@article{newell_kapps_cai_rai_st armour_horman_rock_witchey_greenbaum_patisaul_2023, title={Maternal organophosphate flame retardant exposure alters the developing mesencephalic dopamine system in fetal rat}, volume={191}, ISSN={["1096-0929"]}, DOI={10.1093/toxsci/kfac137}, abstractNote={Organophosphate flame retardants (OFPRs) have become the predominant substitution for legacy brominated flame retardants but there is concern about their potential developmental neurotoxicity (DNT). OPFRs readily dissociate from the fireproofed substrate to the environment, and they (or their metabolites) have been detected in diverse matrices including air, water, soil, and biota, including human urine and breastmilk. Given this ubiquitous contamination, it becomes increasingly important to understand the potential effects of OPFRs on the developing nervous system. We have previously shown that maternal exposure to OPFRs results in neuroendocrine disruption, alterations to developmental metabolism of serotonin (5-HT) and axonal extension in male fetal rats, and potentiates adult anxiety-like behaviors. The development of the serotonin and dopamine systems occur in parallel and interact, therefore, we first sought to enhance our prior 5-HT work by first examining the ascending 5-HT system on embryonic day 14 using whole mount clearing of fetal heads and 3D brain imaging. We also investigated the effects of maternal OPFR exposure on the development of the mesocortical dopamine system in the same animals through 2D and 3D analysis following immunohistochemistry for tyrosine hydroxylase (TH). Maternal OPFR exposure induced morphological changes to the putative ventral tegmental area and substantia nigra in both sexes and reduced the overall volume of this structure in males, while 5-HT nuclei were unchanged. Additionally, dopaminergic axogenesis was disrupted in OPFR exposed animals, as the dorsoventral spread of ventral telencephalic TH afferents were greater at embryonic day 14, while sparing 5-HT fibers. These results indicate maternal exposure to OPFRs alters the development trajectory of the embryonic dopaminergic system and adds to growing evidence of OPFR developmental neurotoxicity.}, number={2}, journal={TOXICOLOGICAL SCIENCES}, author={Newell, Andrew J. and Kapps, Victoria A. and Cai, Yuheng and Rai, Mani Ratnam and St Armour, Genevieve and Horman, Brian M. and Rock, Kylie D. and Witchey, Shannah K. and Greenbaum, Alon and Patisaul, Heather B.}, year={2023}, month={Feb}, pages={357–373} }
 @article{schkoda_horman_witchey_jansson_macari_patisaul_2023, title={Skeletal effects following developmental flame-retardant exposure are specific to sex and chemical class in the adult Wistar rat}, volume={5}, ISSN={["2673-3080"]}, DOI={10.3389/ftox.2023.1216388}, abstractNote={Introduction: Accumulating evidence reveals that endocrine disrupting chemicals (EDCs) can disrupt aspects of metabolic programming, suggesting that skeletal development may be at risk, a possibility that is rarely examined. The commercial flame retardant (FR) mixture, Firemaster 550 (FM 550), has repeatedly been shown to negatively influence metabolic programming, raising concerns that skeletal integrity may consequently be impaired. We have previously shown that gestational and lactational exposure to 1,000 µg FM 550 negatively affected sex-specific skeletal traits in male, but not female, rats assessed at 6 months of age. Whether this outcome is primarily driven by the brominated (BFR) or organophosphate ester (OPFR) portions of the mixture or the effects persist to older ages is unknown. Materials and methods: To address this, in the present study, dams were orally exposed throughout gestation and lactation to either 1,000 μg BFR, 1,000 µg OPFR, or 2,000 µg FM 550. Offspring (n = 8/sex/exposure) were weaned at PND 21 and assessed for femoral cortical and trabecular bone parameters at 8 months of age by high-resolution X-ray micro-computed tomography (micro-CT). Serum levels of serotonin, osteocalcin, alkaline phosphatase, and calcium were quantified. Results: FM 550 affected both sexes, but the females were more appreciably impacted by the OPFRs, while the males were more vulnerable to the BFRs. Conclusion: Although sex specificity was expected due to the sexual dimorphic nature of skeletal physiology, the mechanisms accounting for the male- and female-specific phenotypes remain to be determined. Future work aims to clarify these unresolved issues.}, journal={FRONTIERS IN TOXICOLOGY}, author={Schkoda, Stacy and Horman, Brian and Witchey, Shannah K. and Jansson, Anton and Macari, Soraia and Patisaul, Heather B.}, year={2023}, month={Jul} }
 @article{witchey_doyle_fredenburg_st armour_horman_odenkirk_aylor_baker_patisaul_2022, title={Impacts of Gestational FireMaster 550 (FM 550) Exposure on the Neonatal Cortex are Sex Specific and Largely Attributable to the Organophosphate Esters}, volume={9}, ISSN={["1423-0194"]}, DOI={10.1159/000526959}, abstractNote={Introduction: 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. Methods: 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. Results: 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. Conclusions: 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.}, journal={NEUROENDOCRINOLOGY}, author={Witchey, S. K. and Doyle, M. G. and Fredenburg, J. D. and St Armour, G. and Horman, B. and Odenkirk, M. T. and Aylor, D. L. and Baker, E. S. and Patisaul, H. B.}, year={2022}, month={Sep} }
 @article{witchey_al samara_horman_stapleton_patisaula_2020, title={Perinatal exposure to FireMaster (R) 550 (FM550), brominated or organophosphate flame retardants produces sex and compound specific effects on adult Wistar rat socioemotional behavior}, volume={126}, ISSN={["1095-6867"]}, DOI={10.1016/j.yhbeh.2020.104853}, abstractNote={Firemaster 550 (FM550) is a flame retardant (FR) mixture that has become one of the most commonly used FRs in household items such as foam-based furniture and baby products. Because this mixture readily leaches from products, contamination of the environment and human tissues is widespread. Prior work by us and others has reported sex-specific behavioral deficits in rodents and zebrafish following early life exposure. In an effort to understand the mechanisms by which these behavioral effects occur, here we explored the effects of its constituents on behavioral outcomes previously shown to be altered by developmental FM550 exposure. The FM550 commercial mixture is composed of two brominated compounds (BFR) and two organophosphate compounds (OPFRs) at almost equivalent proportions. Both the BFR and the OPFR components are differentially metabolized and structurally distinct, but similar to known neurotoxicants. Here we examined adult Wistar rat offspring socioemotional behaviors following perinatal exposure (oral, to the dam) to vehicle, 2000 μg/day FM550, 1000 μg/day BFR or 1000 μg/day OPFR from gestation day 0 to weaning. Beginning on postnatal day 65 offspring from all groups were subjected to a series of behavioral tasks including open field, elevated plus maze, marble burying, social interaction tests, and running wheel. Effects were exposure-, sex- and task-specific, with BFR exposure resulting in the most consistent behavioral deficits. Overall, exposed females showed more deficits compared to males across all dose groups and tasks. These findings help elucidate how different classes of flame retardants, independently and as a mixture, contribute to sex-specific behavioral effects of exposure.}, journal={HORMONES AND BEHAVIOR}, author={Witchey, Shannah K. and Al Samara, Loujain and Horman, Brian M. and Stapleton, Heather M. and Patisaula, Heather B.}, year={2020}, month={Nov} }
 @article{witchey_fuchs_patisaul_2019, title={Perinatal bisphenol A (BPA) exposure alters brain oxytocin receptor (OTR) expression in a sex- and region- specific manner: A CLARITY-BPA consortium follow-up study}, volume={74}, ISSN={["1872-9711"]}, DOI={10.1016/j.neuro.2019.06.007}, abstractNote={Bisphenol A (BPA) is a well-characterized endocrine disrupting chemical (EDC) used in plastics, epoxy resins and other products. Neurodevelopmental effects of BPA exposure are a major concern with multiple rodent and human studies showing that early life BPA exposure may impact the developing brain and sexually dimorphic behaviors. The CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity) program was established to assess multiple endpoints, including neural, across a wide dose range. Studies from our lab as part of (and prior to) CLARITY-BPA have shown that BPA disrupts estrogen receptor expression in the developing brain, and some evidence of oxytocin (OT) and oxytocin receptor (OTR) disruption in the hypothalamus and amygdala. While BPA disruption of steroid hormone function is well documented, less is known about its capacity to alter nonapeptide signals. In this CLARITY-BPA follow up study, we used remaining juvenile rat tissues to test the hypothesis that developmental BPA exposure affects OTR expression across the brain. Perinatal BPA exposure (2.5, 25, or 2500 μg/kg body weight (bw)/day) spanned gestation and lactation with dams gavaged from gestational day 6 until birth and then the offspring gavaged directly through weaning. Ethinyl estradiol (0.5 μg/kg bw/day) was used as a reference estrogen. Animals of both sexes were sacrificed as juveniles and OTR expression assessed by receptor binding. Our results demonstrate prenatal exposure to BPA can eliminate sex differences in OTR expression in three hypothalamic regions, and that male OTR expression may be more susceptible. Our data also identify a sub-region of the BNST with sexually dimorphic OTR expression not previously reported in juvenile rats that is also susceptible to BPA.}, journal={NEUROTOXICOLOGY}, author={Witchey, Shannah K. and Fuchs, Joelle and Patisaul, Heather B.}, year={2019}, month={Sep}, pages={139–148} }