@article{siegler_shaughnessy_horman_vierling_king_patisaul_huhman_alexander_dudek_2024, title={Identification of hippocampal area CA2 in hamster and vole brain}, volume={532}, ISSN={["1096-9861"]}, DOI={10.1002/cne.25603}, abstractNote={AbstractPrairie voles (Microtus ochrogaster) and Syrian, or golden, hamsters (Mesocricetus auratus) are closely related to mice (Mus musculus) and are commonly used in studies of social behavior including social interaction, social memory, and aggression. Hippocampal area CA2 is known to play a key role in these behaviors in mice and responds to social stimuli in rats, but CA2 has yet to be characterized in hamsters or voles, which are also used in studies of social behaviors. Here, we used immunofluorescence to determine whether CA2 could be molecularly identified in tissue from voles and hamsters. We found that  staining for many CA2 markers was similar in these three species, with labeling seen in neurons at the distal end of the mossy fibers . In contrast, although perineuronal nets (PNNs) surround CA2 cells in mice, PNN staining differed across species. In voles, both CA2 and CA3 were labeled, whereas in hamsters, labeling was seen primarily in CA3. These results demonstrate that CA2 can be molecularly distinguished from neighboring CA1 and CA3 areas in voles and hamsters with several antibodies commonly used in mice. However, PNN staining is not useful for identifying CA2 in voles or hamsters, suggestive of differing roles for either PNNs or for the hippocampal subregions in social behavior. These findings reveal commonalities across species in the molecular profile of CA2 and should facilitate future studies of CA2 in these species.}, number={3}, journal={JOURNAL OF COMPARATIVE NEUROLOGY}, author={Siegler, Preston N. and Shaughnessy, Emma K. and Horman, Brian and Vierling, Tia T. and King, Darron H. and Patisaul, Heather B. and Huhman, Kim L. and Alexander, Georgia M. and Dudek, Serena M.}, year={2024}, month={Mar} }
 @article{schkoda_horman_witchey_armour_nelson_gaeta_scott_patisaul_2024, title={Sex-specific effects on elements of the social brain neural network in Wistar rats from perinatal exposure to FireMaster 550 or its components}, volume={105}, ISSN={["1872-9711"]}, DOI={10.1016/j.neuro.2024.09.001}, abstractNote={Developmental exposure to chemical flame retardants (FRs) has been linked to a variety of neurodevelopmental disorders and abnormal socioemotional behaviors in human and laboratory animal studies. We have previously shown in Wistar rats that gestational and lactational exposure to the FR mixture Firemaster 550 (FM 550) or its brominated or organophosphate ester (OPFR) components (at 2000 µg, 1000 µg, and 1000 µg oral to the dam respectively (absolute and not by bodyweight)) results in increased anxiety-like behaviors in females and decreased sociality in both sexes. Using their siblings, this study characterized sex and chemical specific targets of disruption in brain regions underlying each behavioral phenotype. Offspring were exposed across gestation and lactation then prepared for either immunohistochemistry or autoradiography at postnatal day 90 to quantify expression of serotonin, estrogen receptor α (ERα), and oxytocin receptor (OTR) in multiple brain regions. No effect of exposure was found in males for any biological target. In females, serotonin innervation was increased in the medial amygdala of FM 550 exposed animals while ERα expression in the bed nucleus of the stria terminalis (BNST) was reduced by FM 550 and OPFR. Evidence of disrupted OTR was observed in males, particularly the BNST but considered an exploratory finding given the small sample size. These results begin to shed light on the mechanisms by which developmental FR exposure alters socioemotional behaviors of relevance to neurodevelopmental disorders.}, journal={NEUROTOXICOLOGY}, author={Schkoda, Stacy and Horman, Brian and Witchey, Shannah and Armour, Genevieve St. and Nelson, Mason and Gaeta, Emily and Scott, Madeline and Patisaul, Heather B.}, year={2024}, month={Dec}, pages={111–120} }
 @article{marinello_gillera_han_richardson_st armour_horman_patisaul_2023, title={Gestational exposure to FireMaster® 550 (FM 550) disrupts the placenta-brain axis in a socially monogamous rodent species, the prairie vole (<i>Microtus ochrogaster</i>)}, volume={576}, ISSN={["1872-8057"]}, DOI={10.1016/j.mce.2023.112041}, abstractNote={Gestational flame retardant (FR) exposure has been linked to heightened risk of neurodevelopmental disorders, but the mechanisms remain largely unknown. Historically, toxicologists have relied on traditional, inbred rodent models, yet those do not always best model human vulnerability or biological systems, especially social systems. Here we used prairie voles (Microtus ochrogaster), a monogamous and bi-parental rodent, leveraged for decades to decipher the underpinnings of social behaviors, to examine the impact of fetal FR exposure on gene targets in the mid-gestational placenta and fetal brain. We previously established gestational exposure to the commercial mixture Firemaster 550 (FM 550) impairs sociality, particularly in males. FM 550 exposure disrupted placental monoamine production, particularly serotonin, and genes required for axon guidance and cellular respiration in the fetal brains. Effects were dose and sex specific. These data provide insights on the mechanisms by which FRs impair neurodevelopment and later in life social behaviors.}, journal={MOLECULAR AND CELLULAR ENDOCRINOLOGY}, author={Marinello, William P. and Gillera, Sagi Enicole A. and Han, Yoonhee and Richardson, Jason R. and St Armour, Genevieve and Horman, Brian M. and Patisaul, Heather B.}, year={2023}, month={Oct} }
 @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{marinello_gillera_fanning_malinsky_rhodes_horman_patisaul_2022, title={Effects of developmental exposure to FireMaster (R) 550 (FM 550) on microglia density, reactivity and morphology in a prosocial animal model}, volume={91}, ISSN={["1872-9711"]}, url={http://dx.doi.org/10.1016/j.neuro.2022.04.015}, DOI={10.1016/j.neuro.2022.04.015}, abstractNote={Microglia are known to shape brain sex differences critical for social and reproductive behaviors. Chemical exposures can disrupt brain sexual differentiation but there is limited data regarding how they may impact microglia distribution and function. We focused on the prevalent flame retardant mixture Firemaster 550 (FM 550) which is used in foam-based furniture and infant products including strollers and nursing pillows because it disrupts sexually dimorphic behaviors. We hypothesized early life FM 550 exposure would disrupt microglial distribution and reactivity in brain regions known to be highly sexually dimorphic or associated with social disorders in humans. We used prairie voles (Microtus ochrogaster) because they display spontaneous prosocial behaviors not seen in rats or mice and are thus a powerful model for studying chemical exposure-related impacts on social behaviors and their underlying neural systems. We have previously demonstrated that perinatal FM 550 exposure sex-specifically impacts socioemotional behaviors in prairie voles. We first established that, unlike in rats, the postnatal colonization of the prairie vole brain is not sexually dimorphic. Vole dams were then exposed to FM 550 (0, 500, 1000, 2000 µg/day) via subcutaneous injections through gestation, and pups were directly exposed beginning the day after birth until weaning. Adult offspring’s brains were assessed for number and type (ramified, intermediate, ameboid) of microglia in the medial prefrontal cortex (mPFC), cerebellum (lobules VI-VII) and amygdala. Effects were sex- and dose-specific in the regions of interests. Overall, FM 550 exposure resulted in reduced numbers of microglia in most regions examined, with the 1000 µg FM 550 exposed males particularly affected. To further quantify differences in microglia morphology in the 1000 µg FM 550 group, Sholl and skeleton analysis were carried out on individual microglia. Microglia from control females had a more ramified phenotype compared to control males while 1000 µg FM 550-exposed males had decreased branching and ramification compared to same-sex controls. Future studies will examine the impact on the exposure to FM 550 on microglia during development given the critical role of these cells in shaping neural circuits.}, journal={NEUROTOXICOLOGY}, publisher={Elsevier BV}, author={Marinello, William P. and Gillera, Sagi Enicole A. and Fanning, Marley J. and Malinsky, Lacey B. and Rhodes, Cassie L. and Horman, Brian M. and Patisaul, Heather B.}, year={2022}, month={Jul}, pages={140–154} }
 @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={<b><i>Introduction:</i></b> 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. <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> 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. <b><i>Conclusions:</i></b> 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{gillera_marinello_nelson_horman_patisaul_2022, title={Individual and Combined Effects of Paternal Deprivation and Developmental Exposure to Firemaster 550 on Socio-Emotional Behavior in Prairie Voles}, volume={10}, ISSN={["2305-6304"]}, url={https://doi.org/10.3390/toxics10050268}, DOI={10.3390/toxics10050268}, abstractNote={The prevalence of neurodevelopmental disorders (NDDs) is rapidly rising, suggesting a confluence of environmental factors that are likely contributing, including developmental exposure to environmental contaminants. Unfortunately, chemical exposures and social stressors frequently occur simultaneously in many communities, yet very few studies have sought to establish the combined effects on neurodevelopment or behavior. Social deficits are common to many NDDs, and we and others have shown that exposure to the chemical flame retardant mixture, Firemaster 550 (FM 550), or paternal deprivation impairs social behavior and neural function. Here, we used a spontaneously prosocial animal model, the prairie vole (Microtus ochrogaster), to explore the effects of perinatal chemical (FM 550) exposure alone or in combination with an early life stressor (paternal absence) on prosocial behavior. Dams were exposed to vehicle (sesame oil) or 1000 µg FM 550 orally via food treats from conception through weaning and the paternal absence groups were generated by removing the sires the day after birth. Adult offspring of both sexes were then subjected to open-field, sociability, and a partner preference test. Paternal deprivation (PD)-related effects included increased anxiety, decreased sociability, and impaired pair-bonding in both sexes. FM 550 effects include heightened anxiety and partner preference in females but reduced partner preference in males. The combination of FM 550 exposure and PD did not exacerbate any behaviors in either sex except for distance traveled by females in the partner preference test and, to a lesser extent, time spent with, and the number of visits to the non-social stimulus by males in the sociability test. FM 550 ameliorated the impacts of parental deprivation on partner preference behaviors in both sexes. This study is significant because it provides evidence that chemical and social stressors can have unique behavioral effects that differ by sex but may not produce worse outcomes in combination.}, number={5}, journal={TOXICS}, author={Gillera, Sagi Enicole A. and Marinello, William P. and Nelson, Mason A. and Horman, Brian M. and Patisaul, Heather B.}, year={2022}, month={May} }
 @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={AbstractOrganophosphate flame retardants (OPFRs) 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 3-dimensional (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 2-dimensional 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, whereas 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 DNT.}, 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{krentzel_kimble_dorris_horman_meitzen_patisaul_2021, title={FireMaster (R) 550 (FM 550) exposure during the perinatal period impacts partner preference behavior and nucleus accumbens core medium spiny neuron electrophysiology in adult male and female prairie voles, Microtus ochrogaster}, volume={134}, ISSN={["1095-6867"]}, DOI={10.1016/j.yhbeh.2021.105019}, abstractNote={One of the most widely used flame retardant (FR) mixtures in household products is Firemaster 550 (FM 550). FM 550 leaches from items such as foam-based furniture and infant products, resulting in contamination of the household environment and biota. Previous studies indicate sex-specific behavioral deficits in rodents and zebrafish in response to developmental FM 550 exposure. These deficits include impacts on social and attachment behaviors in a prosocial rodent: the prairie vole (Microtus ochrogaster). The prairie vole is a laboratory-acclimated rodent that exhibits spontaneous attachment behaviors including pair bonding. Here we extend previous work by addressing how developmental exposure to FM 550 impacts pair bonding strength via an extended-time partner preference test, as well as neuron electrophysiological properties in a region implicated in pair bond behavior, the nucleus accumbens (NAcc) core. Dams were exposed to vehicle or 1000 μg of FM 550 via subcutaneous injections throughout gestation, and female and male pups were directly exposed beginning the day after birth until weaning. Pair bond behavior of adult female and male offspring was assessed using a three hour-long partner preference test. Afterwards, acute brain slices of the NAcc core were produced and medium spiny neuron electrophysiological attributes recorded via whole cell patch-clamp. Behavioral impacts were sex-specific. Partner preference behavior was increased in exposed females but decreased in exposed males. Electrophysiological impacts were similar between sexes and specific to attributes related to input resistance. Input resistance was decreased in neurons recorded from both sexes exposed to FM 550 compared to vehicle. This study supports the hypothesis that developmental exposure to FM 550 impacts attachment behaviors and demonstrates a novel FM 550 effect on neural electrophysiology.}, journal={HORMONES AND BEHAVIOR}, author={Krentzel, Amanda A. and Kimble, Laney C. and Dorris, David M. and Horman, Brian M. and Meitzen, John and Patisaul, Heather B.}, year={2021}, month={Aug} }
 @article{gillera_marinello_cao_horman_stapleton_patisaul_2021, title={Sex-specific Disruption of the Prairie Vole Hypothalamus by Developmental Exposure to a Flame Retardant Mixture}, volume={162}, ISSN={["1945-7170"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85111789129&partnerID=MN8TOARS}, DOI={10.1210/endocr/bqab100}, abstractNote={Abstract
               Prevalence of neurodevelopmental disorders (NDDs) with social deficits is conspicuously rising, particularly in boys. Flame retardants (FRs) have long been associated with increased risk, and prior work by us and others in multiple species has shown that developmental exposure to the common FR mixture Firemaster 550 (FM 550) sex-specifically alters socioemotional behaviors including anxiety and pair bond formation. In rats, FRs have also been shown to impair aspects of osmoregulation. Because vasopressin (AVP) plays a role in both socioemotional behavior and osmotic balance we hypothesized that AVP and its related nonapeptide oxytocin (OT) would be vulnerable to developmental FM 550 exposure. We used the prairie vole (Microtus ochrogaste) to test this because it is spontaneously prosocial. Using siblings of prairie voles used in a prior study that assessed behavioral deficits resulting from developmental FM 550 exposure across 3 doses, here we tested the hypothesis that FM 550 sex-specifically alters AVP and OT neuronal populations in critical nuclei, such as the paraventricular nucleus (PVN), that coordinate those behaviors, as well as related dopaminergic (determined by tyrosine hydroxylase (TH) immunolabeling) populations. Exposed females had fewer AVP neurons in the anterior PVN and more A13 TH neurons in the zona incerta than controls. By contrast, in FM 550 males, A13 TH neuron numbers in the zona incerta were decreased but only in 1 dose group. These results expand on previous work showing evidence of endocrine disruption of OT/AVP pathways, including to subpopulations of PVN AVP neurons that coordinate osmoregulatory functions in the periphery.}, number={8}, journal={ENDOCRINOLOGY}, publisher={The Endocrine Society}, author={Gillera, Sagi Enicole A. and Marinello, William P. and Cao, Kevin T. and Horman, Brian M. and Stapleton, Heather M. and Patisaul, Heather B.}, year={2021}, month={Aug} }
 @article{pace_horman_patisaul_muddiman_2020, title={Analysis of neurotransmitters in rat placenta exposed to flame retardants using IR-MALDESI mass spectrometry imaging}, volume={412}, ISSN={["1618-2650"]}, DOI={10.1007/s00216-020-02626-4}, abstractNote={Chemical exposures can adversely impact fetal development. For many compounds, including common flame retardants, the mechanisms by which this occurs remain unclear, but emerging evidence suggests that disruption at the level of the placenta may play a role. Understanding how the placenta might be vulnerable to chemical exposures is challenging due to its complex structure. The primary objective of this study was to develop a method for detecting placental neurotransmitters and related metabolites without chemical derivatization so changes in the abundance and spatial distribution of neurotransmitters in rat placenta following chemical exposure could be determined using infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) mass spectrometry imaging. Without chemical derivatization, 49 neurotransmitters and their related metabolites were putatively identified in untreated rat placenta sections using mass measurement accuracy and spectral accuracy. A few neurotransmitters were less abundant in placentas that were exposed to various flame retardants and were further investigated by KEGG metabolic pathway analysis. Many of these downregulated neurotransmitters shared the same enzyme responsible for metabolism, aromaticl-amino acid decarboxylase, suggesting a mechanistic role. These data constitute a new approach that could help identify novel mechanisms of toxicity in complex tissues. Graphical abstract.}, number={15}, journal={ANALYTICAL AND BIOANALYTICAL CHEMISTRY}, author={Pace, Crystal L. and Horman, Brian and Patisaul, Heather and Muddiman, David C.}, year={2020}, month={Jun}, pages={3745–3752} }
 @article{macari_rock_santos_lima_szawka_moss_horman_patisaul_2020, title={Developmental Exposure to the Flame Retardant Mixture Firemaster 550 Compromises Adult Bone Integrity in Male but not Female Rats}, volume={21}, ISSN={["1422-0067"]}, DOI={10.3390/ijms21072553}, abstractNote={Flame retardants (FRs) are used in a variety of common items from furniture to carpet to electronics to reduce flammability and combustion, but the potential toxicity of these compounds is raising health concerns globally. Organophosphate FRs (OPFRs) are becoming more prevalent as older, brominated FRs are phased out, but the toxicity of these compounds, and the FR mixtures that contain them, is poorly understood. Work in a variety of in vitro model systems has suggested that FRs may induce metabolic reprogramming such that bone density is compromised at the expense of increasing adiposity. To address this hypothesis, the present studies maternally exposed Wistar rat dams orally across gestation and lactation to 1000 µg daily of the FR mixture Firemaster 550 (FM 550) which contains a mixture of brominated FRs and OPFRs. At six months of age, the offspring of both sexes were examined for evidence of compromised bone composition. Bone density, composition, and marrow were all significantly affected, but only in males. The fact that the phenotype was observed months after exposure suggests that FM 550 altered some fundamental aspect of mesenchymal stem cell reprogramming. The severity of the phenotype and the human-relevance of the dose employed, affirm this is an adverse outcome meriting further exploration.}, number={7}, journal={INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, author={Macari, Soraia and Rock, Kylie D. and Santos, Mariana S. and Lima, Virginia T. M. and Szawka, Raphael E. and Moss, Jamal and Horman, Brian and Patisaul, Heather B.}, year={2020}, month={Apr} }
 @article{rock_st armour_horman_phillips_ruis_stewart_jima_muddiman_stapleton_patisaul_2020, title={Effects of Prenatal Exposure to a Mixture of Organophosphhate Flame Ritardants on Placental Gene Expression and Serotonergic Innervaion in the Fetal Rat Brain}, volume={176}, ISSN={["1096-0929"]}, DOI={10.1093/toxsci/kfaa046}, abstractNote={AbstractThere is a growing need to understand the potential neurotoxicity of organophosphate flame retardants (OPFRs) and plasticizers because use and, consequently, human exposure, is rapidly expanding. We have previously shown in rats that developmental exposure to the commercial flame retardant mixture Firemaster 550 (FM 550), which contains OPFRs, results in sex-specific behavioral effects, and identified the placenta as a potential target of toxicity. The placenta is a critical coordinator of fetal growth and neurodevelopment, and a source of neurotransmitters for the developing brain. We have shown in rats and humans that flame retardants accumulate in placental tissue, and induce functional changes, including altered neurotransmitter production. Here, we sought to establish if OPFRs (triphenyl phosphate and a mixture of isopropylated triarylphosphate isomers) alter placental function and fetal forebrain development, with disruption of tryptophan metabolism as a primary pathway of interest. Wistar rat dams were orally exposed to OPFRs (0, 500, 1000, or 2000 μg/day) or a serotonin (5-HT) agonist 5-methoxytryptamine for 14 days during gestation and placenta and fetal forebrain tissues collected for analysis by transcriptomics and metabolomics. Relative abundance of genes responsible for the transport and synthesis of placental 5-HT were disrupted, and multiple neuroactive metabolites in the 5-HT and kynurenine metabolic pathways were upregulated. In addition, 5-HTergic projections were significantly longer in the fetal forebrains of exposed males. These findings suggest that OPFRs have the potential to impact the 5-HTergic system in the fetal forebrain by disrupting placental tryptophan metabolism.}, number={1}, journal={TOXICOLOGICAL SCIENCES}, author={Rock, Kylie D. and St Armour, Genevieve and Horman, Brian and Phillips, Allison and Ruis, Matthew and Stewart, Allison K. and Jima, Dereje and Muddiman, David C. and Stapleton, Heather M. and Patisaul, Heather B.}, year={2020}, month={Jul}, pages={203–223} }
 @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{ruis_rock_hall_horman_patisaul_stapleton_2019, title={PBDEs Concentrate in the Fetal Portion of the Placenta: Implications for Thyroid Hormone Dysregulation}, volume={160}, ISSN={["1945-7170"]}, DOI={10.1210/en.2019-00463}, abstractNote={Abstract
               During pregnancy, the supply of thyroid hormone (TH) to the fetus is critically important for fetal growth, neural development, metabolism, and maintenance of pregnancy. Additionally, in cases where maternal and placental TH regulation is significantly altered, there is an increased risk of several adverse pregnancy outcomes. It is unclear what may be disrupting placental TH regulation; however, studies suggest that environmental contaminants, such as polybrominated diphenyl ethers (PBDEs), could be playing a role. In this study, Wistar rats were gestationally exposed to a mixture of PBDEs for 10 days. THs and PBDEs were quantified in paired maternal serum, dissected placenta, and fetuses, and mRNA expression of transporters in the placenta was assessed. Significantly higher concentrations of PBDEs were observed in the fetal portion of the placenta compared with the maternal side, suggesting that PBDEs are actively transported across the interface. PBDEs were also quantified in 10 recently collected human maternal and fetal placental tissues; trends paralleled observations in the rat model. We also observed an effect of PBDEs on T3 levels in dam serum, as well as suggestive changes in the T3 levels of the placenta and fetus that varied by fetal sex. mRNA expression in the placenta also significantly varied by fetal sex and dose. These observations suggest the placenta is a significant modifier of fetal exposures, and that PBDEs are impacting TH regulation in a sex-specific manner during this critical window of development.}, number={11}, journal={ENDOCRINOLOGY}, author={Ruis, Matthew T. and Rock, Kylie D. and Hall, Samantha M. and Horman, Brian and Patisaul, Heather B. and Stapleton, Heather M.}, year={2019}, month={Nov}, pages={2748–2758} }
 @article{rock_gillera_devarasetty_horman_knudsen_birnbaum_fenton_patisaul_2019, title={Sex-specific behavioral effects following developmental exposure to tetrabromobisphenol A (TBBPA) in Wistar rats}, volume={75}, ISSN={0161-813X}, url={http://dx.doi.org/10.1016/j.neuro.2019.09.003}, DOI={10.1016/j.neuro.2019.09.003}, abstractNote={Tetrabromobisphenol A (TBBPA) has become a ubiquitous indoor contaminant due to its widespread use as an additive flame retardant in consumer products. Reported evidence of endocrine disruption and accumulation of TBBPA in brain tissue has raised concerns regarding its potential effects on neurodevelopment and behavior. The goal of the present study was to examine the impact of developmental TBBPA exposure, across a wide range of doses, on sexually dimorphic non-reproductive behaviors in male and female Wistar rats. We first ran a pilot study using a single TBBPA dose hypothesized to produce behavioral effects. Wistar rat dams were orally exposed using cookie treats to 0 or 0.1 mg TBBPA/kg bw daily from gestational day (GD) 9 to postnatal day (PND) 21 to assess offspring (both sexes) activity and anxiety-related behaviors. Significant effects were evident in females, with exposure increasing activity levels. Thus, this dose was used as the lowest TBBPA dose in a subsequent, larger study conducted as part of a comprehensive assessment of TBBPA toxicity. Animals were exposed to 0, 0.1, 25, or 250 mg TBBPA/kg bw daily by oral gavage starting on GD 6 through PND 90 (dosed dams GD 6 – PND 21, dosed offspring PND 22 – PND 90). Significant behavioral findings were observed for male offspring, with increased anxiety-like behavior as the primary phenotype. These findings demonstrate that exposure to environmental contaminants, like TBBPA, can have sex-specific effects on behavior highlighting the vulnerability of the developing brain.}, journal={NeuroToxicology}, publisher={Elsevier BV}, author={Rock, Kylie D. and Gillera, Sagi Enicole A. and Devarasetty, Pratyush and Horman, Brian and Knudsen, Gabriel and Birnbaum, Linda S. and Fenton, Suzanne E. and Patisaul, Heather B.}, year={2019}, month={Dec}, pages={136–147} }
 @article{rock_horman_phillips_mcritchie_watson_deese-spruill_jima_sumner_stapleton_patisaul_et al._2018, title={EDC IMPACT: Molecular effects of developmental FM 550 exposure in Wistar rat placenta and fetal forebrain}, volume={7}, ISSN={["2049-3614"]}, DOI={10.1530/ec-17-0373}, abstractNote={Firemaster 550 (FM 550) is a flame retardant (FR) mixture that has become one of the most commonly used FRs in foam-based furniture and baby products. Human exposure to this commercial mixture, composed of brominated and organophosphate components, is widespread. We have repeatedly shown that developmental exposure can lead to sex-specific behavioral effects in rats. Accruing evidence of endocrine disruption and potential neurotoxicity has raised concerns regarding the neurodevelopmental effects of FM 550 exposure, but the specific mechanisms of action remains unclear. Additionally, we observed significant, and in some cases sex-specific, accumulation of FM 550 in placental tissue following gestational exposure. Because the placenta is an important source of hormones and neurotransmitters for the developing brain, it may be a critical target of toxicity to consider in the context of developmental neurotoxicity. Using a mixture of targeted and exploratory approaches, the goal of the present study was to identify possible mechanisms of action in the developing forebrain and placenta. Wistar rat dams were orally exposed to FM 550 (0, 300 or 1000 µg/day) for 10 days during gestation and placenta and fetal forebrain tissue collected for analysis. In placenta, evidence of endocrine, inflammatory and neurotransmitter signaling pathway disruption was identified. Notably, 5-HT turnover was reduced in placental tissue and fetal forebrains indicating that 5-HT signaling between the placenta and the embryonic brain may be disrupted. These findings demonstrate that environmental contaminants, like FM 550, have the potential to impact the developing brain by disrupting normal placental functions.}, number={2}, journal={ENDOCRINE CONNECTIONS}, author={Rock, K. D. and Horman, B. and Phillips, A. L. and McRitchie, S. L. and Watson, S. and Deese-Spruill, J. and Jima, D. and Sumner, S. and Stapleton, H. M. and Patisaul, Heather and et al.}, year={2018}, month={Feb}, pages={305–324} }
 @article{baldwin_phillips_horman_arambula_rebuli_stapleton_patisaul_2017, title={Sex Specific Placental Accumulation and Behavioral Effects of Developmental Firemaster 550 Exposure in Wistar Rats}, volume={7}, ISSN={["2045-2322"]}, DOI={10.1038/s41598-017-07216-6}, abstractNote={AbstractFiremaster® 550 (FM 550) is a commercial flame retardant mixture of brominated and organophosphate compounds applied to polyurethane foam used in furniture and baby products. Due to widespread human exposure, and structural similarities with known endocrine disruptors, concerns have been raised regarding possible toxicity. We previously reported evidence of sex specific behavioral effects in rats resulting from developmental exposure. The present study expands upon this prior finding by testing for a greater range of behavioral effects, and measuring the accumulation of FM 550 compounds in placental tissue. Wistar rat dams were orally exposed to FM 550 during gestation (0, 300 or 1000 µg/day; GD 9 – 18) for placental measurements or perinatally (0, 100, 300 or 1000 µg/day; GD 9 – PND 21) to assess activity and anxiety-like behaviors. Placental accumulation was dose dependent, and in some cases sex specific, with the brominated components reaching the highest levels. Behavioral changes were predominantly associated with a loss or reversal of sex differences in activity and anxiety-like behaviors. These findings demonstrate that environmental chemicals may sex-dependently accumulate in the placenta. That sex-biased exposure might translate to sex-specific adverse outcomes such as behavioral deficits is a possibility that merits further investigation.}, journal={SCIENTIFIC REPORTS}, author={Baldwin, Kylie R. and Phillips, Allison L. and Horman, Brian and Arambula, Sheryl E. and Rebuli, Meghan E. and Stapleton, Heather M. and Patisaul, Heather B.}, year={2017}, month={Aug} }
 @article{smith_lee_dausch_horman_patisaul_mccarty_sombers_2017, title={Simultaneous Voltammetric Measurements of Glucose and Dopamine Demonstrate the Coupling of Glucose Availability with Increased Metabolic Demand in the Rat Striatum}, volume={8}, ISSN={1948-7193 1948-7193}, url={http://dx.doi.org/10.1021/acschemneuro.6b00363}, DOI={10.1021/acschemneuro.6b00363}, abstractNote={Cerebral blood flow ensures delivery of nutrients, such as glucose, to brain sites with increased metabolic demand. However, little is known about rapid glucose dynamics at discrete locations during neuronal activation in vivo. Acute exposure to many substances of abuse elicits dopamine release and neuronal activation in the striatum; however, the concomitant changes in striatal glucose remain largely unknown. Recent developments have combined fast-scan cyclic voltammetry with glucose oxidase enzyme modified carbon-fiber microelectrodes to enable the measurement of glucose dynamics with subsecond temporal resolution in the mammalian brain. This work evaluates several waveforms to enable the first simultaneous detection of endogenous glucose and dopamine at single recording sites. These molecules, one electroactive and one nonelectroactive, were found to fluctuate in the dorsal striatum in response to electrical stimulation of the midbrain and systemic infusion of cocaine/raclopride. The data reveal the second-by-second dynamics of these species in a striatal microenvironment, and directly demonstrate the coupling of glucose availability with increased metabolic demand. This work provides a foundation that will enable detailed investigation of local mechanisms that regulate the coupling of cerebral blood flow with metabolic demand under normal conditions, and in animal studies of drug abuse and addiction.}, number={2}, journal={ACS Chemical Neuroscience}, publisher={American Chemical Society (ACS)}, author={Smith, Samantha K. and Lee, Christie A. and Dausch, Matthew E. and Horman, Brian M. and Patisaul, Heather B. and McCarty, Gregory S. and Sombers, Leslie A.}, year={2017}, month={Jan}, pages={272–280} }
 @article{phillips_chen_rock_horman_patisaul_stapleton_2016, title={Transplacental and Lactational Transfer of Firemaster (R) 550 Components in Dosed Wistar Rats}, volume={153}, ISSN={["1096-0929"]}, DOI={10.1093/toxsci/kfw122}, abstractNote={UNLABELLED
Firemaster® 550 (FM 550) is a commercial mixture of organophosphate and brominated flame retardants currently in use as a replacement for pentaBDE. Its organophosphate components include triphenyl phosphate (TPHP) and a suite of isopropylated triarylphosphate isomers (ITPs); its brominated components include 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (EH-TBB) and bis (2-ethylhexyl)-2,3,4,5-tetrabromophthalate (BEH-TEBP). Taken together, these chemicals have been shown to be endocrine disrupting and potentially toxic, and human exposure to them is widespread. In this study, maternal transfer of FM 550 components, and in some cases their metabolites, was investigated in dosed Wistar rats. Gestational and lactational transfer were examined separately, with dams orally exposed to 300 or 1000 µg of FM 550 for 10 consecutive days during gestation (gestational day [GD] 9-18) or lactation (postnatal day [PND] 3-12). Levels of parent compounds were measured in fetus and whole pup tissue homogenates, and in dam and pup serum, and several metabolites were measured in dam and pup urine. EH-TBB body burdens resulting from lactational transfer were approximately 200- to 300-fold higher than those resulting from placental transfer, whereas low levels of BEH-TEBP were transferred during both lactation and gestation. TPHP and ITPs were rapidly metabolized by the dams and were not detected in whole tissue homogenates. However, diphenyl phosphate (DPHP) and mono-isopropylphenyl phenyl phosphate (ip-PPP) were detected in urine from the dosed animals. This study is the first to confirm ip-PPP as a urinary metabolite of ITPs and establish a pharmacokinetic profile of FM 550 in a mammalian model.


KEY WORDS
Firemaster 550 ;: lactational transfer ;: gestational transfer; metabolites; rodent.}, number={2}, journal={TOXICOLOGICAL SCIENCES}, author={Phillips, Allison L. and Chen, Albert and Rock, Kylie D. and Horman, Brian and Patisaul, Heather B. and Stapleton, Heather M.}, year={2016}, month={Oct}, pages={246–257} }
 @article{hoffman_fang_horman_patisaul_garantziotis_birnbaum_stapleton_2014, title={Urinary Tetrabromobenzoic Acid (TBBA) as a Biomarker of Exposure to the Flame Retardant Mixture Firemaster
            
              ®
            
            550}, volume={122}, ISSN={0091-6765 1552-9924}, url={http://dx.doi.org/10.1289/ehp.1308028}, DOI={10.1289/ehp.1308028}, abstractNote={Background: Firemaster® 550 (FM550) is commonly added to residential furniture to reduce its flammability. Recent toxicological evidence suggests that FM550 may be endocrine disrupting and obesogenic.Objectives: Our objectives were to develop methods to assess exposure to FM550 in human populations and to identify potential routes of exposure.Methods: Using mass spectrometry methods, we developed a method to measure 2,3,4,5-tetrabromobenzoic acid (TBBA), a urinary metabolite of the major brominated FM550 component 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (TBB). The method was applied to a cohort of adult volunteers (n = 64). Participants completed questionnaires, provided urine and handwipe samples, and collected dust samples from their homes. We measured TBB and the other major brominated FM550 component, bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate (TBPH), in paired dust and handwipe samples.Results: TBBA was detected in 72.4% of urine samples. Although TBBA is a rapidly formed metabolite, analyses indicated moderate temporal reliability (interclass correlation coefficient = 0.56; 95% confidence interval: 0.46, 0.66). TBB and TBPH were detected frequently in dust samples [geometric mean (GM) = 315.1 and 364.7 ng/g, respectively] and in handwipes (GM = 31.4 and 23.4 ng, respectively). Levels of TBB and TBPH in dust were positively correlated with levels in handwipes. In addition, levels of TBB in handwipes were positively correlated with urinary TBBA. Results suggest frequent hand washing may reduce the mass of TBB on participants’ hands and reduce urinary TBBA levels.Conclusions: Cumulatively, our data indicate that exposures to FM550 are widespread and that the home environment may be an important source of exposure. Urinary TBBA provides a potentially useful biomarker of FM550 exposure for epidemiologic studies.Citation: Hoffman K, Fang M, Horman B, Patisaul HB, Garantziotis S, Birnbaum LS, Stapleton HM. 2014. Urinary tetrabromobenzoic acid (TBBA) as a biomarker of exposure to the flame retardant mixture Firemaster® 550. Environ Health Perspect 122:963–969; http://dx.doi.org/10.1289/ehp.1308028}, number={9}, journal={Environmental Health Perspectives}, publisher={Environmental Health Perspectives}, author={Hoffman, Kate and Fang, Mingliang and Horman, Brian and Patisaul, Heather B. and Garantziotis, Stavros and Birnbaum, Linda S. and Stapleton, Heather M.}, year={2014}, month={Sep}, pages={963–969} }