Endocrine-disrupting chemicals (EDCs) are compounds in the environment that perturb endocrine systems. EDCs are ubiquitous in the modern world, and detectable in virtually all humans and wildlife. Many effects of EDCs are mediated by hormone receptors such as estrogen receptors (ERs) that are widely distributed in the brain, and thereby EDCs perturb neurobiological functions. The hypothalamus, hippocampus and amygdala are brain regions with high expression of ERs, and are proven targets for endocrine disruption. However, the cellular, molecular and physiological processes for these effects, and the functional behavioral implications for exposures of these brain regions to EDCs, are not well explored. Furthermore, the brain has a number of structural and functional sexual dimorphisms that develop early in life, a process that is sculpted by actions of estrogens on ERs, and disrupted by EDCs. Therefore, it is the overarching goal of this research to determine the molecular and cellular mechanisms by which exposure of developing fetuses to ecologically-relevant levels of EDCs perturb the sexual differentiation of specific brain areas, and the consequences on behaviors regulated by these regions. The proposed studies will fill a gap in knowledge by testing effects of perinatal exposure to a class of endocrine-disrupting chemicals, specifically polychlorinated biphenyls (PCBs), on sexually dimorphic neurobiological processes. PCBs are a ubiquitous and persistent environmental contaminant, and while banned for decades, they are still prevalent in soil and groundwater, leach into food and water, and are detectable in tissues of virtually all humans. The proposed studies will use a well-established rat model already in use in the PIs'labs to test effects of exposure to PCBs during a critical hormone-sensitive developmental window of late gestation, a critical period for brain sexual differentiation during which the developing nervous system is exquisitely sensitive to both endogenous and exogenous hormones, particularly estrogens. The experiments will quantify expression of a network of estrogen-regulated genes (Aim 1);elucidate some potential epigenetic mechanisms for regulation of identified targets (Aim 2);determine the manifestation of gene expression changes through protein immunohistochemistry (Aim 3);and ascertain the final outcome as a behavioral phenotype (Aim 4). These experiments have broad implications for humans as exposure to PCBs is universal, persistent, and has wide-ranging effects on health and disease. Therefore, understanding the latent effects of PCBs on neural development, and their underlying mechanisms, can inform public policy, medical interventions, and prevention. In addition, results on PCBs, used as a """"""""model"""""""" EDC for decades, can help us better understand effects of other estrogenic EDCs still in common use such as those in plastics, pesticides, and beyond.

Public Health Relevance

Exposures of humans to PCBs and other estrogenic EDCs are universal, and these compounds have wide- ranging effects on health and disease. Therefore, understanding the latent effects of PCBs on neural development, and their underlying mechanisms, can inform medical interventions and prevention, and guide public health policy. The rat model is highly conserved with humans, and it enables us to test the cause-and- effect relationship between prenatal PCBs, the development of adult disease, and the neural mechanisms underlying these biomedical processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES020662-03
Application #
8475402
Study Section
Special Emphasis Panel (ZRG1-EMNR-Q (02))
Program Officer
Heindel, Jerrold
Project Start
2011-09-09
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
3
Fiscal Year
2013
Total Cost
$359,684
Indirect Cost
$123,978
Name
University of Texas Austin
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712
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Bell, Margaret R; Hart, Bethany G; Gore, Andrea C (2016) Two-hit exposure to polychlorinated biphenyls at gestational and juvenile life stages: 2. Sex-specific neuromolecular effects in the brain. Mol Cell Endocrinol 420:125-37
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Gore, A C; Chappell, V A; Fenton, S E et al. (2015) EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals. Endocr Rev 36:E1-E150
Reilly, Michael P; Weeks, Connor D; Topper, Viktoria Y et al. (2015) The effects of prenatal PCBs on adult social behavior in rats. Horm Behav 73:47-55
Crews, David; Gillette, Ross; Miller-Crews, Isaac et al. (2014) Nature, nurture and epigenetics. Mol Cell Endocrinol 398:42-52
Gillette, Ross; Miller-Crews, Isaac; Nilsson, Eric E et al. (2014) Sexually dimorphic effects of ancestral exposure to vinclozolin on stress reactivity in rats. Endocrinology 155:3853-66

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