Epidemiological data suggest that the incidence of both precocious puberty and impaired fecundity are increasing. It has been hypothesized that exposure to endocrine active compounds (EACs), may play a role in this trend. Advanced puberty and persistent estrus have been documented for many EACs in rodents but very little is known about the mechanisms by which EACs produce these effects. This lack of knowledge makes it difficult to predict how a potential EAC may ultimately affect human health. In females, puberty results from the maturation of the hypothalamic-pituitary-gonadal (HPG) axis and culminates with the onset of cyclic gonadotropin releasing hormone (GnRH) pulses that stimulate ovulation. The anterior ventral periventricular nucleus (AVPV) is the primary regulator of GnRH neuronal activity. The specific hypothesis behind the proposed research is that the disruption of puberty by neonatal exposure to the EACs Bisphenol-A (BPA) and genistein (GEN) results from the improper sexual differentiation of the AVPV and thus the estrogen receptor (ER)-initiated signal transduction pathways that regulate GnRH secretion. This hypothesis is supported by the following preliminary data. First, both compounds advanced pubertal onset. Second, both compounds defeminized an AVPV neuronal phenotype that contains ER?. Third, GEN disrupted the estrus cycle postpuberty. And finally, both compounds defeminized adult AVPV volume. Using behavioral, anatomical and molecular techniques the investigators will compare the effects of BPA and GEN with agonists specific for the two forms of the estrogen receptor (ER? and ER?) to characterize the signal transduction pathways through which EACs affect the timing and progression of puberty. For all studies, the dose of EAC administered will fall within the range relevant to human exposure.
AIM 1 : Characterize the effect of neonatal BPA, GEN, the ER? agonist DPN or the ER? agonist PPT exposure on kisspeptin and galanin signaling in the AVPV at puberty onset.
AIM 2 : Map the expression of ER? and ER? in the prepubertal rat AVPV and determine if this pattern is disrupted by BPA, GEN or DPN or PPT.
AIM 3 : Examine how estrus cyclicity and sexual behavior post-puberty are affected by neonatal exposure to BPA, GEN, DPN or PPT.
AIM 4 : Characterize the impact of neonatal BPA, GEN, DPN or PPT on AVPV volume, AVPV ER and kisspeptin content, and hormone-stimulated GnRH neuronal activation post-puberty.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Special Emphasis Panel (ZES1-JAB-C (R1))
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Heindel, Jerrold
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North Carolina State University Raleigh
Schools of Earth Sciences/Natur
United States
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Veiga-Lopez, Almudena; Pennathur, Subramaniam; Kannan, Kurunthachalam et al. (2015) Impact of gestational bisphenol A on oxidative stress and free fatty acids: Human association and interspecies animal testing studies. Endocrinology 156:911-22
Cao, Jinyan; Joyner, Linwood; Mickens, Jillian A et al. (2014) Sex-specific Esr2 mRNA expression in the rat hypothalamus and amygdala is altered by neonatal bisphenol A exposure. Reproduction 147:537-54
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Patisaul, Heather B (2012) Infertility in the Southern White Rhino: is diet the source of the problem? Endocrinology 153:1568-71
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Losa-Ward, Sandra M; Todd, Karina L; McCaffrey, Katherine A et al. (2012) Disrupted organization of RFamide pathways in the hypothalamus is associated with advanced puberty in female rats neonatally exposed to bisphenol A. Biol Reprod 87:28

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