The ability of an organism to attain and maintain reproductive competence involves the intricate coordination of a suite of hypothalamic genes that must be turned on/off in coordination with the life stage and the environment. Among those factors regulating reproductive neuroendocrine gene expression are circulating sex steroid hormones, including estradiol. While sex hormones are required to modulate reproductive life transitions in both an age- and sex-dependent manner, their underlying mechanisms are not well understood. This proposal focuses on elucidating the epigenetic molecular mechanisms by which an organism's hormonal environment modulates its hypothalamic gene expression to ensure the coordination of proper reproductive physiology with life stage. The focus will be the estrogen receptor alpha (ERa) and kisspeptin, chosen because these hypothalamic genes are expressed in a sexually dimorphic manner, they undergo robust changes across the life cycle, and because exogenous estrogen exposure during early life development perturbs their gene expression and disrupts reproductive development and aging.
Aim 1 will test whether the epigenetic modification of DNA methylation affects the programming of ERa and kisspeptin gene expression in hypothalamic regions.
Aim 2 will test the hypothesis that the epigenetic event of histone acetylation is important for the activation and maintenance of the expression of these genes in adulthood, and during the process of reproductive senescence. Experiments will be carried out in male and female rats, making comparisons by sex and age. A subset of animals will be exposed to prenatal estradiol, which disrupts reproductive processes and hastens reproductive aging. As a whole, these studies will provide novel epigenetic molecular data on the organization and maintenance of key hypothalamic genes required for proper reproductive function and further illuminates the link between gene expression and the hormonal environment.

Public Health Relevance

The proposed experiments in rats are highly relevant to human health because the hormones and physiology of reproduction are highly conserved. These studies are particularly important for understanding the loss of reproductive function as a model for menopause (women) /andropause (men). Although they are not diseases, these life transitions are associated with considerably elevated risk for cardiovascular disease, breast, prostate and uterine cancer, metabolic disorders and osteoporosis, all of which are hormone- dependent. Additionally, these life changes are associated with central nervous system problems including hot flashes, sleep deprivation, depression and anxiety. Therefore, a better understanding of the neural molecular mechanisms regulating these events could prove beneficial to promoting healthy aging.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F06-E (20))
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Mackiewicz, Miroslaw
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University of Texas Austin
Schools of Arts and Sciences
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Walker, Deena M; Gore, Andrea C (2017) Epigenetic impacts of endocrine disruptors in the brain. Front Neuroendocrinol 44:1-26
Topper, Viktoria Y; Walker, Deena M; Gore, Andrea C (2015) Sexually dimorphic effects of gestational endocrine-disrupting chemicals on microRNA expression in the developing rat hypothalamus. Mol Cell Endocrinol 414:42-52
Walker, Deena M; Goetz, Benjamin M; Gore, Andrea C (2014) Dynamic postnatal developmental and sex-specific neuroendocrine effects of prenatal polychlorinated biphenyls in rats. Mol Endocrinol 28:99-115
Walker, Deena M; Kermath, Bailey A; Woller, Michael J et al. (2013) Disruption of reproductive aging in female and male rats by gestational exposure to estrogenic endocrine disruptors. Endocrinology 154:2129-43
Walker, Deena M; Kirson, Dean; Perez, Lorenzo F et al. (2012) Molecular profiling of postnatal development of the hypothalamus in female and male rats. Biol Reprod 87:129
Patisaul, Heather B; Sullivan, Alana W; Radford, Meghan E et al. (2012) Anxiogenic effects of developmental bisphenol A exposure are associated with gene expression changes in the juvenile rat amygdala and mitigated by soy. PLoS One 7:e43890
Gore, Andrea C; Walker, Deena M; Zama, Aparna M et al. (2011) Early life exposure to endocrine-disrupting chemicals causes lifelong molecular reprogramming of the hypothalamus and premature reproductive aging. Mol Endocrinol 25:2157-68