway responsiveness and helps establish LRP1 as the causal gene at this GWAS locus.}, number={3}, journal={American Journal of Respiratory Cell and Molecular Biology}, author={Nichols, C.E. and House, J.S. and Li, H. and Ward, J.M. and Wyss, A. and Williams, J.G. and Deterding, L.J. and Bradbury, J.A. and Miller, L. and Zeldin, D.C. and et al.}, year={2021}, pages={368–378} }
 @article{alick_maguire_murphy_fuemmeler_hoyo_house_2021, title={Periconceptional Maternal Diet Characterized by High Glycemic Loading Is Associated with Offspring Behavior in NEST}, volume={13}, url={https://doi.org/10.3390/nu13093180}, DOI={10.3390/nu13093180}, abstractNote={Maternal periconceptional diets have known associations with proper offspring neurodevelopment. Mechanisms for such associations include improper energy/nutrient balances between mother and fetus, as well as altered offspring epigenetics during development due to maternal nutrient and inflammatory status. Using a comprehensive food frequency questionnaire and assessing offspring temperament with the Infant-Toddler Social and Emotional Assessment (n = 325, mean age = 13.9 months), we sought to test whether a maternal periconceptional diet characterized by high glycemic loading (MGL) would affect offspring temperament using adjusted ordinal regression. After limiting false discovery to 10%, offspring born to mothers in tertile 3 of glycemic loading (referent = tertile 1) were more likely to be in the next tertile of anxiety [OR (95% CI) = 4.51 (1.88–11.07)] and inhibition-related behaviors [OR (95% CI) = 3.42 (1.49–7.96)]. Male offspring were more likely to exhibit impulsive [OR (95% CI) = 5.55 (1.76–18.33)], anxiety [OR (95% CI) = 4.41 (1.33–15.30)], sleep dysregulation [OR (95% CI) = 4.14 (1.34–13.16)], empathy [6.68 (1.95–24.40)], and maladaptive behaviors [OR (95% CI) = 9.86 (2.81–37.18)], while females were more likely to exhibit increased anxiety-related behaviors [OR (95% CI) = 15.02 (3.14–84.27)]. These associations persisted when concurrently modeled with the maternal–Mediterranean dietary pattern. In a subset (n = 142), we also found MGL associated with increased mean methylation of the imprint control region of SGCE/PEG10. In conclusion, these findings highlight the importance of maternal dietary patterns on offspring neurodevelopment, offering avenues for prevention options for mothers.}, number={9}, journal={Nutrients}, publisher={MDPI AG}, author={Alick, Candice L. and Maguire, Rachel L. and Murphy, Susan K. and Fuemmeler, Bernard F. and Hoyo, Cathrine and House, John S.}, year={2021}, month={Sep}, pages={3180} }
 @article{snow_henriquez_fisher_vallanat_house_schladweiler_wood_kodavanti_2021, title={Peripheral metabolic effects of ozone exposure in healthy and diabetic rats on normal or high-cholesterol diet}, volume={415}, ISSN={0041-008X}, url={http://dx.doi.org/10.1016/j.taap.2021.115427}, DOI={10.1016/j.taap.2021.115427}, abstractNote={Epidemiological studies show that individuals with underlying diabetes and diet-associated ailments are more susceptible than healthy individuals to adverse health effects of air pollution. Exposure to air pollutants can induce metabolic stress and increase cardiometabolic disease risk. Using male Wistar and Wistar-derived Goto-Kakizaki (GK) rats, which exhibit a non-obese type-2 diabetes phenotype, we investigated whether two key metabolic stressors, type-2 diabetes and a high-cholesterol atherogenic diet, exacerbate ozone-induced metabolic effects. Rats were fed a normal control diet (ND) or high-cholesterol diet (HCD) for 12 weeks and then exposed to filtered air or 1.0-ppm ozone (6 h/day) for 1 or 2 days. Metabolic responses were analyzed at the end of each day and after an 18-h recovery period following the 2-day exposure. In GK rats, baseline hyperglycemia and glucose intolerance were exacerbated by HCD vs. ND and by ozone vs. air. HCD also resulted in higher insulin in ozone-exposed GK rats and circulating lipase, aspartate transaminase, and alanine transaminase in all groups (Wistar>GK). Histopathological effects induced by HCD in the liver, which included macrovesicular vacuolation and hepatocellular necrosis, were more severe in Wistar vs. GK rats. Liver gene expression in Wistar and GK rats fed ND showed numerous strain differences, including evidence of increased lipid metabolizing activity and ozone-induced alterations in glucose and lipid transporters, specifically in GK rats. Collectively, these findings indicate that peripheral metabolic alterations induced by diabetes and high-cholesterol diet can enhance susceptibility to the metabolic effects of inhaled pollutants.}, journal={Toxicology and Applied Pharmacology}, publisher={Elsevier BV}, author={Snow, Samantha J. and Henriquez, Andres R. and Fisher, Anna and Vallanat, Beena and House, John S. and Schladweiler, Mette C. and Wood, Charles E. and Kodavanti, Urmila P.}, year={2021}, month={Mar}, pages={115427} }
 @misc{marvel_house_wheeler_song_zhou_wright_chiu_rusyn_motsinger-reif_reif_2021, title={The COVID-19 Pandemic Vulnerability Index (PVI) Dashboard: Monitoring County-Level Vulnerability Using Visualization, Statistical Modeling, and Machine Learning}, volume={129}, ISSN={["1552-9924"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85099420902&partnerID=MN8TOARS}, DOI={10.1289/EHP8690}, abstractNote={Vol. 129, No. 1 Research LetterOpen AccessThe COVID-19 Pandemic Vulnerability Index (PVI) Dashboard: Monitoring County-Level Vulnerability Using Visualization, Statistical Modeling, and Machine Learning Skylar W. Marvel, John S. House, Matthew Wheeler, Kuncheng Song, Yi-Hui Zhou, Fred A. Wright, Weihsueh A. Chiu, Ivan Rusyn, Alison Motsinger-Reif, and David M. Reif Skylar W. Marvel Bioinformatics Research Center, Department of Biological Sciences, North Carolina State University (NCSU), Raleigh, North Carolina, USA , John S. House Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA , Matthew Wheeler Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA , Kuncheng Song Bioinformatics Research Center, Department of Biological Sciences, North Carolina State University (NCSU), Raleigh, North Carolina, USA , Yi-Hui Zhou Bioinformatics Research Center, Department of Biological Sciences, North Carolina State University (NCSU), Raleigh, North Carolina, USA , Fred A. Wright Bioinformatics Research Center, Department of Biological Sciences, North Carolina State University (NCSU), Raleigh, North Carolina, USA Department of Statistics, NCSU, Raleigh, North Carolina, USA , Weihsueh A. Chiu Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA , Ivan Rusyn Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA , Alison Motsinger-Reif Address correspondence to Alison Motsinger-Reif, 111 T.W. Alexander Dr., Rall Building, Research Triangle Park, NC 27709 USA. Email: E-mail Address: [email protected], or David M. Reif, Box 7566, 1 Lampe Dr., Raleigh NC 27695 USA. Email: E-mail Address: [email protected] Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA , and David M. Reif Address correspondence to Alison Motsinger-Reif, 111 T.W. Alexander Dr., Rall Building, Research Triangle Park, NC 27709 USA. Email: E-mail Address: [email protected], or David M. Reif, Box 7566, 1 Lampe Dr., Raleigh NC 27695 USA. Email: E-mail Address: [email protected] Bioinformatics Research Center, Department of Biological Sciences, North Carolina State University (NCSU), Raleigh, North Carolina, USA Published:5 January 2021CID: 017701https://doi.org/10.1289/EHP8690AboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InReddit IntroductionExpert groups have coalesced around a roadmap to address the current COVID-19 pandemic centered on social distancing, monitoring case counts and health care capacity, and, eventually, moving to pharmaceutical interventions. However, responsibility for navigating the pandemic response falls largely on state and local officials. To make equitable decisions on allocating resources, caring for vulnerable subpopulations, and implementing local- and state-level interventions, access to current pandemic data and key vulnerabilities at the community level are essential (National Academies of Sciences, Engineering, and Medicine 2020). Although numerous predictive models and interactive monitoring applications have been developed using pandemic-related data sets (Wynants et al. 2020), their capacity to aid in dynamic, community-level decision-making is limited. We developed the interactive COVID-19 Pandemic Vulnerability Index (PVI) Dashboard ( https://covid19pvi.niehs.nih.gov/) to address this need by presenting a visual synthesis of dynamic information at the county level to monitor disease trajectories, communicate local vulnerabilities, forecast key outcomes, and guide informed responses (Figure 1).Figure 1. COVID-19 PVI Dashboard. Dashboard screenshot displaying PVI profiles atop a choropleth map layer indicating overall COVID-19 PVI rank. The PVI Scorecard and associated data for Clarendon County, South Carolina, has been selected. The scorecard summarizes the overall PVI score and rank compared with all 3,142 U.S. counties on each indicator slice. The scrollable score distributions at left compare the selected county PVI to the distributions of overall and slice-wise scores across the United States. The panels below the map are populated with county-specific information on observed trends in cases and deaths, cumulative numbers for the county, historical timelines (for cumulative cases, cumulative deaths, PVI, and PVI rank), daily case and death counts for the most recent 14-d period, and a 14-d forecast of predicted cases and deaths. The information displayed for both observed COVID-19 data and PVI layers is scrollable back through March 2020. Documentation of additional features and usage, including advanced options (accessible via the collapsed menu at the upper left), is provided in a Quick Start Guide (linked at the upper right corner). Note: Pop, population; PVI, Pandemic Vulnerability Index.MethodsThe current PVI model integrates multiple data streams into an overall score derived from 12 key indicators—including well-established, general vulnerability factors for public health, plus emerging factors relevant to the pandemic—distributed across four domains: current infection rates, baseline population concentration, current interventions, and health and environmental vulnerabilities. The PVI profiles translate numerical results into visual representations, with each vulnerability factor represented as a component slice of a radar chart (Figure 2). The PVI profile for each county is calculated using the Toxicological Prioritization Index (ToxPi) framework for data integration within a geospatial context (Marvel et al. 2018; Bhandari et al. 2020). Data sources in the current model (version 11.2.1) include the Social Vulnerability Index (SVI) of the Centers for Disease Control and Prevention (CDC) for emergency response and hazard mitigation planning (Horney et al. 2017), testing rates from the COVID Tracking Project (Atlantic Monthly Group 2020), social distancing metrics from mobile device data ( https://www.unacast.com/covid19/social-distancing-scoreboard), and dynamic measures of disease spread and case numbers ( https://usafacts.org/issues/coronavirus/). Methodological details concerning the integration of data streams—plus the complete, daily time series of all source data since February 2020 and resultant PVI scores—are maintained on the public Github project page (COVID19PVI 2020). Over this period, the PVI has been strongly associated with key vulnerability-related outcome metrics (by rank-correlation), with updates of its performance assessment posted with model updates alongside data at the Github project page (COVID19PVI 2020).Figure 2. Translation of data into COVID-19 PVI profiles. Information from all 3,142 U.S. counties is translated into PVI slices. The illustration shows how air pollution data (average density of fine particulate matterPM2.5 per county) are compared for two example counties. The county with the higher relative measurement (County Y) has a longer air pollution slice than the county with a lower measurement (County X). This procedure is repeated for all slices, resulting in an integrated, overall PVI profile. Note: pop, population; PVI, Pandemic Vulnerability Index.In addition to the PVI itself—which is a summary, human-centric visualization of relative vulnerability drivers—the dashboard is supported by rigorous statistical modeling of the underlying data to enable quantitative analysis and provide short-term, local predictions of cases and deaths [complete methodological details are maintained at the Github project page (COVID19PVI 2020)]. Generalized linear models of cumulative outcome data indicated that, after population size, the most significant predictors were the proportion of Black residents, mean fine particulate matter [particulate matter less than or equal to 2.5 micrometers≤2.5μm in diameter (fine particulate matterPM2.5)], percentage of population with insurance coverage (which was positively associated), and proportion of Hispanic residents. The local predictions of cases and deaths (see the "Predictions" panel in Figure 1) are updated daily using a Bayesian spatiotemporal random-effects model to build forecasts up to 2 weeks out.DiscussionThe PVI Dashboard supports decision-making and dynamic monitoring in several ways. The display can be tailored to add or remove layers of information, filtered by region (e.g., all counties within a state) or clustered by profile shape similarity. The timelines for both PVI models and observed COVID-19 outcomes facilitate tracking the impact of interventions and directing local resource allocations. The "Predictions" panel (Figure 1) connects these historical numbers to local forecasts of cases and deaths. By communicating an integrated concept of vulnerability that considers both dynamic (infection rate and interventions) and static (community population and health care characteristics) drivers, the interactive dashboard can promote buy-in from diverse audiences, which is necessary for effective public health interventions. This messaging can assist in addressing known racial disparities in COVID-19 case and death rates (Tan et al. 2020) or populations, and the PVI Dashboard is part of the "Unique Populations" tab of the CDC's COVID-19 Data Tracker ( https://covid.cdc.gov/covid-data-tracker). By filtering the display to highlight vulnerability drivers within an overall score context, the dashboard can inform targeted interventions for specific localities.Unfortunately, the pandemic endures across the United States, with broad disparities based on the local environment (Tan et al. 2020). We present the PVI Dashboard as a dynamic container for contextualizing these disparities. It is a modular tool that will evolve to incorporate new data sources and analytics as they emerge (e.g., concurrent flu infections, school and business reopening statistics, heterogeneous public health practices). This flexibility positions it well as a resource for integrated prioritization of eventual vaccine distribution and monitoring its local impact. The PVI Dashboard can empower local and state officials to take informed action to combat the pandemic by communicating interactive, visual profiles of vulnerability atop an underlying statistical framework that enables the comparison of counties and the evaluation of the PVI's component data.AcknowledgmentsWe thank the information technology and web services staff at the National Institute of Environmental Health Sciences (NIEHS)/National Institutes of Health (NIH) for their help and support, as well as J.K. Cetina and D.J. Reif for their useful technical input and advice. This work was supported by NIEHS/NIH grants (P42 ES027704, P30 ES029067, P42 ES031009, and P30 ES025128) and NIEHS/NIH intramural funds (Z ES103352-01).ReferencesAtlantic Monthly Group.2020. The COVID Tracking Project. https://covidtracking.com/ [accessed 15 November 2020]. Google ScholarBhandari S, Lewis PGT, Craft E, Marvel SW, Reif DM, Chiu WA. 2020. HGBEnviroScreen: enabling community action through data integration in the Houston–Galveston–Brazoria region. Int J Environ Res Public Health 17(4):1130, PMID: 32053902, 10.3390/ijerph17041130. Crossref, Medline, Google ScholarCOVID19PVI.2020. COVID19PVI/data. https://github.com/COVID19PVI/data [accessed 15 November 2020]. Google ScholarHorney J, Nguyen M, Salvesen D, Dwyer C, Cooper J, Berke P. 2017. Assessing the quality of rural hazard mitigation plans in the southeastern United States. J Plan Educ Res 37(1):56–65, 10.1177/0739456X16628605. Crossref, Google ScholarMarvel SW, To K, Grimm FA, Wright FA, Rusyn I, Reif DM. 2018. ToxPi Graphical User Interface 2.0: dynamic exploration, visualization, and sharing of integrated data models. BMC Bioinformatics 19(1):80, PMID: 29506467, 10.1186/s12859-018-2089-2. Crossref, Medline, Google ScholarNational Academies of Sciences, Engineering, and Medicine.2020. Framework for Equitable Allocation of COVID-19 Vaccine. Gayle H, Foege W, Brown L, Kahn B, eds. Washington, DC: National Academies Press. Google ScholarTan TQ, Kullar R, Swartz TH, Mathew TA, Piggott DA, Berthaud V. 2020. Location matters: geographic disparities and impact of coronavirus disease 2019. J Infect Dis 222(12):1951–1954, PMID: 32942299, 10.1093/infdis/jiaa583. Crossref, Medline, Google ScholarWynants L, Van Calster B, Collins GS, Riley RD, Heinze G, Schuit E, et al.2020. Prediction models for diagnosis and prognosis of covid-19: systematic review and critical appraisal. BMJ 369:m1328, PMID: 32265220, 10.1136/bmj.m1328. Crossref, Medline, Google ScholarThe authors declare they have no actual or potential competing financial interests.FiguresReferencesRelatedDetails Vol. 129, No. 1 January 2021Metrics About Article Metrics Publication History Manuscript received20 November 2020Manuscript revised14 December 2020Manuscript accepted21 December 2020Originally published5 January 2021 Financial disclosuresPDF download License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. Note to readers with disabilities EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact [email protected]. Our staff will work with you to assess and meet your accessibility needs within 3 working days.}, number={1}, journal={ENVIRONMENTAL HEALTH PERSPECTIVES}, author={Marvel, Skylar W. and House, John S. and Wheeler, Matthew and Song, Kuncheng and Zhou, Yi-Hui and Wright, Fred A. and Chiu, Weihsueh A. and Rusyn, Ivan and Motsinger-Reif, Alison and Reif, David M.}, year={2021}, month={Jan} }
 @article{colonna_henriquez_house_motsinger-reif_alewel_fisher_ren_snow_schladweiler_miller_et al._2021, title={The Role of Hepatic Vagal Tone in Ozone-Induced Metabolic Dysfunction in the Liver}, volume={181}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85107319660&partnerID=MN8TOARS}, DOI={10.1093/toxsci/kfab025}, abstractNote={Abstract}, number={2}, journal={Toxicological Sciences}, publisher={Oxford University Press (OUP)}, author={Colonna, Catherine H and Henriquez, Andres R and House, John S and Motsinger-Reif, Alison A and Alewel, Devin I and Fisher, Anna and Ren, Hongzu and Snow, Samantha J and Schladweiler, Mette C and Miller, Desinia B and et al.}, year={2021}, pages={229–245} }
 @article{gonzalez-nahm_nihlani_s. house_l. maguire_g. skinner_hoyo_2020, title={Associations between Maternal Cadmium Exposure with Risk of Preterm Birth and Low after Birth Weight Effect of Mediterranean Diet Adherence on Affected Prenatal Outcomes}, volume={8}, ISSN={["2305-6304"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85094109102&partnerID=MN8TOARS}, DOI={10.3390/toxics8040090}, abstractNote={Prenatal cadmium exposure at non-occupational levels has been associated with poor birth outcomes. The intake of essential metals, such as iron and selenium, may mitigate cadmium exposure effects. However, at high levels, these metals can be toxic. The role of dietary patterns rich in these metals is less studied. We used a linear and logistic regression in a cohort of 185 mother–infant pairs to assess if a Mediterranean diet pattern during pregnancy modified the associations between prenatal cadmium exposure and (1) birth weight and (2) preterm birth. We found that increased cadmium exposure during pregnancy was associated with lower birth weight (β = −210.4; 95% CI: −332.0, −88.8; p = 0.008) and preterm birth (OR = 0.11; 95% CI: 0.01, 0.72; p = 0.04); however, these associations were comparable in offspring born to women reporting high adherence to a Mediterranean diet (β = −274.95; 95% CI: −701.17, 151.26; p = 0.20) and those with low adherence (β = −64.76; 95% CI: −359.90, 230.37; p = 0.66). While the small sample size limits inference, our findings suggest that adherence to a Mediterranean dietary pattern may not mitigate cadmium exposure effects. Given the multiple organs targeted by cadmium and its slow excretion rate, larger studies are required to clarify these findings.}, number={4}, journal={TOXICS}, publisher={MDPI AG}, author={Gonzalez-Nahm, Sarah and Nihlani, Kiran and S. House, John and L. Maguire, Rachel and G. Skinner, Harlyn and Hoyo, Cathrine}, year={2020}, month={Dec} }
 @article{house_motsinger-reif_2020, title={Fibrate pharmacogenomics: Expanding past the genome}, volume={21}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85082767117&partnerID=MN8TOARS}, DOI={10.2217/pgs-2019-0140}, abstractNote={ Fibrates are a medication class prescribed for decades as ‘broad-spectrum’ lipid-modifying agents used to lower blood triglyceride levels and raise high-density lipoprotein cholesterol levels. Such lipid changes are associated with a decrease in cardiovascular disease, and fibrates are commonly used to reduce risk of dangerous cardiovascular outcomes. As with most drugs, it is well established that response to fibrate treatment is variable, and this variation is heritable. This has motivated the investigation of pharmacogenomic determinants of response, and multiple studies have discovered a number of genes associated with fibrate response. Similar to other complex traits, the interrogation of single nucleotide polymorphisms using candidate gene or genome-wide approaches has not revealed a substantial portion of response variation. However, recent innovations in technological platforms and advances in statistical methodologies are revolutionizing the use and integration of other ‘omes’ in pharmacogenomics studies. Here, we detail successes, challenges, and recent advances in fibrate pharmacogenomics. }, number={4}, journal={Pharmacogenomics}, author={House, J.S. and Motsinger-Reif, A.A.}, year={2020}, pages={293–306} }
 @article{house_bouzos_fahy_francisco_lloyd_wright_motsinger-reif_asuri_wheeler_2020, title={Low-Dose Silver Nanoparticle Surface Chemistry and Temporal Effects on Gene Expression in Human Liver Cells}, volume={16}, ISSN={["1613-6829"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85082473420&partnerID=MN8TOARS}, DOI={10.1002/smll.202000299}, abstractNote={Abstract}, number={21}, journal={SMALL}, author={House, John S. and Bouzos, Evangelia and Fahy, Kira M. and Francisco, Victorino Miguel and Lloyd, Dillon T. and Wright, Fred A. and Motsinger-Reif, Alison A. and Asuri, Prashanth and Wheeler, Korin E.}, year={2020}, month={May} }
 @article{marvel_house_wheeler_song_zhou_wright_chiu_rusyn_motsinger-reif_reif_2020, title={The COVID-19 Pandemic Vulnerability Index (PVI) Dashboard: Monitoring county-level vulnerability using visualization, statistical modeling, and machine learning}, volume={8}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85098201055&partnerID=MN8TOARS}, DOI={10.1101/2020.08.10.20169649}, abstractNote={Abstract}, journal={medRxiv}, publisher={Cold Spring Harbor Laboratory}, author={Marvel, Skylar W. and House, John S. and Wheeler, Matthew and Song, Kuncheng and Zhou, Yihui and Wright, Fred A. and Chiu, Weihsueh A. and Rusyn, Ivan and Motsinger-Reif, Alison and Reif, David M.}, year={2020} }
 @article{sakolish_house_chramiec_liu_chen_halligan_vunjak-novakovic_rusyn_2020, title={Tissue-Engineered Bone Tumor as a Reproducible Human in Vitro Model for Studies of Anticancer Drugs}, volume={173}, ISSN={["1096-0929"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85077489572&partnerID=MN8TOARS}, DOI={10.1093/toxsci/kfz220}, abstractNote={Abstract}, number={1}, journal={TOXICOLOGICAL SCIENCES}, author={Sakolish, Courtney and House, John S. and Chramiec, Alan and Liu, Yizhong and Chen, Zunwei and Halligan, Susan P. and Vunjak-Novakovic, Gordana and Rusyn, Ivan}, year={2020}, month={Jan}, pages={65–76} }
 @article{tam_hall_messenger_jima_house_linder_smart_2019, title={C/EBP beta suppresses keratinocyte autonomous type 1 IFN response and p53 to increase cell survival and susceptibility to UVB-induced skin cancer}, volume={40}, ISSN={["1460-2180"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85083447649&partnerID=MN8TOARS}, DOI={10.1093/carcin/bgz012}, abstractNote={Abstract}, number={9}, journal={CARCINOGENESIS}, author={Tam, Hann W. and Hall, Jonathan R. and Messenger, Zachary J. and Jima, Dereje D. and House, John S. and Linder, Keith and Smart, Robert C.}, year={2019}, month={Sep}, pages={1099–1109} }
 @article{house_hall_park_planchart_money_maguire_huang_mattingly_skaar_tzeng_et al._2019, title={Cadmium exposure and MEG3 methylation differences between Whites and African Americans in the NEST Cohort}, volume={5}, ISSN={2058-5888}, url={http://dx.doi.org/10.1093/eep/dvz014}, DOI={10.1093/eep/dvz014}, abstractNote={Abstract}, number={3}, journal={Environmental Epigenetics}, publisher={Oxford University Press (OUP)}, author={House, John S and Hall, Jonathan and Park, Sarah S and Planchart, Antonio and Money, Eric and Maguire, Rachel L and Huang, Zhiqing and Mattingly, Carolyn J and Skaar, David and Tzeng, Jung Ying and et al.}, editor={Skinner, MikeEditor}, year={2019}, month={Jul} }
 @article{onel_beykal_ferguson_chiu_mcdonald_zhou_house_wright_sheen_rusyn_et al._2019, title={Grouping of complex substances using analytical chemistry data: A framework for quantitative evaluation and visualization}, volume={14}, ISSN={["1932-6203"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85073118823&partnerID=MN8TOARS}, DOI={10.1371/journal.pone.0223517}, abstractNote={A detailed characterization of the chemical composition of complex substances, such as products of petroleum refining and environmental mixtures, is greatly needed in exposure assessment and manufacturing. The inherent complexity and variability in the composition of complex substances obfuscate the choices for their detailed analytical characterization. Yet, in lieu of exact chemical composition of complex substances, evaluation of the degree of similarity is a sensible path toward decision-making in environmental health regulations. Grouping of similar complex substances is a challenge that can be addressed via advanced analytical methods and streamlined data analysis and visualization techniques. Here, we propose a framework with unsupervised and supervised analyses to optimally group complex substances based on their analytical features. We test two data sets of complex oil-derived substances. The first data set is from gas chromatography-mass spectrometry (GC-MS) analysis of 20 Standard Reference Materials representing crude oils and oil refining products. The second data set consists of 15 samples of various gas oils analyzed using three analytical techniques: GC-MS, GC×GC-flame ionization detection (FID), and ion mobility spectrometry-mass spectrometry (IM-MS). We use hierarchical clustering using Pearson correlation as a similarity metric for the unsupervised analysis and build classification models using the Random Forest algorithm for the supervised analysis. We present a quantitative comparative assessment of clustering results via Fowlkes–Mallows index, and classification results via model accuracies in predicting the group of an unknown complex substance. We demonstrate the effect of (i) different grouping methodologies, (ii) data set size, and (iii) dimensionality reduction on the grouping quality, and (iv) different analytical techniques on the characterization of the complex substances. While the complexity and variability in chemical composition are an inherent feature of complex substances, we demonstrate how the choices of the data analysis and visualization methods can impact the communication of their characteristics to delineate sufficient similarity.}, number={10}, journal={PLOS ONE}, author={Onel, Melis and Beykal, Burcu and Ferguson, Kyle and Chiu, Weihsueh A. and McDonald, Thomas J. and Zhou, Lan and House, John S. and Wright, Fred A. and Sheen, David A. and Rusyn, Ivan and et al.}, year={2019}, month={Oct} }
 @article{grimm_house_wilson_sirenko_iwata_wright_ball_rusyn_2019, title={Multi-dimensional in vitro bioactivity profiling for grouping of glycol ethers}, volume={101}, ISSN={["1096-0295"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85057214979&partnerID=MN8TOARS}, DOI={10.1016/j.yrtph.2018.11.011}, abstractNote={High-content screening data derived from physiologically-relevant in vitro models promise to improve confidence in data-integrative groupings for read-across in human health safety assessments. The biological data-based read-across concept is especially applicable to bioactive chemicals with defined mechanisms of toxicity; however, the challenge of data-derived groupings for chemicals that are associated with little or no bioactivity has not been explored. In this study, we apply a suite of organotypic and population-based in vitro models for comprehensive bioactivity profiling of twenty E-Series and P-Series glycol ethers, solvents with a broad variation in toxicity ranging from relatively non-toxic to reproductive and hematopoetic system toxicants. Both E-Series and P-Series glycol ethers elicited cytotoxicity only at high concentrations (mM range) in induced pluripotent stem cell-derived hepatocytes and cardiomyocytes. Population-variability assessment comprised a study of cytotoxicity in 94 human lymphoblast cell lines from 9 populations and revealed differences in inter-individual variability across glycol ethers, but did not indicate population-specific effects. Data derived from various phenotypic and transcriptomic assays revealed consistent bioactivity trends between both cardiomyocytes and hepatocytes, indicating a more universal, rather than cell-type specific mode-of-action for the tested glycol ethers in vitro. In vitro bioactivity-based similarity assessment using Toxicological Priority Index (ToxPi) showed that glycol ethers group according to their alcohol chain length, longer chains were associated with increased bioactivity. While overall in vitro bioactivity profiles did not correlate with in vivo toxicity data on glycol ethers, in vitro bioactivity of E-series glycol ethers were indicative of and correlated with in vivo irritation scores.}, journal={REGULATORY TOXICOLOGY AND PHARMACOLOGY}, publisher={Elsevier BV}, author={Grimm, Fabian A. and House, John S. and Wilson, Melinda R. and Sirenko, Oksana and Iwata, Yasuhiro and Wright, Fred A. and Ball, Nicholas and Rusyn, Ivan}, year={2019}, month={Feb}, pages={91–102} }
 @article{sai_parsons_house_kathariou_ninomiya-tsuji_2019, title={Necroptosis mediators RIPK3 and MLKL suppress intracellular Listeria replication independently of host cell killing}, volume={218}, ISSN={["1540-8140"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85067213651&partnerID=MN8TOARS}, DOI={10.1083/jcb.201810014}, abstractNote={RIPK3, a key mediator of necroptosis, has been implicated in the host defense against viral infection primary in immune cells. However, gene expression analysis revealed that RIPK3 is abundantly expressed not only in immune organs but also in the gastrointestinal tract, particularly in the small intestine. We found that orally inoculated Listeria monocytogenes, a bacterial foodborne pathogen, efficiently spread and caused systemic infection in Ripk3-deficient mice while almost no dissemination was observed in wild-type mice. Listeria infection activated the RIPK3-MLKL pathway in cultured cells, which resulted in suppression of intracellular replication of Listeria. Surprisingly, Listeria infection–induced phosphorylation of MLKL did not result in host cell killing. We found that MLKL directly binds to Listeria and inhibits their replication in the cytosol. Our findings have revealed a novel functional role of the RIPK3-MLKL pathway in nonimmune cell-derived host defense against Listeria invasion, which is mediated through cell death–independent mechanisms.}, number={6}, journal={JOURNAL OF CELL BIOLOGY}, publisher={Rockefeller University Press}, author={Sai, Kazuhito and Parsons, Cameron and House, John S. and Kathariou, Sophia and Ninomiya-Tsuji, Jun}, year={2019}, month={Jun}, pages={1994–2005} }
 @article{henriquez_house_snow_miller_schladweiler_fisher_ren_valdez_kodavanti_kodavanti_2019, title={Ozone-Induced Dysregulation of Neuroendocrine Axes Requires Adrenal-Derived Stress Hormones}, volume={172}, ISSN={["1096-0929"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85077224518&partnerID=MN8TOARS}, DOI={10.1093/toxsci/kfz182}, abstractNote={Abstract}, number={1}, journal={TOXICOLOGICAL SCIENCES}, author={Henriquez, Andres R. and House, John S. and Snow, Samantha J. and Miller, Colette N. and Schladweiler, Mette C. and Fisher, Anna and Ren, Hongzu and Valdez, Matthew and Kodavanti, Prasada R. and Kodavanti, Urmila P.}, year={2019}, month={Nov}, pages={38–50} }
 @article{burnett_blanchette_grimm_house_reif_wright_chiu_rusyn_2019, title={Population-based toxicity screening in human induced pluripotent stem cell-derived cardiomyocytes}, volume={381}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85070968757&partnerID=MN8TOARS}, DOI={10.1016/j.taap.2019.114711}, abstractNote={The potential for cardiotoxicity is carefully evaluated for pharmaceuticals, as it is a major safety liability. However, environmental chemicals are seldom tested for their cardiotoxic potential. Moreover, there is a large variability in both baseline and drug-induced cardiovascular risk in humans, but data are lacking on the degree to which susceptibility to chemically-induced cardiotoxicity may also vary. Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes have become an important in vitro model for drug screening. Thus, we hypothesized that a population-based model of iPSC-derived cardiomyocytes from a diverse set of individuals can be used to assess potential hazard and inter-individual variability in chemical effects on these cells. We conducted concentration-response screening of 134 chemicals (pharmaceuticals, industrial and environmental chemicals and food constituents) in iPSC-derived cardiomyocytes from 43 individuals, comprising both sexes and diverse ancestry. We measured kinetic calcium flux and conducted high-content imaging following chemical exposure, and utilized a panel of functional and cytotoxicity parameters in concentration-response for each chemical and donor. We show reproducible inter-individual variability in both baseline and chemical-induced effects on iPSC-derived cardiomyocytes. Further, chemical-specific variability in potency and degree of population variability were quantified. This study shows the feasibility of using an organotypic population-based human in vitro model to quantitatively assess chemicals for which little cardiotoxicity information is available. Ultimately, these results advance in vitro toxicity testing methodologies by providing an innovative tool for population-based cardiotoxicity screening, contributing to the paradigm shift from traditional animal models of toxicity to in vitro toxicity testing methods.}, journal={Toxicology and Applied Pharmacology}, author={Burnett, S.D. and Blanchette, A.D. and Grimm, F.A. and House, J.S. and Reif, D.M. and Wright, F.A. and Chiu, W.A. and Rusyn, I.}, year={2019} }
 @article{grimm_blanchette_house_ferguson_hsieh_dalaijamts_wright_anson_wright_chiu_et al._2018, title={A Human Population-Based Organotypic In Vitro Model for Cardiotoxicity Screening}, volume={35}, ISSN={["1868-8551"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85054462389&partnerID=MN8TOARS}, DOI={10.14573/altex.1805301}, abstractNote={Assessing inter-individual variability in responses to xenobiotics remains a substantial challenge, both in drug development with respect to pharmaceuticals and in public health with respect to environmental chemicals. Although approaches exist to characterize pharmacokinetic variability, there are no methods to routinely address pharmacodynamic variability. In this study, we aimed to demonstrate the feasibility of characterizing inter-individual variability in a human in vitro model. Specifically, we hypothesized that genetic variability across a population of iPSC-derived cardiomyocytes translates into reproducible variability in both baseline phenotypes and drug responses. We measured baseline and drug-related effects in iPSC-derived cardiomyocytes from 27 healthy donors on kinetic Ca2+ flux and high-content live cell imaging. Cells were treated in concentration-response with cardiotoxic drugs: isoproterenol (β-adrenergic receptor agonist/positive inotrope), propranolol (β-adrenergic receptor antagonist/negative inotrope), and cisapride (hERG channel inhibitor/QT prolongation). Cells from four of the 27 donors were further evaluated in terms of baseline and treatment-related gene expression. Reproducibility of phenotypic responses was evaluated across batches and time. iPSC-derived cardiomyocytes exhibited reproducible donor-specific differences in baseline function and drug-induced effects. We demonstrate the feasibility of using a panel of population-based organotypic cells from healthy donors as an animal replacement experimental model. This model can be used to rapidly screen drugs and chemicals for inter-individual variability in cardiotoxicity. This approach demonstrates the feasibility of quantifying inter-individual variability in xenobiotic responses and can be expanded to other cell types for which in vitro populations can be derived from iPSCs.}, number={4}, journal={ALTEX-ALTERNATIVES TO ANIMAL EXPERIMENTATION}, author={Grimm, Fabian A. and Blanchette, Alexander and House, John S. and Ferguson, Kyle and Hsieh, Nan-Hung and Dalaijamts, Chimeddulam and Wright, Alec A. and Anson, Blake and Wright, Fred A. and Chiu, Weihsueh A. and et al.}, year={2018}, pages={441–452} }
 @article{messenger_hall_jima_house_tam_tokarz_smart_2018, title={C/EBPβ deletion in oncogenic Ras skin tumors is a synthetic lethal event}, volume={9}, ISSN={2041-4889}, url={http://dx.doi.org/10.1038/S41419-018-1103-Y}, DOI={10.1038/s41419-018-1103-y}, abstractNote={Abstract}, number={11}, journal={Cell Death & Disease}, publisher={Springer Science and Business Media LLC}, author={Messenger, Zachary J. and Hall, Jonathan R. and Jima, Dereje D. and House, John S. and Tam, Hann W. and Tokarz, Debra A. and Smart, Robert C.}, year={2018}, month={Oct} }
 @article{house_mendez_maguire_gonzalez-nahm_huang_daniels_murphy_fuemmeler_wright_hoyo_2018, title={Periconceptional maternal mediterranean diet is associated with favorable offspring behaviors and altered CpG methylation of imprinted genes}, volume={6}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85053720031&partnerID=MN8TOARS}, DOI={10.3389/fcell.2018.00107}, abstractNote={Background: Maternal diet during pregnancy has been shown to influence the child neuro-developmental outcomes. Studies examining effects of dietary patterns on offspring behavior are sparse. Objective: Determine if maternal adherence to a Mediterranean diet is associated with child behavioral outcomes assessed early in life, and to evaluate the role of differentially methylated regions (DMRs) regulating genomically imprinted genes in these associations. Methods: Among 325 mother/infant pairs, we used regression models to evaluate the association between tertiles of maternal periconceptional Mediterranean diet adherence (MDA) scores derived from a Food Frequency Questionnaire, and social and emotional scores derived from the Infant Toddler Social and Emotional Assessment (ITSEA) questionnaire in the second year of life. Methylation of nine genomically imprinted genes was measured to determine if MDA was associated with CpG methylation. Results: Child depression was inversely associated with maternal MDA (Bonferroni-corrected p = 0.041). While controlling for false-discovery, compared to offspring of women with the lowest MDA tertile, those with MDA scores in middle and high MDA tertiles had decreased odds for atypical behaviors [OR (95% CI) = 0.40 (0.20, 0.78) for middle and 0.40 (0.17, 0.92) for highest tertile], for maladaptive behaviors [0.37 (0.18, 0.72) for middle tertile and 0.42 (0.18, 0.95) for highest tertile] and for an index of autism spectrum disorder behaviors [0.46 (0.23, 0.90) for middle and 0.35 (0.15, 0.80) for highest tertile]. Offspring of women with the highest MDA tertile were less likely to exhibit depressive [OR = 0.28 (0.12, 0.64)] and anxiety [0.42 (0.18, 0.97)] behaviors and increased odds of social relatedness [2.31 (1.04, 5.19)] behaviors when compared to low MDA mothers. Some associations varied by sex. Perinatal MDA score was associated with methylation differences for imprinted control regions of PEG10/SGCE [females: Beta (95% CI) = 1.66 (0.52, 2.80) – Bonferroni-corrected p = 0.048; males: -0.56 (-1.13, -0.00)], as well as both MEG3 and IGF2 in males [0.97 (0.00, 1.94)] and -0.92 (-1.65, -0.19) respectively. Conclusion: In this ethnically diverse cohort, maternal adherence to a Mediterranean diet in early pregnancy was associated with favorable neurobehavioral outcomes in early childhood and with sex-dependent methylation differences of MEG3, IGF2, and SGCE/PEG10 DMRs.}, number={SEP}, journal={Frontiers in Cell and Developmental Biology}, author={House, John S. and Mendez, M. and Maguire, R.L. and Gonzalez-Nahm, S. and Huang, Z. and Daniels, J. and Murphy, S.K. and Fuemmeler, B.F. and Wright, F.A. and Hoyo, C.}, year={2018}, pages={107} }
 @article{venkatratnam_house_konganti_mckenney_threadgill_chiu_aylor_wright_rusyn_2018, title={Population-based dose-response analysis of liver transcriptional response to trichloroethylene in mouse}, volume={29}, ISSN={["1432-1777"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85040693289&partnerID=MN8TOARS}, DOI={10.1007/s00335-018-9734-y}, abstractNote={Studies of gene expression are common in toxicology and provide important clues to mechanistic understanding of adverse effects of chemicals. Most prior studies have been performed in a single strain or cell line; however, gene expression is heavily influenced by the genetic background, and these genotype-expression differences may be key drivers of inter-individual variation in response to chemical toxicity. In this study, we hypothesized that the genetically diverse Collaborative Cross mouse population can be used to gain insight and suggest mechanistic hypotheses for the dose- and genetic background-dependent effects of chemical exposure. This hypothesis was tested using a model liver toxicant trichloroethylene (TCE). Liver transcriptional responses to TCE exposure were evaluated 24 h after dosing. Transcriptomic dose–responses were examined for both TCE and its major oxidative metabolite trichloroacetic acid (TCA). As expected, peroxisome- and fatty acid metabolism-related pathways were among the most dose–responsive enriched pathways in all strains. However, nearly half of the TCE-induced liver transcriptional perturbation was strain-dependent, with abundant evidence of strain/dose interaction, including in the peroxisomal signaling-associated pathways. These effects were highly concordant between the administered TCE dose and liver levels of TCA. Dose–response analysis of gene expression at the pathway level yielded points of departure similar to those derived from the traditional toxicology studies for both non-cancer and cancer effects. Mapping of expression–genotype–dose relationships revealed some significant associations; however, the effects of TCE on gene expression in liver appear to be highly polygenic traits that are challenging to positionally map. This study highlights the usefulness of mouse population-based studies in assessing inter-individual variation in toxicological responses, but cautions that genetic mapping may be challenging because of the complexity in gene exposure–dose relationships.}, number={1-2}, journal={MAMMALIAN GENOME}, author={Venkatratnam, Abhishek and House, John S. and Konganti, Kranti and McKenney, Connor and Threadgill, David W. and Chiu, Weihsueh A. and Aylor, David L. and Wright, Fred A. and Rusyn, Ivan}, year={2018}, month={Feb}, pages={168–181} }
 @article{sakolish_weber_kelly_himmelfarb_mouneimne_grimm_house_wade_han_chiu_et al._2018, title={Technology Transfer of the Microphysiological Systems: A Case Study of the Human Proximal Tubule Tissue Chip}, volume={8}, ISSN={["2045-2322"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85054437254&partnerID=MN8TOARS}, DOI={10.1038/s41598-018-33099-2}, abstractNote={Abstract}, number={1}, journal={SCIENTIFIC REPORTS}, author={Sakolish, Courtney and Weber, Elijah J. and Kelly, Edward J. and Himmelfarb, Jonathan and Mouneimne, Roula and Grimm, Fabian A. and House, John S. and Wade, Terry and Han, Arum and Chiu, Weihsueh A. and et al.}, year={2018}, month={Oct} }
 @article{house_grimm_jima_zhou_rusyn_wright_2017, title={A pipeline for high-throughput concentration response modeling of gene expression for toxicogenomics}, volume={8}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85034032104&partnerID=MN8TOARS}, DOI={10.3389/fgene.2017.00168}, abstractNote={Cell-based assays are an attractive option to measure gene expression response to exposure, but the cost of whole-transcriptome RNA sequencing has been a barrier to the use of gene expression profiling for in vitro toxicity screening. In addition, standard RNA sequencing adds variability due to variable transcript length and amplification. Targeted probe-sequencing technologies such as TempO-Seq, with transcriptomic representation that can vary from hundreds of genes to the entire transcriptome, may reduce some components of variation. Analyses of high-throughput toxicogenomics data require renewed attention to read-calling algorithms and simplified dose–response modeling for datasets with relatively few samples. Using data from induced pluripotent stem cell-derived cardiomyocytes treated with chemicals at varying concentrations, we describe here and make available a pipeline for handling expression data generated by TempO-Seq to align reads, clean and normalize raw count data, identify differentially expressed genes, and calculate transcriptomic concentration–response points of departure. The methods are extensible to other forms of concentration–response gene-expression data, and we discuss the utility of the methods for assessing variation in susceptibility and the diseased cellular state.}, number={NOV}, journal={Frontiers in Genetics}, author={House, JS and Grimm, FA and Jima, DD and Zhou, YH and Rusyn, I and Wright, FA}, year={2017} }
 @article{henriquez_house_miller_snow_fisher_ren_schladweiler_ledbetter_wright_kodavanti_2017, title={Adrenal-derived stress hormones modulate ozone-induced lung injury and inflammation}, volume={329}, ISSN={["1096-0333"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85020944922&partnerID=MN8TOARS}, DOI={10.1016/j.taap.2017.06.009}, abstractNote={Ozone-induced systemic effects are modulated through activation of the neuro-hormonal stress response pathway. Adrenal demedullation (DEMED) or bilateral total adrenalectomy (ADREX) inhibits systemic and pulmonary effects of acute ozone exposure. To understand the influence of adrenal-derived stress hormones in mediating ozone-induced lung injury/inflammation, we assessed global gene expression (mRNA sequencing) and selected proteins in lung tissues from male Wistar-Kyoto rats that underwent DEMED, ADREX, or sham surgery (SHAM) prior to their exposure to air or ozone (1 ppm), 4 h/day for 1 or 2 days. Ozone exposure significantly changed the expression of over 2300 genes in lungs of SHAM rats, and these changes were markedly reduced in DEMED and ADREX rats. SHAM surgery but not DEMED or ADREX resulted in activation of multiple ozone-responsive pathways, including glucocorticoid, acute phase response, NRF2, and PI3K-AKT. Predicted targets from sequencing data showed a similarity between transcriptional changes induced by ozone and adrenergic and steroidal modulation of effects in SHAM but not ADREX rats. Ozone-induced increases in lung Il6 in SHAM rats coincided with neutrophilic inflammation, but were diminished in DEMED and ADREX rats. Although ozone exposure in SHAM rats did not significantly alter mRNA expression of Ifnγ and Il-4, the IL-4 protein and ratio of IL-4 to IFNγ (IL-4/IFNγ) proteins increased suggesting a tendency for a Th2 response. This did not occur in ADREX and DEMED rats. We demonstrate that ozone-induced lung injury and neutrophilic inflammation require the presence of circulating epinephrine and corticosterone, which transcriptionally regulates signaling mechanisms involved in this response.}, journal={TOXICOLOGY AND APPLIED PHARMACOLOGY}, author={Henriquez, Andres and House, John and Miller, Desinia B. and Snow, Samantha J. and Fisher, Anna and Ren, Hongzu and Schladweiler, Mette C. and Ledbetter, Allen D. and Wright, Fred and Kodavanti, Urmila P.}, year={2017}, month={Aug}, pages={249–258} }
 @article{house_wyss_hoppin_richards_long_umbach_henneberger_freeman_le_dp_et al._2017, title={Early-life farm exposures and adult asthma and atopy in the Agricultural Lung Health Study}, volume={140}, ISSN={0091-6749}, url={http://dx.doi.org/10.1016/j.jaci.2016.09.036}, DOI={10.1016/j.jaci.2016.09.036}, abstractNote={BackgroundPrevious studies, mostly from Europe, suggest that early-life farming exposures protect against childhood asthma and allergy; few data exist on asthma and allergy in adults.ObjectiveWe sought to examine associations between early-life farming exposures and current asthma and atopy in an older adult US farming population.MethodsWe analyzed data from 1746 farmers and 1555 spouses (mean age, 63) from a case-control study nested within the Agricultural Health Study. Current asthma and early-life farming exposures were assessed via questionnaires. We defined atopy based on specific IgE > 0.70 IU/mL to at least 1 of 10 allergens measured in blood. We used logistic regression, adjusted for age, sex, race, state (Iowa or North Carolina), and smoking (pack years), to estimate associations between early-life exposures and asthma (1198 cases and 2031 noncases) or atopy (578 cases and 2526 noncases).ResultsExposure to the farming environment in utero and in early childhood had little or no association with asthma but was associated with reduced odds of atopy. The strongest association was seen for having a mother who performed farm activities while pregnant (odds ratio, 0.60; 95% CI, 0.48-0.74) and remained significant in models with correlated early-life exposures including early childhood farm animal contact and raw milk consumption.ConclusionsIn a large US farming population, early-life farm exposures, particularly maternal farming activities while pregnant, were strongly associated with reduced risk of atopy in adults. These results extend previous work done primarily on childhood outcomes and suggest that protective associations of early-life farming exposures on atopy endure across the life course. Previous studies, mostly from Europe, suggest that early-life farming exposures protect against childhood asthma and allergy; few data exist on asthma and allergy in adults. We sought to examine associations between early-life farming exposures and current asthma and atopy in an older adult US farming population. We analyzed data from 1746 farmers and 1555 spouses (mean age, 63) from a case-control study nested within the Agricultural Health Study. Current asthma and early-life farming exposures were assessed via questionnaires. We defined atopy based on specific IgE > 0.70 IU/mL to at least 1 of 10 allergens measured in blood. We used logistic regression, adjusted for age, sex, race, state (Iowa or North Carolina), and smoking (pack years), to estimate associations between early-life exposures and asthma (1198 cases and 2031 noncases) or atopy (578 cases and 2526 noncases). Exposure to the farming environment in utero and in early childhood had little or no association with asthma but was associated with reduced odds of atopy. The strongest association was seen for having a mother who performed farm activities while pregnant (odds ratio, 0.60; 95% CI, 0.48-0.74) and remained significant in models with correlated early-life exposures including early childhood farm animal contact and raw milk consumption. In a large US farming population, early-life farm exposures, particularly maternal farming activities while pregnant, were strongly associated with reduced risk of atopy in adults. These results extend previous work done primarily on childhood outcomes and suggest that protective associations of early-life farming exposures on atopy endure across the life course.}, number={1}, journal={Journal of Allergy and Clinical Immunology}, publisher={Elsevier BV}, author={House, J.S. and Wyss, A.B. and Hoppin, J.A. and Richards, M. and Long, S. and Umbach, D.M. and Henneberger, P.K. and Freeman, Beane and Le, Sandler and Dp, Long O.'Connell and et al.}, year={2017}, month={Jul}, pages={249–256.e14} }
 @article{wyss_house_hoppin_richards_hankinson_long_henneberger_beane freeman_sandler_o’connell_et al._2017, title={Raw milk consumption and other early-life farm exposures and adult pulmonary function in the Agricultural Lung Health Study}, volume={73}, ISSN={0040-6376 1468-3296}, url={http://dx.doi.org/10.1136/thoraxjnl-2017-210031}, DOI={10.1136/thoraxjnl-2017-210031}, abstractNote={Literature suggests that early exposure to the farming environment protects against atopy and asthma; few studies have examined pulmonary function. We evaluated associations between early-life farming exposures and pulmonary function in 3061 adults (mean age=63) from a US farming population using linear regression. Childhood raw milk consumption was associated with higher FEV1 (β=49.5 mL, 95% CI 2.8 to 96.1 mL, p=0.04) and FVC (β=66.2 mL, 95% CI 13.2 to 119.1 mL, p=0.01). We did not find appreciable associations with other early-life farming exposures. We report a novel association between raw milk consumption and higher pulmonary function that lasts into older adulthood.}, number={3}, journal={Thorax}, publisher={BMJ}, author={Wyss, Annah B and House, John S and Hoppin, Jane A and Richards, Marie and Hankinson, John L and Long, Stuart and Henneberger, Paul K and Beane Freeman, Laura E and Sandler, Dale P and O’Connell, Elizabeth Long and et al.}, year={2017}, month={Jul}, pages={279–282} }
 @article{house_nichols_li_brandenberger_virgincar_degraff_driehuys_zeldin_london_2017, title={Vagal innervation is required for pulmonary function phenotype in htr4 <sup>–/–</sup> mice}, volume={312}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85017032088&partnerID=MN8TOARS}, DOI={10.1152/ajplung.00495.2016}, abstractNote={ Human genome-wide association studies have identified over 50 loci associated with pulmonary function and related phenotypes, yet follow-up studies to determine causal genes or variants are rare. Single nucleotide polymorphisms in serotonin receptor 4 ( HTR4) are associated with human pulmonary function in genome-wide association studies and follow-up animal work has demonstrated that Htr4 is causally associated with pulmonary function in mice, although the precise mechanisms were not identified. We sought to elucidate the role of neural innervation and pulmonary architecture in the lung phenotype of Htr4−/− animals. We report here that the Htr4−/− phenotype in mouse is dependent on vagal innervation to the lung. Both ex vivo tracheal ring reactivity and in vivo flexiVent pulmonary functional analyses demonstrate that vagotomy abrogates the Htr4−/− airway hyperresponsiveness phenotype. Hyperpolarized 3He gas magnetic resonance imaging and stereological assessment of wild-type and Htr4−/− mice reveal no observable differences in lung volume, inflation characteristics, or pulmonary microarchitecture. Finally, control of breathing experiments reveal substantive differences in baseline breathing characteristics between mice with/without functional HTR4 in breathing frequency, relaxation time, flow rate, minute volume, time of inspiration and expiration and breathing pauses. These results suggest that HTR4’s role in pulmonary function likely relates to neural innervation and control of breathing. }, number={4}, journal={American Journal of Physiology - Lung Cellular and Molecular Physiology}, publisher={American Physiological Society}, author={House, John S. and Nichols, Cody E. and Li, Huiling and Brandenberger, Christina and Virgincar, Rohan S. and DeGraff, Laura M. and Driehuys, Bastiaan and Zeldin, Darryl C. and London, Stephanie J.}, year={2017}, pages={L520–L530} }
 @article{house_li_degraff_flake_zeldin_london_2015, title={Genetic variation in HTR4 and lung function: GWAS follow-up in mouse.}, volume={29}, url={http://europepmc.org/abstract/med/25342126}, DOI={10.1096/fj.14-253898}, abstractNote={Human genome‐wide association studies (GWASs) have identified numerous associations between single nucleotide polymorphisms (SNPs) and pulmonary function. Proving that there is a causal relationship between GWAS SNPs, many of which are noncoding and without known functional impact, and these traits has been elusive. Furthermore, noncoding GWAS‐identified SNPs may exert trans‐regulatory effects rather than impact the proximal gene. Noncoding variants in 5‐hydroxytryptamine (serotonin) receptor 4 (HTR4) are associated with pulmonary function in human GWASs. To gain insight into whether this association is causal, we tested whether Htr4‐null mice have altered pulmonary function. We found that HTR4‐deficient mice have 12% higher baseline lung resistance and also increased methacholine‐induced airway hyperresponsiveness (AHR) as measured by lung resistance (27%), tissue resistance (48%), and tissue elastance (30%). Furthermore, Htr4‐null mice were more sensitive to serotonin‐induced AHR. In models of exposure to bacterial lipopolysaccharide, bleomycin, and allergic airway inflammation induced by house dust mites, pulmonary function and cytokine profiles in Htr4‐null mice differed little from their wild‐type controls. The findings of altered baseline lung function and increased AHR in Htr4‐null mice support a causal relationship between genetic variation in HTR4 and pulmonary function identified in human GWAS.‐House J. S., Li, H., DeGraff, L. M., Flake, G., Zeldin, D. C., London, S. J. Genetic variation in HTR4 and lung function: GWAS follow‐up in mouse. FASEB J. 29, 323–335 (2015). www.fasebj.org}, number={1}, journal={FASEB Journal}, author={House, JS and Li, H and DeGraff, LM and Flake, G and Zeldin, DC and London, SJ}, year={2015}, month={Jan}, pages={323–335} }
 @article{graves_gruzdev_bradbury_degraff_li_house_hoopes_edin_zeldin_2015, title={Quantitative Polymerase Chain Reaction Analysis of the Mouse Cyp2j Subfamily: Tissue Distribution and Regulation.}, volume={43}, url={http://europepmc.org/abstract/med/25994032}, DOI={10.1124/dmd.115.064139}, abstractNote={Members of the cytochrome P450 CYP2J subfamily are expressed in multiple tissues in mice and humans. These enzymes are active in the metabolism of fatty acids to generate bioactive compounds. Herein we report new methods and results for quantitative polymerase chain reaction (qPCR) analysis for the seven genes (Cyp2j5, Cyp2j6, Cyp2j8, Cyp2j9, Cyp2j11, Cyp2j12, and Cyp2j13) of the mouse Cyp2j subfamily. SYBR Green primer sets were developed and compared with commercially available TaqMan primer/probe assays for specificity toward mouse Cyp2j cDNA, and analysis of tissue distribution and regulation of Cyp2j genes. Each TaqMan primer/probe set and SYBR Green primer set were shown to be specific for their intended mouse Cyp2j cDNA. Tissue distribution of the mouse Cyp2j isoforms confirmed similar patterns of expression between the two qPCR methods. Cyp2j5 and Cyp2j13 were highly expressed in male kidneys, and Cyp2j11 was highly expressed in both male and female kidneys. Cyp2j6 was expressed in multiple tissues, with the highest expression in the small intestine and duodenum. Cyp2j8 was detected in various tissues, with highest expression found in the skin. Cyp2j9 was highly expressed in the brain, liver, and lung. Cyp2j12 was predominately expressed in the brain. We also determined the Cyp2j isoform expression in Cyp2j5 knockout mice to determine whether there was compensatory regulation of other Cyp2j isoforms, and we assessed Cyp2j isoform regulation during various inflammatory models, including influenza A, bacterial lipopolysaccharide, house dust mite allergen, and corn pollen. Both qPCR methods detected similar suppression of Cyp2j6 and Cyp2j9 during inflammation in the lung.}, number={8}, journal={Drug Metabolism and Disposition}, author={Graves, JP and Gruzdev, A and Bradbury, JA and DeGraff, LM and Li, H and House, JS and Hoopes, SL and Edin, ML and Zeldin, DC}, year={2015}, month={Aug}, pages={1169–1180} }
 @article{london_gao_gharib_hancock_wilk_house_gibbs_muzny_lumley_franceschini_et al._2014, title={ADAM19 and HTR4 variants and pulmonary function: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.}, volume={7}, url={http://europepmc.org/abstract/med/24951661}, DOI={10.1161/circgenetics.113.000066}, abstractNote={
            Background—
            
              The pulmonary function measures of forced expiratory volume in 1 second (FEV1) and its ratio to forced vital capacity (FVC) are used in the diagnosis and monitoring of lung diseases and predict cardiovascular mortality in the general population. Genome-wide association studies (GWASs) have identified numerous loci associated with FEV1 and FEV1/FVC, but the causal variants remain uncertain. We hypothesized that novel or rare variants poorly tagged by GWASs may explain the significant associations between FEV1/FVC and 2 genes:
              ADAM19
              and
              HTR4
              .
            
          }, number={3}, journal={Circulation: Cardiovascular Genetics}, author={London, S.J. and Gao, W. and Gharib, S.A. and Hancock, D.B. and Wilk, J.B. and House, J.S. and Gibbs, R.A. and Muzny, D.M. and Lumley, T. and Franceschini, N. and et al.}, year={2014}, month={Jun}, pages={350–358} }
 @article{thompson_zhu_hall_house_ranjan_burr_he_owens_smart_2011, title={C/EBP alpha Expression Is Downregulated in Human Nonmelanoma Skin Cancers and Inactivation of C/EBP alpha Confers Susceptibility to UVB-Induced Skin Squamous Cell Carcinomas}, volume={131}, ISSN={["0022-202X"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-79956039252&partnerID=MN8TOARS}, DOI={10.1038/jid.2011.31}, abstractNote={Human epidermis is routinely subjected to DNA damage induced by UVB solar radiation. Cell culture studies have revealed an unexpected role for C/EBPα (CCAAT/enhancer-binding protein-α) in the DNA damage response network, where C/EBPα is induced following UVB DNA damage, regulates the G<sub>1</sub> checkpoint, and diminished or ablated expression of C/EBPα results in G<sub>1</sub> checkpoint failure. In the current study we observed that C/EBPα is induced in normal human epidermal keratinocytes and in the epidermis of human subjects exposed to UVB radiation. The analysis of human skin precancerous and cancerous lesions (47 cases) for C/EBPα expression was conducted. Actinic keratoses, a precancerous benign skin growth and precursor to squamous cell carcinoma (SCC), expressed levels of C/EBPα similar to normal epidermis. Strikingly, all invasive SCCs no longer expressed detectable levels of C/EBPα. To determine the significance of C/EBPα in UVB-induced skin cancer, SKH-1 mice lacking epidermal C/EBPα (CKOα) were exposed to UVB. CKOα mice were highly susceptible to UVB-induced SCCs and exhibited accelerated tumor progression. CKOα mice displayed keratinocyte cell cycle checkpoint failure <i>in vivo</i> in response to UVB that was characterized by abnormal entry of keratinocytes into S phase. Our results demonstrate that C/EBPα is silenced in human SCC and loss of C/EBPα confers susceptibility to UVB-induced skin SCCs involving defective cell cycle arrest in response to UVB.}, number={6}, journal={JOURNAL OF INVESTIGATIVE DERMATOLOGY}, author={Thompson, Elizabeth A. and Zhu, Songyun and Hall, Jonathan R. and House, John S. and Ranjan, Rakesh and Burr, Jeanne A. and He, Yu-Ying and Owens, David M. and Smart, Robert C.}, year={2011}, month={Jun}, pages={1339–1346} }
 @article{house_zhu_ranjan_linder_smart_2010, title={C/EBP alpha and C/EBP beta Are Required for Sebocyte Differentiation and Stratified Squamous Differentiation in Adult Mouse Skin}, volume={5}, ISSN={["1932-6203"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-79952118221&partnerID=MN8TOARS}, DOI={10.1371/journal.pone.0009837}, abstractNote={C/EBPα and C/EBPβ are bZIP transcription factors that are highly expressed in the interfollicular epidermis and sebaceous glands of skin and yet germ line deletion of either family member alone has only mild or no effect on keratinocyte biology and their role in sebocyte biology has never been examined. To address possible functional redundancies and reveal functional roles of C/EBPα and C/EBPβ in postnatal skin, mouse models were developed in which either family member could be acutely ablated alone or together in the epidermis and sebaceous glands of adult mice. Acute removal of either C/EBPα or C/EBPβ alone in adult mouse skin revealed modest to no discernable changes in epidermis or sebaceous glands. In contrast, co-ablation of C/EBPα and C/EBPβ in postnatal epidermis resulted in disruption of stratified squamous differentiation characterized by hyperproliferation of basal and suprabasal keratinocytes and a defective basal to spinous keratinocyte transition involving an expanded basal compartment and a diminished and delayed spinous compartment. Acute co-ablation of C/EBPα and C/EBPβ in sebaceous glands resulted in severe morphological defects, and sebocyte differentiation was blocked as determined by lack of sebum production and reduced expression of stearoyl-CoA desaturase (SCD3) and melanocortin 5 receptor (MC5R), two markers of terminal sebocyte differentiation. Specialized sebocytes of Meibomian glands and preputial glands were also affected. Our results indicate that in adult mouse skin, C/EBPα and C/EBPβ are critically involved in regulating sebocyte differentiation and epidermal homeostasis involving the basal to spinous keratinocyte transition and basal cell cycle withdrawal.}, number={3}, journal={PLOS ONE}, author={House, John S. and Zhu, Songyun and Ranjan, Rakesh and Linder, Keith and Smart, Robert C.}, year={2010}, month={Mar} }
 @article{ewing_zhu_zhu_house_smart_2008, title={C/EBP beta represses p53 to promote cell survival downstream of DNA damage independent of oncogenic Ras and p19(Arf)}, volume={15}, ISSN={["1476-5403"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-54049144611&partnerID=MN8TOARS}, DOI={10.1038/cdd.2008.105}, abstractNote={CCAAT/enhancer-binding protein-beta (C/EBPbeta) is a mediator of cell survival and tumorigenesis. When C/EBPbeta(-/-) mice are treated with carcinogens that produce oncogenic Ras mutations in keratinocytes, they respond with abnormally elevated keratinocyte apoptosis and a block in skin tumorigenesis. Although this aberrant carcinogen-induced apoptosis results from abnormal upregulation of p53, it is not known whether upregulated p53 results from oncogenic Ras and its ability to induce p19(Arf) and/or activate DNA-damage response pathways or from direct carcinogen-induced DNA damage. We report that p19(Arf) is dramatically elevated in C/EBPbeta(-/-) epidermis and that C/EBPbeta represses a p19(Arf) promoter reporter. To determine whether p19(Arf) is responsible for the proapoptotic phenotype in C/EBPbeta(-/-) mice, C/EBPbeta(-/-);p19(Arf-/-) mice were generated. C/EBPbeta(-/-);p19(Arf-/-) mice responded to carcinogen treatment with increased p53 and apoptosis, indicating p19(Arf) is not essential. To ascertain whether oncogenic Ras activation induces aberrant p53 and apoptosis in C/EBPbeta(-/-) epidermis, we generated K14-ER:Ras;C/EBPbeta(-/-) mice. Oncogenic Ras activation induced by 4-hydroxytamoxifen did not produce increased p53 or apoptosis. Finally, when C/EBPbeta(-/-) mice were treated with differing types of DNA-damaging agents, including alkylating chemotherapeutic agents, they displayed aberrant levels of p53 and apoptosis. These results indicate that C/EBPbeta represses p53 to promote cell survival downstream of DNA damage and suggest that inhibition of C/EBPbeta may be a target for cancer cotherapy to increase the efficacy of alkylating chemotherapeutic agents.}, number={11}, journal={CELL DEATH AND DIFFERENTIATION}, author={Ewing, S. J. and Zhu, S. and Zhu, F. and House, J. S. and Smart, R. C.}, year={2008}, month={Nov}, pages={1734–1744} }