Impact of Environmental Estrogens on Sexually Dimorphic Development of the Mouse Mammary Gland

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 DESCRIPTION (provided by applicant) The candidate's overarching long-term career goal is understand how environmental factors in early life contribute to the development of adult diseases including breast cancers in women. Using molecular, genetic, tissue-based and endocrine tools, she wish to address the question, Does breast cancer start in utero? The research objective of this K22 grant application is to understand how the environmental chemical Bisphenol S (BPS), which has estrogenic properties, disrupts the development of the mammary gland. The candidate's preliminary data indicates that perinatal exposure to BPS alters developmental parameters of the male and female mouse mammary gland. She hypothesize that BPS perturbs mammary gland development by sensitizing the response of the epithelial cells to endogenous hormones. The propose two aims: the first will assess whether the effects of BPS on the male mammary gland are due to alterations in the number of cells incorporated in the epithelial compartment during embryogenesis, an altered sensitivity to hormones during the pubertal period, and/or disruptions in circulating hormone levels. The second aim will characterize the role of estrogen receptor in the BPS-induced altered sensitivity of the pubertal female mammary gland to estradiol. The work the candidate has proposed will build off her previous studies of Bisphenol A (BPA) and the mammary gland; her work characterized the effects of low dose perinatal BPA exposures on the mouse gland at several adult ages, described how perinatal BPA exposures altered the sensitivity of the pubertal gland to estradiol, and identified the cellular targets of BPA on the ftal mammary gland during the period of exposure. Thus, the candidate has assembled a collection of tissue, histological, and cell-based tools to explore the effects of environmental chemicals on the mammary gland; during the completion of this award, she will also learn surgical, endocrine and molecular tools that can be applied to the study of this tissue. Finally, as is the intent of te K22 award, the candidate has assembled a team of interdisciplinary experts to serve as sponsors: Dr. R. Thomas Zoeller (University of Massachusetts, Amherst) has agreed to be her primary sponsor. With his expertise in developmental endocrinology, Dr. Zoeller's guidance will allow the candidate to improve her systems-based approaches to endocrinology, and address the possibility that the effects of environmental chemicals on the mammary gland are indirect, via disruption of the hypothalamic-pituitary-gonadal axis. Dr. D. Joseph Jerry (University of Massachusetts, Amherst) and Dr. Suzanne Fenton (NIEHS) will guide the candidate in approaches and techniques for the mammary gland. Dr. Jerry's focus is on the intersection of hormones and genetics, whereas Dr. Fenton's approach is to use the mammary gland to examine environmental toxicants; both of these approaches will significantly benefit her project. Finally, Dr. Susan Nagel (University of Missouri) will provide guidance on xenoestrogens, endocrine disruptor screening methods, and chemical mixtures. Together, the candidate's prior work and the mentoring team she has assembled will ensure that she can achieve her research and career development goals and will help launch her independent career.