@article{guillette_jackson_guillette_mccord_belcher_2022, title={Blood concentrations of per- and polyfluoroalkyl substances are associated with autoimmune-like effects in American alligators from Wilmington, North Carolina}, volume={4}, ISSN={["2673-3080"]}, url={http://dx.doi.org/10.3389/ftox.2022.1010185}, DOI={10.3389/ftox.2022.1010185}, abstractNote={Surface and groundwater of the Cape Fear River basin in central and coastal North Carolina is contaminated with high levels of per- and polyfluoroalkyl substances (PFAS). Elevated levels of PFAS have also been found in blood of fish and wildlife from the Cape Fear River, and in the blood of human populations reliant on contaminated well or surface water from the Cape Fear River basin as a source of drinking water. While the public and environmental health impacts of long-term PFAS exposures are poorly understood, elevated blood concentrations of some PFAS are linked with immunotoxicity and increased incidence of some chronic autoimmune diseases in human populations. The goal of this One Environmental Health study was to evaluate PFAS exposure and biomarkers related to immune health in populations of American alligators (Alligator mississippiensis), a protected and predictive sentinel species of adverse effects caused by persistent toxic pollutants. We found that serum PFAS concentrations in alligator populations from the Cape Fear River were increased compared to a reference population of alligators from the adjoining Lumber River basin. The elevated serum PFAS concentrations in the Cape Fear River alligators were associated with increased innate immune activities, and autoimmune-like phenotypes in this population. In addition to evidence of significantly higher double stranded-DNA binding autoantibodies in adult Cape Fear River alligators, our qRT-PCR analysis found remarkably high induction of Interferon-α signature genes implicated in the pathology of human autoimmune disease. We interpret the association of increased PFAS exposure with disrupted immune functions to suggest that PFAS broadly alters immune activities resulting in autoimmune-like pathology in American alligators. This work substantiates and extends evidence from experimental models and human epidemiology studies showing that some PFAS are immune toxicants.}, journal={FRONTIERS IN TOXICOLOGY}, publisher={Frontiers Media SA}, author={Guillette, T. C. and Jackson, Thomas W. and Guillette, Matthew and McCord, James and Belcher, Scott M.}, year={2022}, month={Oct} }
 @article{jackson_baars_belcher_2022, title={Gestational Cd Exposure in the CD-1 Mouse Sex-Specifically Disrupts Essential Metal Ion Homeostasis}, volume={2}, ISSN={["1096-0929"]}, url={https://doi.org/10.1093/toxsci/kfac027}, DOI={10.1093/toxsci/kfac027}, abstractNote={Abstract In CD-1 mice, gestational-only exposure to cadmium (Cd) causes female-specific hepatic insulin resistance, metabolic disruption, and obesity. To evaluate whether sex differences in uptake and changes in essential metal concentrations contribute to metabolic outcomes, placental and liver Cd and essential metal concentrations were quantified in male and female offspring perinatally exposed to 500 ppb CdCl2. Exposure resulted in increased maternal liver Cd+2 concentrations (364 µg/kg) similar to concentrations found in non-occupationally exposed human liver. At gestational day (GD) 18, placental Cd and manganese concentrations were significantly increased in exposed males and females, and zinc was significantly decreased in females. Placental efficiency was significantly decreased in GD18-exposed males. Increases in hepatic Cd concentrations and a transient prenatal increase in zinc were observed in exposed female liver. Fetal and adult liver iron concentrations were decreased in both sexes, and decreases in hepatic zinc, iron, and manganese were observed in exposed females. Analysis of GD18 placental and liver metallothionein mRNA expression revealed significant Cd-induced upregulation of placental metallothionein in both sexes, and a significant decrease in fetal hepatic metallothionein in exposed females. In placenta, expression of metal ion transporters responsible for metal ion uptake was increased in exposed females. In liver of exposed adult female offspring, expression of the divalent cation importer (Slc39a14/Zip14) decreased, whereas expression of the primary exporter (Slc30a10/ZnT10) increased. These findings demonstrate that Cd can preferentially cross the female placenta, accumulate in the liver, and cause lifelong dysregulation of metal ion concentrations associated with metabolic disruption.}, journal={TOXICOLOGICAL SCIENCES}, publisher={Oxford University Press (OUP)}, author={Jackson, Thomas W. and Baars, Oliver and Belcher, Scott M.}, year={2022}, month={Feb} }
 @article{jackson_scheibly_polera_belcher_2021, title={Rapid Characterization of Human Serum Albumin Binding for Per- and Polyfluoroalkyl Substances Using Differential Scanning Fluorimetry}, volume={55}, ISSN={["1520-5851"]}, url={https://doi.org/10.1021/acs.est.1c01200}, DOI={10.1021/acs.est.1c01200}, abstractNote={Per- and polyfluoroalkyl substances (PFAS) are a diverse class of synthetic chemicals that accumulate in the environment. Many proteins, including the primary human serum transport protein albumin (HSA), bind PFAS. The predictive power of physiologically based pharmacokinetic modeling approaches is currently limited by a lack of experimental data defining albumin-binding properties for most PFAS. A novel thermal denaturation assay was optimized to evaluate changes in the thermal stability of HSA in the presence of increasing concentrations of known ligands and a structurally diverse set of PFAS. Assay performance was initially evaluated for fatty acids and HSA-binding drugs ibuprofen and warfarin. Concentration-response relationships were determined and dissociation constants (Kd) for each compound were calculated using regression analysis of the dose-dependent changes in HSA melting temperature. Estimated Kd values for HSA binding of octanoic acid, decanoic acid, hexadecenoic acid, ibuprofen, and warfarin agreed with established values. The binding affinities for 24 PFAS that included perfluoroalkyl carboxylic acids (C4-C12), perfluoroalkyl sulfonic acids (C4-C8), mono- and polyether perfluoroalkyl ether acids, and polyfluoroalkyl fluorotelomer substances were determined. These results demonstrate the utility of this differential scanning fluorimetry assay as a rapid high-throughput approach for determining the relative protein-binding properties and identification of chemical structures involved in binding for large numbers of structurally diverse PFAS.}, number={18}, journal={ENVIRONMENTAL SCIENCE & TECHNOLOGY}, publisher={American Chemical Society (ACS)}, author={Jackson, Thomas W. and Scheibly, Chris M. and Polera, M. E. and Belcher, Scott M.}, year={2021}, month={Sep}, pages={12291–12301} }
 @article{jackson_ryherd_scheibly_sasser_guillette_belcher_2020, title={Gestational Cd Exposure in the CD-1 Mouse Induces Sex-Specific Hepatic Insulin Insensitivity, Obesity, and Metabolic Syndrome in Adult Female Offspring}, volume={178}, ISSN={["1096-0929"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85097035964&partnerID=MN8TOARS}, DOI={10.1093/toxsci/kfaa154}, abstractNote={There is compelling evidence that developmental exposure to toxic metals increases risk for obesity and obesity-related morbidity including cardiovascular disease and type 2 diabetes. To explore the hypothesis that developmental Cd exposure increases risk of obesity later in life, male, and female CD-1 mice were maternally exposed to 500 ppb CdCl2 in drinking water during a human gestational equivalent period (gestational day 0-postnatal day 10 [GD0-PND10]). Hallmark indicators of metabolic disruption, hepatic steatosis, and metabolic syndrome were evaluated prior to birth through adulthood. Maternal blood Cd levels were similar to those observed in human pregnancy cohorts, and Cd was undetected in adult offspring. There were no observed impacts of exposure on dams or pregnancy-related outcomes. Results of glucose and insulin tolerance testing revealed that Cd exposure impaired offspring glucose homeostasis on PND42. Exposure-related increases in circulating triglycerides and hepatic steatosis were apparent only in females. By PND120, Cd-exposed females were 30% heavier with 700% more perigonadal fat than unexposed control females. There was no evidence of dyslipidemia, steatosis, increased weight gain, nor increased adiposity in Cd-exposed male offspring. Hepatic transcriptome analysis on PND1, PND21, and PND42 revealed evidence for female-specific increases in oxidative stress and mitochondrial dysfunction with significant early disruption of retinoic acid signaling and altered insulin receptor signaling consistent with hepatic insulin sensitivity in adult females. The observed steatosis and metabolic syndrome-like phenotypes resulting from exposure to 500 ppb CdCl2 during the pre- and perinatal period of development equivalent to human gestation indicate that Cd acts developmentally as a sex-specific delayed obesogen.}, number={2}, journal={TOXICOLOGICAL SCIENCES}, author={Jackson, Thomas W. and Ryherd, Garret L. and Scheibly, Chris M. and Sasser, Aubrey L. and Guillette, T. C. and Belcher, Scott M.}, year={2020}, month={Dec}, pages={264–280} }
 @article{jackson_bendfeldt_beam_rock_belcher_2020, title={Heterozygous mutation of sonic hedgehog receptor (Ptch1) drives cerebellar overgrowth and sex-specifically alters hippocampal and cortical layer structure, activity, and social behavior in female mice}, volume={78}, ISSN={["1872-9738"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85080064843&partnerID=MN8TOARS}, DOI={10.1016/j.ntt.2020.106866}, abstractNote={Sonic hedgehog (SHH) signaling is essential for the differentiation and migration of early stem cell populations during cerebellar development. Dysregulation of SHH-signaling can result in cerebellar overgrowth and the formation of the brain tumor medulloblastoma. Treatment for medulloblastoma is extremely aggressive and patients suffer life-long side effects including behavioral deficits. Considering that other behavioral disorders including autism spectrum disorders, holoprosencephaly, and basal cell nevus syndrome are known to present with cerebellar abnormalities, it is proposed that some behavioral abnormalities could be inherent to the medulloblastoma sequalae rather than treatment. Using a haploinsufficient SHH receptor knockout mouse model (Ptch1+/−), a partner preference task was used to explore activity, social behavior and neuroanatomical changes resulting from dysregulated SHH signaling. Compared to wild-type, Ptch1+/− females displayed increased activity by traveling a greater distance in both open-field and partner preference tasks. Social behavior was also sex-specifically modified in Ptch1+/− females that interacted more with both novel and familiar animals in the partner preference task compared to same-sex wild-type controls. Haploinsufficiency of PTCH1 resulted in cerebellar overgrowth in lobules IV/V and IX of both sexes, and female-specific decreases in hippocampal size and isocortical layer thickness. Taken together, neuroanatomical changes related to deficient SHH signaling may alter social behavior.}, journal={NEUROTOXICOLOGY AND TERATOLOGY}, author={Jackson, Thomas W. and Bendfeldt, Gabriel A. and Beam, Kelby A. and Rock, Kylie D. and Belcher, Scott M.}, year={2020} }
 @article{guillette_jackson_belcher_2018, title={Duality of estrogen receptor beta action in cancer progression}, volume={41}, ISSN={["1471-4973"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85047091078&partnerID=MN8TOARS}, DOI={10.1016/j.coph.2018.05.001}, abstractNote={The physiological actions of estrogens are primarily mediated by the nuclear hormone receptors estrogen receptor alpha (ERα) and beta (ERβ). Activities of these nuclear steroid hormone receptors in etiology and progression of many hormone-responsive cancers are well-established, yet the specific role of each receptor, and their various expressed isoforms, in estrogen-responsive cancers remains unclear. Recent advances in nuclear receptor profiling, characterization of expressed splice variants, and the availability of new experimental cancer models, has extended the understanding of the complex interplay between the differentially expressed nuclear estrogen receptors. In this review, we discuss proposed roles of ERβ in several subtypes of cancers that lack significant ERα expression and define current understanding of how different ERs collaborate to regulate cellular processes.}, journal={CURRENT OPINION IN PHARMACOLOGY}, author={Guillette, T. C. and Jackson, Thomas W. and Belcher, Scott M.}, year={2018}, month={Aug}, pages={66–73} }