TY - JOUR TI - The AGMK1-9T7 cell model of neoplasia: Evolution of DNA copy-number aberrations and miRNA expression during transition from normal to metastatic cancer cells AU - Lewis, Andrew M., Jr. AU - Thomas, Rachael AU - Breen, Matthew AU - Peden, Keith AU - Teferedegne, Belete AU - Foseh, Gideon AU - Motsinger-Reif, Alison AU - Rotroff, Daniel AU - Lewis, Gladys T2 - PLOS ONE AB - To study neoplasia in tissue culture, cell lines representing the evolution of normal cells to tumor cells are needed. To produce such cells, we developed the AGMK1-9T7 cell line, established cell banks at 10-passage intervals, and characterized their biological properties. Here we examine the evolution of chromosomal DNA copy-number aberrations and miRNA expression in this cell line from passage 1 to the acquisition of a tumorigenic phenotype at passage 40. We demonstrated the use of a human microarray platform for DNA copy-number profiling of AGMK1-9T7 cells using knowledge of synteny to 'recode' data from human chromosome coordinates to those of the African green monkey. This approach revealed the accumulation of DNA copy-number gains and losses in AGMK1-9T7 cells from passage 3 to passage 40, which spans the period in which neoplastic transformation occurred. These alterations occurred in the sequences of genes regulating DNA copy-number imbalance of several genes that regulate endothelial cell angiogenesis, survival, migration, and proliferation. Regarding miRNA expression, 195 miRNAs were up- or down-regulated at passage 1 at levels that appear to be biologically relevant (i.e., log2 fold change >2.0 (q<0.05)). At passage 10, the number of up/down-regulated miRNAs fell to 63; this number increased to 93 at passage 40. Principal-component analysis grouped these miRNAs into 3 clusters; miRNAs in sub-clusters of these groups could be correlated with initiation, promotion, and progression, stages that have been described for neoplastic development. Thirty-four of the AGMK1-9T7 miRNAs have been associated with these stages in human cancer. Based on these data, we propose that the evolution of AGMK1-9T7 cells represents a detailed model of neoplasia in vitro. DA - 2022/10/24/ PY - 2022/10/24/ DO - 10.1371/journal.pone.0275394 VL - 17 IS - 10 SP - SN - 1932-6203 ER - TY - JOUR TI - MagicalRsq: Machine-learning-based genotype imputation quality calibration AU - Sun, Quan AU - Yang, Yingxi AU - Rosen, Jonathan D. AU - Jiang, Min-Zhi AU - Chen, Jiawen AU - Liu, Weifang AU - Wen, Jia AU - Raffield, Laura M. AU - Pace, Rhonda G. AU - Zhou, Yi-Hui AU - Wright, Fred A. AU - Blackman, Scott M. AU - Bamshad, Michael J. AU - Gibson, Ronald L. AU - Cutting, Garry R. AU - Knowles, Michael R. AU - Schrider, Daniel R. AU - Fuchsberger, Christian AU - Li, Yun T2 - AMERICAN JOURNAL OF HUMAN GENETICS AB - Whole-genome sequencing (WGS) is the gold standard for fully characterizing genetic variation but is still prohibitively expensive for large samples. To reduce costs, many studies sequence only a subset of individuals or genomic regions, and genotype imputation is used to infer genotypes for the remaining individuals or regions without sequencing data. However, not all variants can be well imputed, and the current state-of-the-art imputation quality metric, denoted as standard Rsq, is poorly calibrated for lower-frequency variants. Here, we propose MagicalRsq, a machine-learning-based method that integrates variant-level imputation and population genetics statistics, to provide a better calibrated imputation quality metric. Leveraging WGS data from the Cystic Fibrosis Genome Project (CFGP), and whole-exome sequence data from UK BioBank (UKB), we performed comprehensive experiments to evaluate the performance of MagicalRsq compared to standard Rsq for partially sequenced studies. We found that MagicalRsq aligns better with true R2 than standard Rsq in almost every situation evaluated, for both European and African ancestry samples. For example, when applying models trained from 1,992 CFGP sequenced samples to an independent 3,103 samples with no sequencing but TOPMed imputation from array genotypes, MagicalRsq, compared to standard Rsq, achieved net gains of 1.4 million rare, 117k low-frequency, and 18k common variants, where net gains were gained numbers of correctly distinguished variants by MagicalRsq over standard Rsq. MagicalRsq can serve as an improved post-imputation quality metric and will benefit downstream analysis by better distinguishing well-imputed variants from those poorly imputed. MagicalRsq is freely available on GitHub. DA - 2022/11/3/ PY - 2022/11/3/ DO - 10.1016/j.ajhg.2022.09.009 VL - 109 IS - 11 SP - 1986-1997 SN - 1537-6605 ER - TY - JOUR TI - TCDD alters essential transcriptional regulators of osteogenic differentiation in multipotent mesenchymal stem cells AU - Watson, AtLee T. D. AU - Carmona Baez, Aldo AU - Jima, Dereje AU - Reif, David AU - Ding, Jun AU - Roberts, Reade AU - Kullman, Seth W. T2 - TOXICOLOGICAL SCIENCES AB - Differentiation of multipotent mesenchymal stem cells (MSCs) into bone-forming osteoblasts requires strict coordination of transcriptional pathways. Aryl hydrocarbon receptor ligands, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), have been shown to alter osteoblast differentiation in vitro and bone formation in multiple developmental in vivo models. The goal of the present study was to establish a global transcriptomic landscape during early, intermediate, and apical stages of osteogenic differentiation in vitro in response to TCDD exposure. Human bone-derived mesenchymal stem cells (hBMSCs) were cultured in growth media (GM), osteogenic differentiation media (ODM), or ODM containing 10 nM TCDD (ODM + TCDD), thus enabling a comparison of the transcriptomic profiles of undifferentiated, differentiated, and differentiated-TCDD-exposed hBMSCs, respectively. In this test system, exposure to TCDD attenuated the differentiation of hBMSCs into osteoblasts as evidenced by reduced alkaline phosphatase activity and mineralization. At various timepoints, we observed altered expression of genes that play a role in the Wnt, fibroblast growth factor, bone morphogenetic protein/transforming growth factor beta developmental pathways, as well as pathways related to extracellular matrix organization and deposition. Reconstruction of gene regulatory networks with the interactive dynamic regulatory event miner (iDREM) analysis revealed modulation of transcription factors (TFs) including POLR3G, NR4A1, RDBP, GTF2B, POU2F2, and ZEB1, which may putatively influence osteoblast differentiation and the requisite deposition and mineralization of bone extracellular matrix. We demonstrate that the combination of RNA-Seq data in conjunction with the iDREM regulatory model captures the transcriptional dynamics underlying MSC differentiation under different conditions in vitro. Model predictions are consistent with existing knowledge and provide a new tool to identify novel pathways and TFs that may facilitate a better understanding of the osteoblast differentiation process, perturbation by exogenous agents, and potential intervention strategies targeting those specific pathways. DA - 2022/11/12/ PY - 2022/11/12/ DO - 10.1093/toxsci/kfac120 VL - 11 SP - SN - 1096-0929 KW - mesenchymal stem cell KW - AhR KW - cell differentiation ER - TY - JOUR TI - Utilizing a Population-Genetic Framework to Test for Gene-Environment Interactions between Zebrafish Behavior and Chemical Exposure AU - Thunga, Preethi AU - Truong, Lisa AU - Rericha, Yvonne AU - Du, Jane La AU - Morshead, Mackenzie AU - Tanguay, Robyn L. AU - Reif, David M. T2 - TOXICS AB - Individuals within genetically diverse populations display broad susceptibility differences upon chemical exposures. Understanding the role of gene-environment interactions (GxE) in differential susceptibility to an expanding exposome is key to protecting public health. However, a chemical's potential to elicit GxE is often not considered during risk assessment. Previously, we've leveraged high-throughput zebrafish (Danio rerio) morphology screening data to reveal patterns of potential GxE effects. Here, using a population genetics framework, we apportioned variation in larval behavior and gene expression in three different PFHxA environments via mixed-effect modeling to assess significance of GxE term. We estimated the intraclass correlation (ICC) between full siblings from different families using one-way random-effects model. We found a significant GxE effect upon PFHxA exposure in larval behavior, and the ICC of behavioral responses in the PFHxA exposed population at the lower concentration was 43.7%, while that of the control population was 14.6%. Considering global gene expression data, a total of 3746 genes showed statistically significant GxE. By showing evidence that heritable genetics are directly affecting gene expression and behavioral susceptibility of individuals to PFHxA exposure, we demonstrate how standing genetic variation in a heterogeneous population such as ours can be leveraged to test for potential GxE. DA - 2022/12// PY - 2022/12// DO - 10.3390/toxics10120769 VL - 10 IS - 12 SP - SN - 2305-6304 UR - https://doi.org/10.3390/toxics10120769 KW - gene-environment interaction KW - chemical risk-assessment KW - zebrafish behavior KW - toxicity screening ER - TY - JOUR TI - Assessing the Nucleotide-Level Impact of Spaceflight Stress using RNA-Sequencing Data AU - Knight, Montana S. AU - Doherty, Colleen J. AU - Nielsen, Dahlia M. AB - Abstract Understanding the effects of space radiation and microgravity on DNA integrity is critical to assess the impact of long-term spaceflight. However, studying spaceflight’s effect on terrestrial life is difficult. NASA created GeneLab, a public Omics database for spaceflight-related data, to help combat these limitations. While GeneLab has very few DNA-based data sets, transcriptome information is abundant. This study used RNA-Seq data from GeneLab to examine DNA sequence variants linked to spaceflight stress exposure. More mutations were observed in spaceflight samples than in the ground control samples. This increase in variants was not reduced in samples grown under artificial gravity in space, suggesting that microgravity did not significantly affect the amount of DNA damage in this experiment. There was also an increase in transversion mutations, consistent with known forms of radiation-induced damage. This work demonstrates that RNA-Seq data is a useful resource for evaluating DNA damage from spaceflight and provides a baseline for the types of mutations that could be detected. DA - 2022/12/2/ PY - 2022/12/2/ DO - 10.1101/2022.12.01.518235 UR - https://doi.org/10.1101/2022.12.01.518235 ER - TY - JOUR TI - Identification and single-base gene-editing functional validation of a cis-EPO variant as a genetic predictor for EPO-increasing therapies AU - Harlow, Charli E. AU - Gandawijaya, Josan AU - Bamford, Rosemary A. AU - Martin, Emily-Rose AU - Wood, Andrew R. AU - Most, Peter J. AU - Tanaka, Toshiko AU - Leonard, Hampton L. AU - Etheridge, Amy S. AU - Innocenti, Federico AU - Beaumont, Robin N. AU - Tyrrell, Jessica AU - Nalls, Mike A. AU - Simonsick, Eleanor M. AU - Garimella, Pranav S. AU - Shiroma, Eric J. AU - Verweij, Niek AU - Meer, Peter AU - Gansevoort, Ron T. AU - Snieder, Harold AU - Gallins, Paul J. AU - Jima, Dereje D. AU - Wright, Fred AU - Zhou, Yi-hui AU - Ferrucci, Luigi AU - Bandinelli, Stefania AU - Hernandez, Dena G. AU - Harst, Pim AU - Patel, Vickas V. AU - Waterworth, Dawn M. AU - Chu, Audrey Y. AU - Oguro-Ando, Asami AU - Frayling, Timothy M. T2 - AMERICAN JOURNAL OF HUMAN GENETICS AB - Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are currently under clinical development for treating anemia in chronic kidney disease (CKD), but it is important to monitor their cardiovascular safety. Genetic variants can be used as predictors to help inform the potential risk of adverse effects associated with drug treatments. We therefore aimed to use human genetics to help assess the risk of adverse cardiovascular events associated with therapeutically altered EPO levels to help inform clinical trials studying the safety of HIF-PHIs. By performing a genome-wide association meta-analysis of EPO (n = 6,127), we identified a cis-EPO variant (rs1617640) lying in the EPO promoter region. We validated this variant as most likely causal in controlling EPO levels by using genetic and functional approaches, including single-base gene editing. Using this variant as a partial predictor for therapeutic modulation of EPO and large genome-wide association data in Mendelian randomization tests, we found no evidence (at p < 0.05) that genetically predicted long-term rises in endogenous EPO, equivalent to a 2.2-unit increase, increased risk of coronary artery disease (CAD, OR [95% CI] = 1.01 [0.93, 1.07]), myocardial infarction (MI, OR [95% CI] = 0.99 [0.87, 1.15]), or stroke (OR [95% CI] = 0.97 [0.87, 1.07]). We could exclude increased odds of 1.15 for cardiovascular disease for a 2.2-unit EPO increase. A combination of genetic and functional studies provides a powerful approach to investigate the potential therapeutic profile of EPO-increasing therapies for treating anemia in CKD. DA - 2022/9/1/ PY - 2022/9/1/ DO - 10.1016/j.ajhg.2022.08.004 VL - 109 IS - 9 SP - 1638-1652 SN - 1537-6605 ER - TY - JOUR TI - Pleiotropic modifiers of age-related diabetes and neonatal intestinal obstruction in cystic fibrosis AU - Aksit, Melis A. AU - Ling, Hua AU - Pace, Rhonda G. AU - Raraigh, Karen S. AU - Onchiri, Frankline AU - Faino, Anna V. AU - Pagel, Kymberleigh AU - Pugh, Elizabeth AU - Stilp, Adrienne M. AU - Sun, Quan AU - Blue, Elizabeth E. AU - Wright, Fred A. AU - Zhou, Yi-Hui AU - Bamshad, Michael J. AU - Gibson, Ronald L. AU - Knowles, Michael R. AU - Cutting, Garry R. AU - Blackman, Scott M. T2 - AMERICAN JOURNAL OF HUMAN GENETICS AB - Individuals with cystic fibrosis (CF) develop complications of the gastrointestinal tract influenced by genetic variants outside of CFTR. Cystic fibrosis-related diabetes (CFRD) is a distinct form of diabetes with a variable age of onset that occurs frequently in individuals with CF, while meconium ileus (MI) is a severe neonatal intestinal obstruction affecting ∼20% of newborns with CF. CFRD and MI are slightly correlated traits with previous evidence of overlap in their genetic architectures. To better understand the genetic commonality between CFRD and MI, we used whole-genome-sequencing data from the CF Genome Project to perform genome-wide association. These analyses revealed variants at 11 loci (6 not previously identified) that associated with MI and at 12 loci (5 not previously identified) that associated with CFRD. Of these, variants at SLC26A9, CEBPB, and PRSS1 associated with both traits; variants at SLC26A9 and CEBPB increased risk for both traits, while variants at PRSS1, the higher-risk alleles for CFRD, conferred lower risk for MI. Furthermore, common and rare variants within the SLC26A9 locus associated with MI only or CFRD only. As expected, different loci modify risk of CFRD and MI; however, a subset exhibit pleiotropic effects indicating etiologic and mechanistic overlap between these two otherwise distinct complications of CF. DA - 2022/10/6/ PY - 2022/10/6/ DO - 10.1016/j.ajhg.2022.09.004 VL - 109 IS - 10 SP - 1894-1908 SN - 1537-6605 ER - TY - JOUR TI - A cross-species approach using an in vivo evaluation platform in mice demonstrates that sequence variation in human RABEP2 modulates ischemic stroke outcomes AU - Lee, Han Kyu AU - Kwon, Do Hoon AU - Aylor, David L. AU - Marchuk, Douglas A. T2 - AMERICAN JOURNAL OF HUMAN GENETICS AB - Ischemic stroke, caused by vessel blockage, results in cerebral infarction, the death of brain tissue. Previously, quantitative trait locus (QTL) mapping of cerebral infarct volume and collateral vessel number identified a single, strong genetic locus regulating both phenotypes. Additional studies identified RAB GTPase-binding effector protein 2 (Rabep2) as the casual gene. However, there is yet no evidence that variation in the human ortholog of this gene plays any role in ischemic stroke outcomes. We established an in vivo evaluation platform in mice by using adeno-associated virus (AAV) gene replacement and verified that both mouse and human RABEP2 rescue the mouse Rabep2 knockout ischemic stroke volume and collateral vessel phenotypes. Importantly, this cross-species complementation enabled us to experimentally investigate the functional effects of coding sequence variation in human RABEP2. We chose four coding variants from the human population that are predicted by multiple in silico algorithms to be damaging to RABEP2 function. In vitro and in vivo analyses verify that all four led to decreased collateral vessel connections and increased infarct volume. Thus, there are naturally occurring loss-of-function alleles. This cross-species approach will expand the number of targets for therapeutics development for ischemic stroke. DA - 2022/10/6/ PY - 2022/10/6/ DO - 10.1016/j.ajhg.2022.09.003 VL - 109 IS - 10 SP - 1814-1827 SN - 1537-6605 ER - TY - JOUR TI - Comparative Toxicogenomics Database (CTD): update 2023 AU - Davis, Allan Peter AU - Wiegers, Thomas C. AU - Johnson, Robin J. AU - Sciaky, Daniela AU - Wiegers, Jolene AU - Mattingly, Carolyn J. T2 - NUCLEIC ACIDS RESEARCH AB - Abstract The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) harmonizes cross-species heterogeneous data for chemical exposures and their biological repercussions by manually curating and interrelating chemical, gene, phenotype, anatomy, disease, taxa, and exposure content from the published literature. This curated information is integrated to generate inferences, providing potential molecular mediators to develop testable hypotheses and fill in knowledge gaps for environmental health. This dual nature, acting as both a knowledgebase and a discoverybase, makes CTD a unique resource for the scientific community. Here, we report a 20% increase in overall CTD content for 17 100 chemicals, 54 300 genes, 6100 phenotypes, 7270 diseases and 202 000 exposure statements. We also present CTD Tetramers, a novel tool that computationally generates four-unit information blocks connecting a chemical, gene, phenotype, and disease to construct potential molecular mechanistic pathways. Finally, we integrate terms for human biological media used in the CTD Exposure module to corresponding CTD Anatomy pages, allowing users to survey the chemical profiles for any tissue-of-interest and see how these environmental biomarkers are related to phenotypes for any anatomical site. These, and other webpage visual enhancements, continue to promote CTD as a practical, user-friendly, and innovative resource for finding information and generating testable hypotheses about environmental health. DA - 2022/9/28/ PY - 2022/9/28/ DO - 10.1093/nar/gkac833 SP - SN - 1362-4962 ER - TY - JOUR TI - Wildfires and extracellular vesicles: Exosomal MicroRNAs as mediators of cross-tissue cardiopulmonary responses to biomass smoke AU - Carberry, Celeste K. AU - Koval, Lauren E. AU - Payton, Alexis AU - Hartwell, Hadley AU - Kim, Yong Ho AU - Smith, Gregory J. AU - Reif, David M. AU - Jaspers, Ilona AU - Gilmour, M. Ian AU - Rager, Julia E. T2 - ENVIRONMENT INTERNATIONAL AB - Wildfires are a threat to public health world-wide that are growing in intensity and prevalence. The biological mechanisms that elicit wildfire-associated toxicity remain largely unknown. The potential involvement of cross-tissue communication via extracellular vesicles (EVs) is a new mechanism that has yet to be evaluated. Female CD-1 mice were exposed to smoke condensate samples collected from the following biomass burn scenarios: flaming peat; smoldering peat; flaming red oak; and smoldering red oak, representing lab-based simulations of wildfire scenarios. Lung tissue, bronchoalveolar lavage fluid (BALF) samples, peripheral blood, and heart tissues were collected 4 and 24 h post-exposure. Exosome-enriched EVs were isolated from plasma, physically characterized, and profiled for microRNA (miRNA) expression. Pathway-level responses in the lung and heart were evaluated through RNA sequencing and pathway analyses. Markers of cardiopulmonary tissue injury and inflammation from BALF samples were significantly altered in response to exposures, with the greatest changes occurring from flaming biomass conditions. Plasma EV miRNAs relevant to cardiovascular disease showed exposure-induced expression alterations, including miR-150, miR-183, miR-223-3p, miR-30b, and miR-378a. Lung and heart mRNAs were identified with differential expression enriched for hypoxia and cell stress-related pathways. Flaming red oak exposure induced the greatest transcriptional response in the heart, a large portion of which were predicted as regulated by plasma EV miRNAs, including miRNAs known to regulate hypoxia-induced cardiovascular injury. Many of these miRNAs had published evidence supporting their transfer across tissues. A follow-up analysis of miR-30b showed that it was increased in expression in the heart of exposed mice in the absence of changes to its precursor molecular, pri-miR-30b, suggesting potential transfer from external sources (e.g., plasma). This study posits a potential mechanism through which wildfire exposures induce cardiopulmonary responses, highlighting the role of circulating plasma EVs in intercellular and systems-level communication between tissues. DA - 2022/9// PY - 2022/9// DO - 10.1016/j.envint.2022.107419 VL - 167 SP - SN - 1873-6750 KW - Exosomes KW - Extracellular vesicles KW - Environmental exposures KW - Mixtures KW - Systems biology KW - Wildfires ER - TY - JOUR TI - Clomifene and Assisted Reproductive Technology in Humans Are Associated with Sex-Specific Offspring Epigenetic Alterations in Imprinted Control Regions AU - Lloyd, Dillon T. AU - Skinner, Harlyn G. AU - Maguire, Rachel AU - Murphy, Susan K. AU - Motsinger-Reif, Alison A. AU - Hoyo, Cathrine AU - House, John S. T2 - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES AB - 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. DA - 2022/9// PY - 2022/9// DO - 10.3390/ijms231810450 VL - 23 IS - 18 SP - SN - 1422-0067 KW - differentially methylated regions KW - adverse offspring outcomes KW - infertility ER - TY - JOUR TI - Impacts of Gestational FireMaster 550 (FM 550) Exposure on the Neonatal Cortex are Sex Specific and Largely Attributable to the Organophosphate Esters AU - Witchey, S. K. AU - Doyle, M. G. AU - Fredenburg, J. D. AU - St Armour, G. AU - Horman, B. AU - Odenkirk, M. T. AU - Aylor, D. L. AU - Baker, E. S. AU - Patisaul, H. B. T2 - NEUROENDOCRINOLOGY AB - Flame retardants (FRs) are common bodily and environmental pollutants, creating concern about their potential toxicity. We and others have found that the commercial mixture FireMaster® 550 (FM 550) or its individual brominated (BFR) and organophosphate ester (OPFR) components are potential developmental neurotoxicants. Using Wistar rats, we previously reported that developmental exposure to FM 550 or its component classes produced sex- and compound-specific effects on adult socioemotional behaviors. The underlying mechanisms driving the behavioral phenotypes are unknown.To further mechanistic understanding, here we conducted transcriptomics in parallel with a novel lipidomics approach using cortical tissues from newborn siblings of the rats in the published behavioral study. Inclusion of lipid composition is significant because it is rarely examined in developmental neurotoxicity studies. Pups were gestationally exposed via oral dosing to the dam to FM 550 or the BFR or OPFR components at environmentally relevant doses.The neonatal cortex was highly sexually dimorphic in lipid and transcriptome composition, and males were more significantly impacted by FR exposure. Multiple adverse modes of action for the BFRs and OPFRs on neurodevelopment were identified, with the OPFRs being more disruptive than the BFRs via multiple mechanisms including dysregulation of mitochondrial function and disruption of cholinergic and glutamatergic systems. Disrupted mitochondrial function by environmental factors has been linked to a higher risk of autism spectrum disorders and neurodegenerative disorders. Impacted lipid classes included ceramides, sphingomyelins, and triacylglycerides. Robust ceramide upregulation in the OPFR females could suggest a heightened risk of brain metabolic disease.This study reveals multiple mechanisms by which the components of a common FR mixture are developmentally neurotoxic and that the OPFRs may be the compounds of greatest concern. DA - 2022/9/8/ PY - 2022/9/8/ DO - 10.1159/000526959 SP - SN - 1423-0194 ER - TY - JOUR TI - A resource for integrated genomic analysis of the human liver AU - Zhou, Yi-Hui AU - Gallins, Paul J. AU - Etheridge, Amy S. AU - Jima, Dereje AU - Scholl, Elizabeth AU - Wright, Fred A. AU - Innocenti, Federico T2 - SCIENTIFIC REPORTS AB - In this study, we generated whole-transcriptome RNA-Seq from n = 192 genotyped liver samples and used these data with existing data from the GTEx Project (RNA-Seq) and previous liver eQTL (microarray) studies to create an enhanced transcriptomic sequence resource in the human liver. Analyses of genotype-expression associations show pronounced enrichment of associations with genes of drug response. The associations are primarily consistent across the two RNA-Seq datasets, with some modest variation, indicating the importance of obtaining multiple datasets to produce a robust resource. We further used an empirical Bayesian model to compare eQTL patterns in liver and an additional 20 GTEx tissues, finding that MHC genes, and especially class II genes, are enriched for liver-specific eQTL patterns. To illustrate the utility of the resource to augment GWAS analysis with small sample sizes, we developed a novel meta-analysis technique to combine several liver eQTL data sources. We also illustrate its application using a transcriptome-enhanced re-analysis of a study of neutropenia in pancreatic cancer patients. The associations of genotype with liver expression, including splice variation and its genetic associations, are made available in a searchable genome browser. DA - 2022/9/7/ PY - 2022/9/7/ DO - 10.1038/s41598-022-18506-z VL - 12 IS - 1 SP - SN - 2045-2322 ER - TY - JOUR TI - A Population-Based Human In Vitro Approach to Quantify Inter-Individual Variability in Responses to Chemical Mixtures AU - Ford, Lucie C. AU - Jang, Suji AU - Chen, Zunwei AU - Zhou, Yi-Hui AU - Gallins, Paul J. AU - Wright, Fred A. AU - Chiu, Weihsueh A. AU - Rusyn, Ivan T2 - TOXICS AB - Human cell-based population-wide in vitro models have been proposed as a strategy to derive chemical-specific estimates of inter-individual variability; however, the utility of this approach has not yet been tested for cumulative exposures in mixtures. This study aimed to test defined mixtures and their individual components and determine whether adverse effects of the mixtures were likely to be more variable in a population than those of the individual chemicals. The in vitro model comprised 146 human lymphoblastoid cell lines from four diverse subpopulations of European and African descent. Cells were exposed, in concentration−response, to 42 chemicals from diverse classes of environmental pollutants; in addition, eight defined mixtures were prepared from these chemicals using several exposure- or hazard-based scenarios. Points of departure for cytotoxicity were derived using Bayesian concentration−response modeling and population variability was quantified in the form of a toxicodynamic variability factor (TDVF). We found that 28 chemicals and all mixtures exhibited concentration−response cytotoxicity, enabling calculation of the TDVF. The median TDVF across test substances, for both individual chemicals or defined mixtures, ranged from a default assumption (101/2) of toxicodynamic variability in human population to >10. The data also provide a proof of principle for single-variant genome-wide association mapping for toxicity of the chemicals and mixtures, although replication would be necessary due to statistical power limitations with the current sample size. This study demonstrates the feasibility of using a set of human lymphoblastoid cell lines as an in vitro model to quantify the extent of inter-individual variability in hazardous properties of both individual chemicals and mixtures. The data show that population variability of the mixtures is unlikely to exceed that of the most variable component, and that similarity in genome-wide associations among components may be used to accrue additional evidence for grouping of constituents in a mixture for cumulative assessments. DA - 2022/8// PY - 2022/8// DO - 10.3390/toxics10080441 VL - 10 IS - 8 SP - SN - 2305-6304 KW - population-wide KW - inter-individual variability KW - toxicodynamics KW - chemical mixtures KW - defined mixtures KW - human health risk assessment KW - uncertainty factors KW - genome-wide association study ER - TY - JOUR TI - Grouping of UVCB Substances with Dose-Response Transcriptomics Data from Human Cell-Based Assays AU - House, John S. AU - Grimm, Fabian A. AU - Klaren, William D. AU - Dalzell, Abigail AU - Kuchi, Srikeerthana AU - Zhang, Shu-Dong AU - Lenz, Klaus AU - Boogaard, Peter J. AU - Ketelslegers, Hans B. AU - Gant, Timothy W. AU - Rusyn, Ivan AU - Wright, Fred A. T2 - ALTEX-ALTERNATIVES TO ANIMAL EXPERIMENTATION AB - 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. DA - 2022/// PY - 2022/// DO - 10.14573/altex.2107051 VL - 39 IS - 3 SP - 388-404 SN - 1868-8551 ER - TY - JOUR TI - Model systems and organisms for addressing inter- and intra-species variability in risk assessment AU - Rusyn, Ivan AU - Chiu, Weihsueh A. AU - Wright, Fred A. T2 - REGULATORY TOXICOLOGY AND PHARMACOLOGY AB - Addressing inter- and intra-species differences in potential hazardous effects of chemicals remains a long-standing challenge in human health risk assessment that is typically addressed heuristically through use of 10-fold default “uncertainty” or “safety” factors. Although it has long been recognized that chemical-specific data would be preferable to replace the “defaults,” only recently have there emerged experimental model systems and organisms with the potential to experimentally quantify the population variability in both toxicokinetics and toxicodynamics for specific chemicals. Progress is most evident in the use of population in vitro human cell-based models and population in vivo mouse models. Multiple case studies were published in the past 10–15 years that clearly demonstrate the utility of such models to derive data with direct application to quantifying variability at hazard identification, exposure-response assessment, and mechanistic understanding of toxicity steps of traditional risk assessments. Here, we review recent efforts to develop fit-for-purpose approaches utilizing these novel population-based in vitro and in vivo models in the context of risk assessment. We also describe key challenges and opportunities to broadening application of population-based experimental approaches. We conclude that population-based models are now beginning to realize their potential to address long-standing data gaps in inter- and intra-species variability. DA - 2022/7// PY - 2022/7// DO - 10.1016/j.yrtph.2022.105197 VL - 132 SP - SN - 1096-0295 ER - TY - JOUR TI - Correlation Analysis of Variables From the Atherosclerosis Risk in Communities Study AU - Mandal, Meisha AU - Levy, Josh AU - Ives, Cataia AU - Hwang, Stephen AU - Zhou, Yi-Hui AU - Motsinger-Reif, Alison AU - Pan, Huaqin AU - Huggins, Wayne AU - Hamilton, Carol AU - Wright, Fred AU - Edwards, Stephen T2 - FRONTIERS IN PHARMACOLOGY AB - The need to test chemicals in a timely and cost-effective manner has driven the development of new alternative methods (NAMs) that utilize in silico and in vitro approaches for toxicity prediction. There is a wealth of existing data from human studies that can aid in understanding the ability of NAMs to support chemical safety assessment. This study aims to streamline the integration of data from existing human cohorts by programmatically identifying related variables within each study. Study variables from the Atherosclerosis Risk in Communities (ARIC) study were clustered based on their correlation within the study. The quality of the clusters was evaluated via a combination of manual review and natural language processing (NLP). We identified 391 clusters including 3,285 variables. Manual review of the clusters containing more than one variable determined that human reviewers considered 95% of the clusters related to some degree. To evaluate potential bias in the human reviewers, clusters were also scored via NLP, which showed a high concordance with the human classification. Clusters were further consolidated into cluster groups using the Louvain community finding algorithm. Manual review of the cluster groups confirmed that clusters within a group were more related than clusters from different groups. Our data-driven approach can facilitate data harmonization and curation efforts by providing human annotators with groups of related variables reflecting the themes present in the data. Reviewing groups of related variables should increase efficiency of the human review, and the number of variables reviewed can be reduced by focusing curator attention on variable groups whose theme is relevant for the topic being studied. DA - 2022/7/11/ PY - 2022/7/11/ DO - 10.3389/fphar.2022.883433 VL - 13 SP - SN - 1663-9812 KW - cluster analysis KW - systems biology KW - meta-analysis as topic KW - ARIC KW - cardiovascular disease ER - TY - JOUR TI - Confidence bands and hypothesis tests for hit enrichment curves AU - Ash, Jeremy R. AU - Hughes-Oliver, Jacqueline M. T2 - JOURNAL OF CHEMINFORMATICS AB - Abstract In virtual screening for drug discovery, hit enrichment curves are widely used to assess the performance of ranking algorithms with regard to their ability to identify early enrichment. Unfortunately, researchers almost never consider the uncertainty associated with estimating such curves before declaring differences between performance of competing algorithms. Uncertainty is often large because the testing fractions of interest to researchers are small. Appropriate inference is complicated by two sources of correlation that are often overlooked: correlation across different testing fractions within a single algorithm, and correlation between competing algorithms. Additionally, researchers are often interested in making comparisons along the entire curve, not only at a few testing fractions. We develop inferential procedures to address both the needs of those interested in a few testing fractions, as well as those interested in the entire curve. For the former, four hypothesis testing and (pointwise) confidence intervals are investigated, and a newly developed EmProc approach is found to be most effective. For inference along entire curves, EmProc-based confidence bands are recommended for simultaneous coverage and minimal width. While we focus on the hit enrichment curve, this work is also appropriate for lift curves that are used throughout the machine learning community. Our inferential procedures trivially extend to enrichment factors, as well. DA - 2022/7/28/ PY - 2022/7/28/ DO - 10.1186/s13321-022-00629-0 VL - 14 IS - 1 SP - SN - 1758-2946 KW - Virtual screening KW - Enrichment factor KW - Lift curve KW - Early enrichment KW - Ranking algorithm KW - Empirical process ER - TY - JOUR TI - TwinEQTL: ultrafast and powerful association analysis for eQTL and GWAS in twin studies AU - Xia, Kai AU - Shabalin, Andrey A. AU - Yin, Zhaoyu AU - Chung, Wonil AU - Sullivan, Patrick F. AU - Wright, Fred A. AU - Styner, Martin AU - Gilmore, John H. AU - Santelli, Rebecca C. AU - Zou, Fei T2 - GENETICS AB - We develop a computationally efficient alternative, TwinEQTL, to a linear mixed-effects model for twin genome-wide association study data. Instead of analyzing all twin samples together with linear mixed-effects model, TwinEQTL first splits twin samples into 2 independent groups on which multiple linear regression analysis can be validly performed separately, followed by an appropriate meta-analysis-like approach to combine the 2 nonindependent test results. Through mathematical derivations, we prove the validity of TwinEQTL algorithm and show that the correlation between 2 dependent test statistics at each single-nucleotide polymorphism is independent of its minor allele frequency. Thus, the correlation is constant across all single-nucleotide polymorphisms. Through simulations, we show empirically that TwinEQTL has well controlled type I error with negligible power loss compared with the gold-standard linear mixed-effects models. To accommodate expression quantitative loci analysis with twin subjects, we further implement TwinEQTL into an R package with much improved computational efficiency. Our approaches provide a significant leap in terms of computing speed for genome-wide association study and expression quantitative loci analysis with twin samples. DA - 2022/6/11/ PY - 2022/6/11/ DO - 10.1093/genetics/iyac088 SP - SN - 1943-2631 KW - Twin KW - eQTL KW - GWAS ER - TY - JOUR TI - Genomic map of candidate human imprint control regions: the imprintome AU - Jima, Dereje D. AU - Skaar, David A. AU - Planchart, Antonio AU - Motsinger-Reif, Alison AU - Cevik, Sebnem E. AU - Park, Sarah S. AU - Cowley, Michael AU - Wright, Fred AU - House, John AU - Liu, Andy AU - Jirtle, Randy L. AU - Hoyo, Cathrine T2 - EPIGENETICS AB - 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. DA - 2022/6/25/ PY - 2022/6/25/ DO - 10.1080/15592294.2022.2091815 SP - SN - 1559-2308 KW - Epigenetics KW - genomic imprinting KW - foetal origins KW - whole genome KW - methylation KW - imprint control regions ER - TY - JOUR TI - Characterization of population variability of 1,3-butadiene derived protein adducts in humans and mice AU - Boysen, Gunnar AU - Rusyn, Ivan AU - Chiu, Weihsueh A. AU - Wright, Fred A. T2 - REGULATORY TOXICOLOGY AND PHARMACOLOGY AB - 1,3-butadiene is a known human carcinogen and a chemical to which humans are exposed occupationally and through environmental pollution. Inhalation risk assessment of 1,3-butadiene was completed several decades ago before data on molecular biomarkers of exposure and effect have been reported from both human studies of workers and experimental studies in mice. To improve risk assessment of 1,3-butadiene, the quantitative characterization of uncertainty in estimations of inter-individual variability in cancer-related effects is needed. For this, we ought to take advantage of the availability of the data on 1,3-butadiene hemoglobin adducts, well established biomarkers of the internal dose of the reactive epoxides, from several large-scale human studies and from a study in a Collaborative Cross mouse population. We found that in humans, toxicokinetic uncertainty factor for 99th percentile of the population ranged from 3.27 to 7.9, depending on the hemoglobin adduct. For mice, these values ranged from less than 2 to 7.51, depending on the dose and the adduct. Quantitative estimated from this study can be used to reduce uncertainties in the parameter estimates used in the models to derive the inhalation unit risk, as well as to address possible differences in variability in 1,3-butadiene metabolism that may be dose-related. DA - 2022/7// PY - 2022/7// DO - 10.1016/j.yrtph.2022.105171 VL - 132 SP - SN - 1096-0295 ER - TY - JOUR TI - Characterization of compositional variability in petroleum substances AU - Roman-Hubers, Alina T. AU - Cordova, Alexandra C. AU - Rohde, Arlean M. AU - Chiu, Weihsueh A. AU - McDonald, Thomas J. AU - Wright, Fred A. AU - Dodds, James N. AU - Baker, Erin S. AU - Rusyn, Ivan T2 - FUEL AB - In the process of registration of substances of Unknown or Variable Composition, Complex Reaction Products or Biological Materials (UVCBs), information sufficient to enable substance identification must be provided. Substance identification for UVCBs formed through petroleum refining is particularly challenging due to their chemical complexity, as well as variability in refining process conditions and composition of the feedstocks. This study aimed to characterize compositional variability of petroleum UVCBs both within and across product categories. We utilized ion mobility spectrometry (IMS)-MS as a technique to evaluate detailed chemical composition of independent production cycle-derived samples of 6 petroleum products from 3 manufacturing categories (heavy aromatic, hydrotreated light paraffinic, and hydrotreated heavy paraffinic). Atmospheric pressure photoionization and drift tube IMS-MS were used to identify structurally related compounds and quantified between- and within-product variability. In addition, we determined both individual molecules and hydrocarbon blocks that were most variable in samples from different production cycles. We found that detailed chemical compositional data on petroleum UVCBs obtained from IMS-MS can provide the information necessary for hazard and risk characterization in terms of quantifying the variability of the products in a manufacturing category, as well as in subsequent production cycles of the same product. DA - 2022/6/1/ PY - 2022/6/1/ DO - 10.1016/j.fuel.2022.123547 VL - 317 SP - SN - 1873-7153 KW - UVCB KW - Registration KW - Variability KW - IMS-MS ER - TY - JOUR TI - Systematic developmental toxicity assessment of a structurally diverse library of PFAS in zebrafish AU - Truong, Lisa AU - Rericha, Yvonne AU - Thunga, Preethi AU - Marvel, Skylar AU - Wallis, Dylan AU - Simonich, Michael T. AU - Field, Jennifer A. AU - Cao, Dunping AU - Reif, David M. AU - Tanguay, Robyn L. T2 - JOURNAL OF HAZARDOUS MATERIALS AB - Per- and polyfluoroalkyl substances (PFAS) are a class of widely used chemicals with limited human health effects data relative to the diversity of structures manufactured. To help fill this data gap, an extensive in vivo developmental toxicity screen was performed on 139 PFAS provided by the US EPA. Dechorionated embryonic zebrafish were exposed to 10 nominal water concentrations of PFAS (0.015–100 µM) from 6 to 120 h post-fertilization (hpf). The embryos were assayed for embryonic photomotor response (EPR), larval photomotor response (LPR), and 13 morphological endpoints. A total of 49 PFAS (35%) were bioactive in one or more assays (11 altered EPR, 25 altered LPR, and 31 altered morphology). Perfluorooctanesulfonamide (FOSA) was the only structure that was bioactive in all 3 assays, while Perfluorodecanoic acid (PFDA) was the most potent teratogen. Low PFAS volatility was associated with developmental toxicity (p < 0.01), but no association was detected between bioactivity and five other physicochemical parameters. The bioactive PFAS were enriched for 6 supergroup chemotypes. The results illustrate the power of a multi-dimensional in vivo platform to assess the developmental (neuro)toxicity of diverse PFAS and in the acceleration of PFAS safety research. DA - 2022/6/5/ PY - 2022/6/5/ DO - 10.1016/j.jhazmat.2022.128615 VL - 431 SP - SN - 1873-3336 KW - PFAS KW - Developmental toxicity KW - Structure-activity relationship KW - Abnormal behavior KW - Zebrafish ER - TY - JOUR TI - Leveraging TOPMed imputation server and constructing a cohort-specific imputation reference panel to enhance genotype imputation among cystic fibrosis patients AU - Sun, Quan AU - Liu, Weifang AU - Rosen, Jonathan D. AU - Huang, Le AU - Pace, Rhonda G. AU - Dang, Hong AU - Gallins, Paul J. AU - Blue, Elizabeth E. AU - Ling, Hua AU - Corvol, Harriet AU - Strug, Lisa J. AU - Bamshad, Michael J. AU - Gibson, Ronald L. AU - Pugh, Elizabeth W. AU - Blackman, Scott M. AU - Cutting, Garry R. AU - Wanda K. O'Neal, AU - Zhou, Yi-Hui AU - Wright, Fred A. AU - Knowles, Michael R. AU - Wen, Jia AU - Li, Yun T2 - HUMAN GENETICS AND GENOMICS ADVANCES AB - Cystic fibrosis (CF) is a severe genetic disorder that can cause multiple comorbidities affecting the lungs, the pancreas, the luminal digestive system and beyond. In our previous genome-wide association studies (GWAS), we genotyped approximately 8,000 CF samples using a mixture of different genotyping platforms. More recently, the Cystic Fibrosis Genome Project (CFGP) performed deep (approximately 30×) whole genome sequencing (WGS) of 5,095 samples to better understand the genetic mechanisms underlying clinical heterogeneity among patients with CF. For mixtures of GWAS array and WGS data, genotype imputation has proven effective in increasing effective sample size. Therefore, we first performed imputation for the approximately 8,000 CF samples with GWAS array genotype using the Trans-Omics for Precision Medicine (TOPMed) freeze 8 reference panel. Our results demonstrate that TOPMed can provide high-quality imputation for patients with CF, boosting genomic coverage from approximately 0.3-4.2 million genotyped markers to approximately 11-43 million well-imputed markers, and significantly improving polygenic risk score (PRS) prediction accuracy. Furthermore, we built a CF-specific CFGP reference panel based on WGS data of patients with CF. We demonstrate that despite having approximately 3% the sample size of TOPMed, our CFGP reference panel can still outperform TOPMed when imputing some CF disease-causing variants, likely owing to allele and haplotype differences between patients with CF and general populations. We anticipate our imputed data for 4,656 samples without WGS data will benefit our subsequent genetic association studies, and the CFGP reference panel built from CF WGS samples will benefit other investigators studying CF. DA - 2022/4/14/ PY - 2022/4/14/ DO - 10.1016/j.xhgg.2022.100090 VL - 3 IS - 2 SP - SN - 2666-2477 ER - TY - JOUR TI - ToxPi*GIS Toolkit: creating, viewing, and sharing integrative visualizations for geospatial data using ArcGIS AU - Fleming, Jonathon AU - Marvel, Skylar W. AU - Supak, Stacy AU - Motsinger-Reif, Alison A. AU - Reif, David M. T2 - JOURNAL OF EXPOSURE SCIENCE AND ENVIRONMENTAL EPIDEMIOLOGY AB - Presenting a comprehensive picture of geographic data comprising multiple factors is an inherently integrative undertaking. Visualizing such data in an interactive form is essential for public sharing and geographic information systems (GIS) analysis. The Toxicological Prioritization Index (ToxPi) framework offers a visual analytic integrating data that is compatible with geographic data. ArcGIS is a predominant geospatial software available for presenting and communicating geographic data, yet to our knowledge there is no methodology for integrating ToxPi profiles into ArcGIS maps.We introduce an actively developed suite of software, the ToxPi*GIS Toolkit, for creating, viewing, sharing, and analyzing interactive ToxPi profiles in ArcGIS to allow for new GIS analysis and an avenue for providing geospatial results to the public.The ToxPi*GIS Toolkit is a collection of methods for creating interactive feature layers that contain ToxPi profiles. It currently includes an ArcGIS Toolbox (ToxPiToolbox.tbx) for drawing location-specific ToxPi profiles in a single feature layer, a collection of modular Python scripts that create predesigned layer files containing ToxPi feature layers from the command line, and a collection of Python routines for useful data manipulation and preprocessing. We present workflows documenting ToxPi feature layer creation, sharing, and embedding for both novice and advanced users looking for additional customizability.Map visualizations created with the ToxPi*GIS Toolkit can be made freely available on public URLs, allowing users without ArcGIS Pro access or expertise to view and interact with them. Novice users with ArcGIS Pro access can create de novo custom maps, and advanced users can exploit additional customization options. The ArcGIS Toolbox provides a simple means for generating ToxPi feature layers. We illustrate its usage with current COVID-19 data to compare drivers of pandemic vulnerability in counties across the United States.The integration of ToxPi profiles with ArcGIS provides new avenues for geospatial analysis, visualization, and public sharing of multi-factor data. This allows for comparison of data across a region, which can support decisions that help address issues such as disease prevention, environmental health, natural disaster prevention, chemical risk, and many others. Development of new features, which will advance the interests of the scientific community in many fields, is ongoing for the ToxPi*GIS Toolkit, which can be accessed from www.toxpi.org . DA - 2022/4/26/ PY - 2022/4/26/ DO - 10.1038/s41370-022-00433-w VL - 4 SP - SN - 1559-064X KW - Visual analytics KW - Geographic information systems KW - Data integration ER - TY - JOUR TI - Comparison of National Vulnerability Indices Used by the Centers for Disease Control and Prevention for the COVID-19 Response AU - Wolkin, Amy AU - Collier, Sarah AU - House, John AU - Reif, David AU - Motsinger-Reif, Alison AU - Duca, Lindsey AU - Sharpe, Danielle T2 - PUBLIC HEALTH REPORTS AB - 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. Methods: We described the 3 indices, outlined the underlying data sources and metrics for each, and discussed their use by CDC for the COVID-19 response. We compared the percentile score for each county for each index by calculating Spearman correlation coefficients (Spearman ρ). Results: These indices have some, but not all, component metrics in common. The CDC-SVI is a validated metric that estimates social vulnerability, which comprises the underlying population-level characteristics that influence differences in health risk among communities. To address risk specific to the COVID-19 pandemic, the CCVI and PVI build on the CDC-SVI and include additional variables. The 3 indices were highly correlated. Spearman ρ for comparisons between the CDC-SVI score and the CCVI and between the CCVI and the PVI score was 0.83. Spearman ρ for the comparison between the CDC-SVI score and PVI score was 0.73. Conclusion: The indices can empower local and state public health officials with additional information to focus resources and interventions on disproportionately affected populations to combat the ongoing pandemic and plan for future pandemics. DA - 2022/5/5/ PY - 2022/5/5/ DO - 10.1177/00333549221090262 VL - 5 SP - SN - 1468-2877 UR - https://doi.org/10.1177/00333549221090262 KW - COVID-19 KW - vulnerability KW - social vulnerability index KW - GIS KW - geographic information systems ER - TY - JOUR TI - The Ahr2-Dependent wfikkn1 Gene Influences Zebrafish Transcriptome, Proteome, and Behavior AU - Shankar, Prarthana AU - Garcia, Gloria R. AU - LaDu, Jane K. AU - Sullivan, Christopher M. AU - Dunham, Cheryl L. AU - Goodale, Britton C. AU - Waters, Katrina M. AU - Stanisheuski, Stanislau AU - Maier, Claudia S. AU - Thunga, Preethi AU - Reif, David M. AU - Tanguay, Robyn L. T2 - TOXICOLOGICAL SCIENCES AB - The aryl hydrocarbon receptor (AHR) is required for vertebrate development and is also activated by exogenous chemicals, including polycyclic aromatic hydrocarbons (PAHs) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). AHR activation is well-understood, but roles of downstream molecular signaling events are largely unknown. From previous transcriptomics in 48 h postfertilization (hpf) zebrafish exposed to several PAHs and TCDD, we found wfikkn1 was highly coexpressed with cyp1a (marker for AHR activation). Thus, we hypothesized wfikkn1's role in AHR signaling, and showed that wfikkn1 expression was Ahr2 (zebrafish ortholog of human AHR)-dependent in developing zebrafish exposed to TCDD. To functionally characterize wfikkn1, we made a CRISPR-Cas9 mutant line with a 16-bp deletion in wfikkn1's exon, and exposed wildtype and mutants to dimethyl sulfoxide or TCDD. 48-hpf mRNA sequencing revealed over 700 genes that were differentially expressed (p < .05, log2FC > 1) between each pair of treatment combinations, suggesting an important role for wfikkn1 in altering both the 48-hpf transcriptome and TCDD-induced expression changes. Mass spectrometry-based proteomics of 48-hpf wildtype and mutants revealed 325 significant differentially expressed proteins. Functional enrichment demonstrated wfikkn1 was involved in skeletal muscle development and played a role in neurological pathways after TCDD exposure. Mutant zebrafish appeared morphologically normal but had significant behavior deficiencies at all life stages, and absence of Wfikkn1 did not significantly alter TCDD-induced behavior effects at all life stages. In conclusion, wfikkn1 did not appear to be significantly involved in TCDD's overt toxicity but is likely a necessary functional member of the AHR signaling cascade. DA - 2022/4/4/ PY - 2022/4/4/ DO - 10.1093/toxsci/kfac037 VL - 4 SP - SN - 1096-0929 KW - aryl hydrocarbon receptor (AHR) KW - zebrafish KW - TCDD KW - wfikkn1 KW - transcriptomics KW - behavior ER - TY - JOUR TI - Utilizing Pine Needles to Temporally and Spatially Profile Per- and Polyfluoroalkyl Substances (PFAS) AU - Kirkwood, Kaylie I AU - Fleming, Jonathon AU - Nguyen, Helen AU - Reif, David M. AU - Baker, Erin S. AU - Belcher, Scott M. T2 - ENVIRONMENTAL SCIENCE & TECHNOLOGY AB - As concerns over exposure to per- and polyfluoroalkyl substances (PFAS) are continually increasing, novel methods to monitor their presence and modifications are greatly needed, as some have known toxic and bioaccumulative characteristics while most have unknown effects. This task however is not simple, as the Environmental Protection Agency (EPA) CompTox PFAS list contains more than 9000 substances as of September 2020 with additional substances added continually. Nontargeted analyses are therefore crucial to investigating the presence of this immense list of possible PFAS. Here, we utilized archived and field-sampled pine needles as widely available passive samplers and a novel nontargeted, multidimensional analytical method coupling liquid chromatography, ion mobility spectrometry, and mass spectrometry (LC-IMS-MS) to evaluate the temporal and spatial presence of numerous PFAS. Over 70 PFAS were detected in the pine needles from this study, including both traditionally monitored legacy perfluoroalkyl acids (PFAAs) and their emerging replacements such as chlorinated derivatives, ultrashort chain PFAAs, perfluoroalkyl ether acids including hexafluoropropylene oxide dimer acid (HFPO-DA, "GenX") and Nafion byproduct 2, and a cyclic perfluorooctanesulfonic acid (PFOS) analog. Results from this study provide critical insight related to PFAS transport, contamination, and reduction efforts over the past six decades. DA - 2022/3/15/ PY - 2022/3/15/ DO - 10.1021/acs.est.1c06483 VL - 56 IS - 6 SP - 3441-3451 SN - 1520-5851 KW - Biomonitoring KW - contamination KW - per- and polyfluoroalkyl substances KW - fluoroethers KW - ion mobility KW - mass spectrometry KW - PFAS ER - TY - JOUR TI - Spatial and Temporal Analysis of Impacts of Hurricane Florence on Criteria Air Pollutants and Air Toxics in Eastern North Carolina AU - Bhandari, Sharmila AU - Casillas, Gaston AU - Aly, Noor A. AU - Zhu, Rui AU - Newman, Galen AU - Wright, Fred A. AU - Miller, Anthony AU - Adler, Gabriela AU - Rusyn, Ivan AU - Chiu, Weihsueh A. T2 - INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH AB - Natural and anthropogenic disasters are associated with air quality concerns due to the potential redistribution of pollutants in the environment. Our objective was to conduct a spatiotemporal analysis of air concentrations of benzene, toluene, ethylbenzne, and xylene (BTEX) and criteria air pollutants in North Carolina during and after Hurricane Florence. Three sampling campaigns were carried out immediately after the storm (September 2018) and at four-month intervals. BTEX were measured along major roads. Concurrent criteria air pollutant concentrations were predicted from modeling. Correlation between air pollutants and possible point sources was conducted using spatial regression. Exceedances of ambient air criteria were observed for benzene (in all sampling periods) and PM2.5 (mostly immediately after Florence). For both, there was an association between higher concentrations and fueling stations, particularly immediately after Florence. For other pollutants, concentrations were generally below levels of regulatory concern. Through characterization of air quality under both disaster and "normal" conditions, this study demonstrates spatial and temporal variation in air pollutants. We found that only benzene and PM2.5 were present at levels of potential concern, and there were localized increases immediately after the hurricane. These substances warrant particular attention in future disaster response research (DR2) investigations. DA - 2022/2// PY - 2022/2// DO - 10.3390/ijerph19031757 VL - 19 IS - 3 SP - SN - 1660-4601 KW - air pollution KW - geospatial analyses KW - criteria pollutants KW - volatile organic compounds ER - TY - JOUR TI - Demonstrating a systems approach for integrating disparate data streams to inform decisions on children's environmental health AU - Hubal, Elaine A. Cohen AU - DeLuca, Nicole M. AU - Mullikin, Ashley AU - Slover, Rachel AU - Little, John C. AU - Reif, David M. T2 - BMC PUBLIC HEALTH AB - The use of systems science methodologies to understand complex environmental and human health relationships is increasing. Requirements for advanced datasets, models, and expertise limit current application of these approaches by many environmental and public health practitioners.A conceptual system-of-systems model was applied for children in North Carolina counties that includes example indicators of children's physical environment (home age, Brownfield sites, Superfund sites), social environment (caregiver's income, education, insurance), and health (low birthweight, asthma, blood lead levels). The web-based Toxicological Prioritization Index (ToxPi) tool was used to normalize the data, rank the resulting vulnerability index, and visualize impacts from each indicator in a county. Hierarchical clustering was used to sort the 100 North Carolina counties into groups based on similar ToxPi model results. The ToxPi charts for each county were also superimposed over a map of percentage county population under age 5 to visualize spatial distribution of vulnerability clusters across the state.Data driven clustering for this systems model suggests 5 groups of counties. One group includes 6 counties with the highest vulnerability scores showing strong influences from all three categories of indicators (social environment, physical environment, and health). A second group contains 15 counties with high vulnerability scores driven by strong influences from home age in the physical environment and poverty in the social environment. A third group is driven by data on Superfund sites in the physical environment.This analysis demonstrated how systems science principles can be used to synthesize holistic insights for decision making using publicly available data and computational tools, focusing on a children's environmental health example. Where more traditional reductionist approaches can elucidate individual relationships between environmental variables and health, the study of collective, system-wide interactions can enable insights into the factors that contribute to regional vulnerabilities and interventions that better address complex real-world conditions. DA - 2022/2/15/ PY - 2022/2/15/ DO - 10.1186/s12889-022-12682-3 VL - 22 IS - 1 SP - SN - 1471-2458 KW - Chemical exposure KW - ANOVA KW - ToxPi KW - Children's health KW - Environmental health KW - Systems approach KW - Multivariate analysis KW - Data-driven ER - TY - JOUR TI - Fast Multivariate Probit Estimation via a Two-Stage Composite Likelihood AU - Ting, Bryan AU - Wright, Fred AU - Zhou, Yi-Hui T2 - STATISTICS IN BIOSCIENCES AB - Abstract The multivariate probit is popular for modeling correlated binary data, with an attractive balance of flexibility and simplicity. However, considerable challenges remain in computation and in devising a clear statistical framework. Interest in the multivariate probit has increased in recent years. Current applications include genomics and precision medicine, where simultaneous modeling of multiple traits may be of interest, and computational efficiency is an important consideration. We propose a fast method for multivariate probit estimation via a two-stage composite likelihood. We explore computational and statistical efficiency, and note that the approach sets the stage for extensions beyond the purely binary setting. DA - 2022/2/15/ PY - 2022/2/15/ DO - 10.1007/s12561-022-09338-6 SP - SN - 1867-1772 KW - Composite KW - Likelihood KW - Multivariate KW - Probit KW - Two-stage KW - Two-step ER -