Mammary Gland as a Sensitive End Point to Effects of Endocrine Disruptors

乳腺作为内分泌干扰物影响的敏感终点

• 批准号: 9354102
• 负责人: Suzanne Fenton
• 金额: $ 370.68万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9354102
• 关键词: Adipocytes; Adverse effects; Affect; Aging-Related Process; Alkanesulfonates; Animal Model; Animals; Area; Arsenic; Atlases; Atrazine; Biological Assay; Breast; Breast Cancer Risk Factor; Breast Diseases; Camping; Carcinogens; Cells; Centers for Disease Control and Prevention (U.S.); Chemical Actions; Chemical Exposure; Chemicals; Collaborations; Collection; Contractor; Core Facility; Data; Data Quality; Data Set; Development; Differentiation and Growth; Disease; Dose; Endocrine; Endocrine Disruptors; Endocrine Reproductive Tissue; Endocrine disruption; Epidemic; Epidemiologist; Epithelial; Evaluation; Female; Fetus; Flame Retardants; Future; Gene Expression; Generations; Gland; Goals; Guidelines; Health; Hormones; Human; Hyperplasia; Impairment; Instruction; Interruption; Investigation; Laboratories; Lactation; Lead; Life; Link; Malignant Neoplasms; Malignant neoplasm of male breast; Mammary Gland Parenchyma; Mammary Neoplasms; Mammary gland; Manuscripts; Melissa; Methodology; Military Personnel; Mission; Molecular; Mus; National Institute of Environmental Health Sciences; Obesity; Organic Chemicals; Outcome Study; Paper; Pathway interactions; Population; Predisposition; Protocols documentation; Puberty; Publishing; Rattus; Regulation; Reproductive Endocrinology; Research; Research Personnel; Risk; Risk Assessment; Rodent; Role; Running; Sampling; Science; Services; Sprague-Dawley Rats; Staging; Testing; Time; Tissues; Weight Gain; Woman; Work; age related; analog; base; bisphenol A; blind; breast cancer diagnosis; breast density; cancer risk; density; dosimetry; environmental chemical; exposure route; follow-up; girls; human disease; improved; interest; lipid biosynthesis; male; malignant breast neoplasm; mammary gland development; men; normal aging; novel; obesogen; obesogenic; offspring; perfluorooctanoic acid; pregnant; prenatal; prenatal exposure; pup; reproductive; response; signal processing; tetrabromobisphenol A; tumor

Our research is focused on understanding the effects of environmental chemicals on mammary gland (MG) development, function, and cancer susceptibility. We have expanded this focus area in recent years to include the effect of environmental chemicals on breast cancer risk factors such as puberty timing, obesity, and lactation. The use of animal models for human disease allows us to evaluate different routes of exposure, internal dose of the test chemical, as well as a variety of effects in the rodent that are relevant to human health. During the last several years, we have produced numerous important documents that are being used in the risk regulation of brominated flame retardants (DE-71), perfluorooctanoic acid (PFOA) and atrazine (ATR). Flame retardants are currently regulated at the state level, as a federal risk assessment has not been completed yet. Our work on DE-71 in the rat are completed for now, but we have expanded our study of flame retardants this year to include tetrabromobisphenol A (TBBPA) and Firemaster 550. I continue to advise the ongoing NTP studies regarding the mechanisms of action of these high use and emerging flame retardants. In the female rodent offspring, the mammary gland is one of the most endocrine-sensitive end points that we have evaluated following prenatal chemical exposures. Our current studies using volatile organic chemicals (VOCs), bisphenol analogues, perfluorooctanoic acid (PFOA), TBBPA, and arsenic all demonstrate this finding. We have nearly finished studies evaluating mammary effects of safe level vs 42 ppm arsenic in mice, human relevant VOC mixtures in rats, PFOA mechanism of action and strain differences in mice, and two BPA replacement chemicals in mice. I have also finalized my evaluation of the mammary samples from the BPA-CLARITY study. Unfortunately we are not sure we can use the data from the CLARITY study due to technical issues in the study resulting in animals not being collected in the same stage of the cycle and contamination of the controls with BPA. Numerous manuscripts are expected from these other studies. We have made major progress on our work involving investigation of VOCs and their developmental exposure effects on the mammary gland, specifically in males. These compounds are theorized to have a role in male breast cancer diagnoses in men who were born or grew up at the Camp Lejeune military base in NC, USA. We have nearly finished dosimetry studies in the pregnant and lactating rat and her offspring in conjunction with our CDC collaborators. We have evaluated mammary gland development and carcinogen-induced mammary tumors following prenatal exposure and have prepared two manuscripts on the effects of these compounds in male and female rats. With this study and our mammary gland atlas of Harlan Sprague Dawley rats that will also be published this coming year, we have added significantly to what is known about male rodent mammary gland development, susceptibility to endocrine disruption, and carcinogen-induced mammary cancer. We are working with Melissa Troester, an epidemiologist at UNC, to document normal aging of the male and female mammary gland of mice and rats, in comparison to her human samples. She has shown that in women with breast cancer there is an interruption of the normal aging process, and by using chemically-exposed rodent tissues, we may determine which types of chemicals may predispose populations to increased breast cancer risk via that mode of action. We have nearly finished studies to look at susceptibility to mammary gland hyperplasia in female mice exposed to bisphenol A (BPA), BPAF and BPAS (fluorinated and sulfonated forms)in early life. These studies are all in line with NTP mission or in collaboration with other Federal agencies. Dispositon studies are underway to understand the transfer of these compounds to the developing fetus and the clearance within the pregnant dam. These studies have been held up due to congestion in the mass spec core facility in NIEHS. Our recent studies involving TBBPA and Firemaster are large collaborative studies where we are either running the study for many PIs to get target tissues of interest (TBBPA) or we are providing a service of isolating and evaluating mammary tissue (Firemaster). Both of these flame retardants seem to act as endocrine disruptors, affecting multiple reproductive tissues, fat cells, and hormone levels. Several papers on these studies are forthcoming. Over the next year we will be performing a blind evaluation of about 100 chemicals identified in Tox21 as activating specific endpoints thought to be linked to an obesogenic response. We are using mouse 3T3-L1 low passage cells to assess adipogenesis and lipogenesis. Gene expression and follow-up studies will follow on the chemicals identified as most interesting, either for their potential to act as a potent obesogen or because they were a false positive or negative. We are working with a team of investigators, including Kris Thayer in OHAT, to produce a document on this concept and test other aspects of the chemical response. From the data accumulated in this group effort, we will better understand the utility and shortcomings of the Tox21 data set in predicting obesogens and may be able to develop assays to add to the high throughput methodology.

我们的研究重点是了解环境化学物质对乳腺 (MG) 发育、功能和癌症易感性的影响。近年来，我们扩大了这一重点领域，包括环境化学物质对青春期时机、肥胖和哺乳等乳腺癌危险因素的影响。使用人类疾病动物模型使我们能够评估不同的暴露途径、测试化学品的内部剂量以及与人类健康相关的啮齿动物的各种影响。 在过去几年中，我们编写了许多重要文件，用于溴化阻燃剂 (DE-71)、全氟辛酸 (PFOA) 和莠去津 (ATR) 的风险监管。 由于联邦风险评估尚未完成，阻燃剂目前在州一级受到监管。我们对大鼠 DE-71 的研究目前已经完成，但今年我们扩大了阻燃剂的研究范围，将四溴双酚 A (TBBPA) 和 Firemaster 550 纳入其中。我将继续为正在进行的 NTP 研究提供有关这些高用量和新兴阻燃剂作用机制的建议。 在雌性啮齿动物后代中，乳腺是我们在产前化学暴露后评估的最内分泌敏感的终点之一。我们目前使用挥发性有机化学品 (VOC)、双酚类似物、全氟辛酸 (PFOA)、TBBPA 和砷的研究都证明了这一发现。我们已接近完成研究，评估安全水平与 42 ppm 砷对小鼠的乳腺影响、人类相关 VOC 混合物对大鼠的影响、PFOA 的作用机制和小鼠品系差异，以及两种 BPA 替代化学物质对小鼠的影响。我还完成了对 BPA-CLARITY 研究中乳房样本的评估。 不幸的是，我们不确定是否可以使用 CLARITY 研究的数据，因为研究中的技术问题导致动物没有在周期的同一阶段被收集，并且对照被 BPA 污染。 这些其他研究预计会产生大量手稿。 我们在研究挥发性有机化合物及其对乳腺（特别是男性）发育暴露影响的工作方面取得了重大进展。理论上，这些化合物在美国北卡罗来纳州勒琼军营军事基地出生或长大的男性乳腺癌诊断中发挥作用。我们与疾病预防控制中心的合作者合作，即将完成对怀孕和哺乳期大鼠及其后代的剂量测定研究。我们评估了产前暴露后的乳腺发育和致癌物诱发的乳腺肿瘤，并准备了两份关于这些化合物对雄性和雌性大鼠的影响的手稿。通过这项研究以及将于今年出版的 Harlan Sprague Dawley 大鼠乳腺图谱，我们大大增加了对雄性啮齿动物乳腺发育、内分泌干扰易感性和致癌物诱发乳腺癌的了解。我们正在与北卡罗来纳大学的流行病学家 Melissa Troester 合作，记录小鼠和大鼠的雄性和雌性乳腺的正常衰老情况，并与她的人类样本进行比较。她表明，患有乳腺癌的女性的正常衰老过程会受到干扰，通过使用接触化学物质的啮齿动物组织，我们可以确定哪些类型的化学物质可能通过这种作用方式使人群易患乳腺癌的风险增加。 我们即将完成研究，旨在了解生命早期接触双酚 A (BPA)、BPAF 和 BPAS（氟化和磺化形式）的雌性小鼠对乳腺增生的易感性。这些研究均符合 NTP 的使命或与其他联邦机构合作。处置研究正在进行中，以了解这些化合物向发育中的胎儿的转移以及怀孕母鼠体内的清除。由于 NIEHS 质谱核心设施的拥堵，这些研究被搁置。 我们最近涉及 TBBPA 和 Firemaster 的研究是大型合作研究，我们要么为许多 PI 开展研究以获得感兴趣的目标组织 (TBBPA)，要么提供分离和评估乳腺组织的服务 (Firemaster)。 这两种阻燃剂似乎都会起到内分泌干扰物的作用，影响多种生殖组织、脂肪细胞和激素水平。 关于这些研究的几篇论文即将发表。 明年，我们将对 Tox21 中确定的约 100 种化学物质进行盲法评估，这些化学物质可激活被认为与肥胖反应相关的特定终点。 我们使用小鼠 3T3-L1 低传代细胞来评估脂肪生成和脂肪生成。基因表达和后续研究将针对被确定为最有趣的化学物质进行，要么是因为它们具有作为有效致肥胖剂的潜力，要么是因为它们是假阳性或阴性。我们正在与包括 OHAT 的 Kris Thayer 在内的研究团队合作，编写有关这一概念的文件并测试化学反应的其他方面。从该小组工作中积累的数据中，我们将更好地了解 Tox21 数据集在预测肥胖因素方面的效用和缺点，并可能开发出检测方法以添加到高通量方法中。