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

环境雌激素对小鼠乳腺两性发育的影响

• 批准号: 9114564
• 负责人: Laura N. Vandenberg
• 金额: $ 14.78万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9114564
• 关键词: Address; Adult; Affect; Age; Applications Grants; Architecture; Award; Biology; Breast Epithelial Cells; Cancerous; Cell Count; Cells; Chemicals; Chromatin; DNA; Data; Development; Developmental Endocrinology; Diagnosis; Disease; Dose; Embryonic Development; Endocrine; Endocrine Disruptors; Endocrinology; Ensure; Environmental Estrogen; Environmental Risk Factor; Epidemiology; Epithelial; Epithelial Cells; Epithelium; Estradiol; Estrogen Receptors; Estrogens; Event; Exposure to; Female; Fetal Development; Gene Expression; Genetic; Genetic Predisposition to Disease; Gland; Goals; Grant; Hormones; Immunohistochemistry; In Situ Hybridization; K22 Award; Knowledge; Laboratory Animals; Learning; Lesion; Life; Male mammary gland; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Massachusetts; Mentors; Methods; Missouri; Modeling; Molecular; Molecular Genetics; Mus; National Institute of Environmental Health Sciences; Nipples; Operative Surgical Procedures; Organ; Perinatal; Perinatal Exposure; Play; Precipitation; Property; Puberty; Research; Role; Signal Transduction; Signaling Molecule; Staging; System; Techniques; Testosterone; Tissue Banks; Tissues; Toxic Environmental Substances; Universities; Uterus; Woman; Work; analog; anticancer research; base; bisphenol A; career; career development; cellular targeting; consumer product; environmental chemical; estrogenic; exposed human population; fetal; fetal xenoestrogen exposure; gland development; human male; hypothalamic pituitary gonadal axis; improved; in utero; male; malignant breast neoplasm; mammary epithelium; mammary gland development; mouse development; postnatal; prevent; public health relevance; research and development; research study; response; screening; time use; tool; xenoestrogen

 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.

 描述（由申请人提供） 候选人的总体长期职业目标是了解生命早期的环境因素如何导致包括女性乳腺癌在内的成人疾病的发展。她希望利用分子、遗传、组织和内分泌工具来解决乳腺癌是否在子宫内开始的问题。这项 K22 拨款申请的研究目的是了解具有雌激素特性的环境化学物质双酚 S (BPS) 如何扰乱乳腺的发育。 候选人的初步数据表明，围产期接触 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来扰乱乳腺发育。该研究提出了两个目标：第一个目标是评估 BPS 对男性乳腺的影响是否是由于胚胎发生过程中上皮区室中细胞数量的变化、青春期对激素敏感性的改变和/或循环激素水平的破坏所致。第二个目标是表征雌激素受体在 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以她之前对双酚 A (BPA) 和乳腺的研究为基础；她的工作描述了低剂量围产期 BPA 暴露对几个成年小鼠腺体的影响，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，并确定了暴露期间 BPA 对末乳腺的细胞靶标。因此，候选人组装了一系列组织、组织学和细胞工具来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，正如 K22 奖的目的一样，候选人组建了一个跨学科专家团队作为赞助商：R. Thomas Zoeller 博士（马萨诸塞大学阿默斯特分校）已同意成为她的主要赞助商。凭借其在发育内分泌学方面的专业知识，佐勒博士的指导将使候选人能够改进基于系统的内分泌学方法，并解决环境化学物质通过破坏下丘脑-垂体-性腺轴而对乳腺产生间接影响的可能性。 D. Joseph Jerry 博士（马萨诸塞大学阿默斯特分校）和 Suzanne Fenton 博士（NIEHS）将指导候选人乳腺治疗的方法和技术。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利用乳腺来检查环境毒物；这两种方法都将使她的项目受益匪浅。最后，Susan Nagel 博士（密苏里大学）将提供有关异种雌激素、内分泌干扰物筛查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，并帮助她开启独立的职业生涯。