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

 描述（由申请人提供） 候选人的首要长期职业目标是了解早期生活中的环境因素如何促进成人疾病的发展，包括女性乳腺癌。利用分子、遗传、组织和内分泌工具，她希望解决这个问题：乳腺癌是否始于子宫内？这项K22资助申请的研究目标是了解具有雌激素特性的环境化学物质双酚S（BPS）如何破坏乳腺的发育。 候选人的初步数据表明，围产期暴露于BPS会改变雄性和雌性小鼠乳腺的发育参数。她推测BPS通过使上皮细胞对内源性激素的反应敏感而干扰乳腺发育。提出了两个目标：第一项研究将评估BPS对男性乳腺的影响是否是由于胚胎发生期间上皮区室中细胞数量的改变、青春期期间对激素敏感性的改变和/或循环激素水平的破坏。第二个目的是描述雌激素受体在BPS诱导的青春期女性乳腺对雌二醇敏感性改变中的作用。候选人提出的工作将建立在她以前对双酚A（BPA）和乳腺的研究基础上;她的工作描述了围产期低剂量BPA暴露对几个成年年龄小鼠腺体的影响，描述了围产期BPA暴露如何改变青春期腺体对雌二醇的敏感性，并确定了BPA在暴露期间对胎儿乳腺的细胞靶点。因此，候选人已经收集了组织，组织学和基于细胞的工具，以探索环境化学物质对乳腺的影响;在完成该奖项期间，她还将学习可应用于该组织研究的外科，内分泌和分子工具。最后，作为K22奖的目的，候选人已经组建了一个跨学科专家团队作为赞助商：R博士。托马斯佐勒（马萨诸塞州，阿默斯特大学）已同意成为她的主要赞助商。凭借他在发育内分泌学方面的专业知识，Zoeller博士的指导将使候选人能够改善她基于系统的内分泌学方法，并解决环境化学品对乳腺的影响是间接的可能性，通过破坏下丘脑-垂体-性腺轴。Dr. D.约瑟夫杰里（马萨诸塞州，阿默斯特大学）和苏珊娜芬顿博士（NIEHS）将指导候选人在乳腺的方法和技术。杰里博士的重点是激素和遗传学的交叉点，而芬顿博士的方法是使用乳腺来检查环境毒物;这两种方法将大大有利于她的项目。最后，苏珊内格尔博士（密苏里州大学）将提供关于异种雌激素，内分泌干扰物筛选方法和化学混合物的指导。候选人之前的工作和她组建的指导团队将共同确保她能够实现她的研究和职业发展目标，并将帮助她开始独立的职业生涯。

 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.