The main objective of this research project is to understand how in utero Bisphenol A (BPA) exposure affects fetal gonadal development and reproduction in adulthood in mice. In utero exposure to estrogenic endocrine disruptors such as diethylsfilbestrol (DES) is known to cause sex organ malformafion, reproductive carcinogenesis, and fertility defects in both male and female in humans and rodents. Based on DES studies, it is proposed that in utero exposure to other endocrine disruptors, particularly those that work through estrogen receptors, may lead to reproductive diseases in adulthood. BPA, a chemical used in synthesis of plastics, exhibits estrogenic activities and deleterious effects on reproduction when given to adult rodents. BPA is detected in serum of pregnant women, umbilical cord blood, and fetal plasma, indicafing that developing fetuses are exposed to BPA. Although effects of BPA on adult reproductive organs have been studied extensively, impacts of in utero BPA exposure particularly on fetal gonadal development are not well understood. In vitro experiments have suggested that BPA, similarto other estrogenic compounds, could bind to classical nuclear estrogen receptors (ERa or p), which are present in fetal mouse gonads. Therefore, the main goal ofthis Research Project is to test the hypothesis that in utero exposure to BPA causes gonadal defects in fetal and adult life via ERs. We design two specific aims to 1) investigate whether loss of ERa or |3 in fetal gonads render embryos insensitive to deleterious effects of BPA in reproductive funcstions and 2) study whether overexpression of ER increases the susceptibility of embryos to in utero exposure of BPA. The proposed experiments take advantage of the power of transgenic mouse models in combination of classic toxicological approaches. This project will not only provide animal models to test hypotheses that human models cannot, but also complementary information to interpret results of other components of the formative grant.

Public Health Relevance

Exposure of male embryos to harmful man-made chemicals has a long-term impact on fertility when the exposed embryos reach adulthood. It is therefore critical to understand the biological basis of gonadal development and establish animal models that can be used to study the effects of these chemicals such as BPA.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Exploratory Grants (P20)
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Special Emphasis Panel (ZES1-LKB-G (P2))
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University of Illinois Urbana-Champaign
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Wise, Leslie M; Sadowski, Renee N; Kim, Taehyeon et al. (2016) Long-term effects of adolescent exposure to bisphenol A on neuron and glia number in the rat prefrontal cortex: Differences between the sexes and cell type. Neurotoxicology 53:186-192
Ziv-Gal, Ayelet; Wang, Wei; Zhou, Changqing et al. (2015) The effects of in utero bisphenol A exposure on reproductive capacity in several generations of mice. Toxicol Appl Pharmacol 284:354-62
Sadowski, R N; Wise, L M; Park, P Y et al. (2014) Early exposure to bisphenol A alters neuron and glia number in the rat prefrontal cortex of adult males, but not females. Neuroscience 279:122-31
Peretz, Jackye; Vrooman, Lisa; Ricke, William A et al. (2014) Bisphenol a and reproductive health: update of experimental and human evidence, 2007-2013. Environ Health Perspect 122:775-86
Sadowski, Renee N; Park, Pul; Neese, Steven L et al. (2014) Effects of perinatal bisphenol A exposure during early development on radial arm maze behavior in adult male and female rats. Neurotoxicol Teratol 42:17-24
Peretz, Jackye; Neese, Steven L; Flaws, Jodi A (2013) Mouse strain does not influence the overall effects of bisphenol a-induced toxicity in adult antral follicles. Biol Reprod 89:108
Peretz, Jackye; Flaws, Jodi A (2013) Bisphenol A down-regulates rate-limiting Cyp11a1 to acutely inhibit steroidogenesis in cultured mouse antral follicles. Toxicol Appl Pharmacol 271:249-56
Liu, Chang; Paczkowski, Melissa; Othman, Manal et al. (2012) Investigating the origins of somatic cell populations in the perinatal mouse ovaries using genetic lineage tracing and immunohistochemistry. Methods Mol Biol 825:211-21
Peretz, Jackye; Craig, Zelieann R; Flaws, Jodi A (2012) Bisphenol A inhibits follicle growth and induces atresia in cultured mouse antral follicles independently of the genomic estrogenic pathway. Biol Reprod 87:63
Brannick, Katherine E; Craig, Zelieann R; Himes, Ashley D et al. (2012) Prenatal exposure to low doses of bisphenol A increases pituitary proliferation and gonadotroph number in female mice offspring at birth. Biol Reprod 87:82

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