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: 8336657
• 负责人: Suzanne Fenton
• 金额: $ 157.48万
• 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/8336657
• 关键词: Acids; Acute; Adverse effects; Affect; Amniotic Fluid; Animal Model; Animals; Asians; Atrazine; Birth; Brain; Breast; Breast Diseases; Camping; Carcinogens; Chemical Actions; Chemicals; Complex; Computers; Contractor; Data; Delayed Puberty; Development; Differentiation and Growth; Discipline of Nursing; Dose; Endocrine; Endocrine Disruptors; Environmental Health; Epidemic; Epithelial; European; Evaluation; Female; Flame Retardants; Friction; Future; Generations; Genes; Gland; Goals; Growth and Development function; Health; Herbicides; Hormones; Human; Impairment; Infant formula; Inflammation; Investigation; Laboratory Personnel; Lactation; Lead; Life; Liver; Liver neoplasms; Malignant Neoplasms; Malignant neoplasm of male breast; Mammary Gland Parenchyma; Mammary gland; Measures; Military Personnel; Milk; Molecular; Mus; Nature; Neonatal; Outcome; Outcome Study; Paper; Pathway interactions; Phase; Placenta; Population; Predisposition; Pregnancy; Production; Prostate; Puberty; Publishing; Rattus; Regulation; Reporting; Research; Risk; Risk Assessment; Rodent; Role; Route; Serum; Signal Pathway; Site; Solvents; Staining method; Stains; Surface; Techniques; Testing; Time; Tissues; Training; Update; Urine; Uterine Neoplasms; Validation; Weight Gain; Woman; Work; base; breast cancer diagnosis; computerized data processing; environmental chemical; exposed human population; fetal; girls; ground water; human disease; interest; male; malignant breast neoplasm; mammary gland development; men; mouse model; offspring; prevent; prostatitis; pup; reproductive; response; soy; surfactant; tumor

Our research is focused on understanding the effects of environmental chemicals on mammary gland (MG) development, function, and cancer susceptibility. 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 year, 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 shows that this lipophilic flame retardant mixture is transferred from the dam to the offspring across the placenta and during lactation. The female offspring at birth demonstrates normal MG development, but after nursing the entire lactation period, demonstrates impaired MG development in a dose-responsive manner. Brominated flame retardants are known to bioaccumulate and their lipophilic nature lends to high levels of exposure through milk. Other reproductive tissues and hormones were affected in the study, but the MG seemed to be one of the more sensitive tissues in the female. The NTP is also working on high use and emerging flame retardants and our expertise has been emplyed in those studies. We have also reported MG effects following atrazine exposure during late pregnancy in rats. Atrazine is one of the highest use herbicides in the US. In the female rat offspring, the mammary gland is the most endocrine-sensitive end point evaluated. This year, we published data demonstrating that male puberty and prostate inflammation were both adversely affected by low dose ATR metabolite mixture given during late pregnancy. In this work, we demonstrate that doses that are only 100-fold higher than the levels detected in surface and ground water cause significant prostatitis and levels only 1000-fold above ground water levels significantly delay puberty and induce prostatitis. These data are being considered in the current atrazine risk assessment as the critical end points for acute effects. We have donated our time to inform the US EPA on our on-going research on two different occasions in the last year. Our on-going work on this high use herbicide is to understand its mechanism of action, and its metabolites, on the fetal and early neonatal MG development. We aim to identify genes involved in this response and to determine the similarity of these genes with other chemicals that induce a similar delay in morphological development in the rat or mouse. We predict that there are a common set of genes regulating delayed MG development. Finally, we have published numerous papers investigating the effects of PFOA in the mouse model over the last year. PFOA is a surfactant used in computers, wiring, and firefighting foam to reduce friction, and in non-stick coating and stain-preventing agents and applications. All US inhabitants have PFOA in their serum. The US population is exposed to it in their everyday life. We have developed techniques for measuring the amount of PFOA in serum, urine, amniotic fluid, brain, MG, and liver. We have characterized the amount of PFOA that gets to the various compartments of the body following a single or multiple exposure scenarios. The mammary gland, again, appears to be a sensitive tissue to the effects of PFOA. The liver is another target site for this compound. PFOA is transferred to the offspring through nursing and the amount that is present in milk vs serum was quantitatively determined in our studies. Our research this year has clarified the role of maternal transfer of PFOA to the adverse health outcomes of the offspring. The mammary gland development has been the focus of our work this year and we will soon submit twoother papers on this important compound. In the future, we will report on the low dose effects of PFOA on uterine and liver tumors, as well as determine the lowest doses that will affect the MG development. These studies are in line with current efforts on-going in the NTP, as perfluorinated chemicals are under investigation there, in several capacities. PFOA is undergoing risk regulation at the state level at this point, as a federal risk assessment has not taken place. Production and use of this compound is set to be phased out in 2015, however that does not mean that we will not be exposed any further. Other complex flouro-telomer acids can be broken down to PFOA and those compounds will not be regulated. In addition, European and Asian companies are now beginning PFOA production and therefore, exposure will continue. Federal risk assessment efforts have begun and we have informed the various state and federal committees of our work when asked. We have performed 4 updates this year for the USEPA, NJ state, and MN state departments of environmental health. Our future work will involve investigation of dry cleaning solvents and their developmental exposure effects on the mammary gland, specifically in males, as 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 are also investigating the effects of early life soy infant formula active ingredients on the developing mammary gland in the male and female.

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。 使用人类疾病的动物模型使我们能够评估不同的接触途径，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。 在过去的一年里，我们制作了许多重要的文件，这些文件被用于溴化阻燃剂（DE-71）、全氟辛酸（PFOA）和阿特拉津（ATR）的风险监管。 阻燃剂目前在州一级进行监管，因为联邦风险评估尚未完成。 我们在大鼠中对DE-71的研究表明，这种亲脂性阻燃剂混合物通过胎盘和哺乳期从母体转移到后代。雌性后代在出生时表现出正常的MG发育，但在整个哺乳期哺乳后，表现出剂量反应性方式的MG发育受损。 已知溴化阻燃剂具有生物累积性，其亲脂性导致通过牛奶的高水平接触。 其他生殖组织和激素在研究中受到影响，但MG似乎是女性中更敏感的组织之一。NTP还在研究高使用率和新兴的阻燃剂，我们的专业知识已在这些研究中得到应用。 我们还报告了MG的影响，阿特拉津暴露在大鼠妊娠后期。阿特拉津是美国使用最多的除草剂之一。 在雌性大鼠后代中，乳腺是评价的最敏感的内分泌终点。今年，我们发表的数据表明，男性青春期和前列腺炎症都受到不利影响的低剂量ATR代谢物混合物在怀孕后期。在这项工作中，我们证明，仅比地表水和地下水中检测到的水平高100倍的剂量会导致严重的前列腺炎，而仅比地下水水平高1000倍的剂量会显著延迟青春期并诱发前列腺炎。 目前的阿特拉津风险评估正在考虑将这些数据作为急性效应的关键终点。 去年，我们在两个不同的场合向美国环保署通报了我们正在进行的研究。我们正在进行的工作，这种高使用除草剂是了解其作用机制，其代谢产物，对胎儿和早期新生儿MG的发展。 我们的目标是确定参与这种反应的基因，并确定这些基因与其他化学物质的相似性，这些化学物质诱导大鼠或小鼠的形态发育出现类似的延迟。 我们预测，有一组共同的基因调控延迟MG的发展。 最后，在过去的一年里，我们发表了许多论文，研究PFOA在小鼠模型中的作用。 PFOA是一种表面活性剂，用于计算机、布线和消防泡沫，以减少摩擦，并用于不粘涂层和防污剂和应用。 所有美国居民的血清中都含有PFOA。 美国人在日常生活中会接触到它。 我们已经开发出了 测量血清、尿液、羊水、脑、MG和肝脏中的PFOA量。 我们已经描述了在单次或多次暴露情况下进入身体各个部位的PFOA的量。 乳腺，再次，似乎是一个敏感的组织的影响PFOA。 肝脏是这种化合物的另一个靶点。 PFOA通过哺乳转移到后代，在我们的研究中定量测定了牛奶与血清中的含量。 我们今年的研究已经阐明了母体转移PFOA对后代不良健康结果的作用。乳腺发育一直是我们今年的工作重点，我们将很快提交另外两篇关于这种重要化合物的论文。 在未来，我们将报告PFOA对子宫和肝脏肿瘤的低剂量效应，以及确定影响MG发展的最低剂量。这些研究与目前在《国家臭氧规划》中正在进行的努力是一致的，因为全氟化学品正在该方案中以若干身份进行调查。 PFOA目前正在州一级进行风险监管，因为联邦风险评估尚未进行。 这种化合物的生产和使用将在2015年逐步淘汰，但这并不意味着我们不会进一步暴露。 其他复杂的氟调聚酸可以分解为PFOA，这些化合物将不受管制。 此外，欧洲和亚洲公司现在开始生产PFOA，因此，风险将继续存在。 联邦风险评估工作已经开始，我们已经在被要求时向各个州和联邦委员会通报了我们的工作。 我们今年已经为美国环保局、新泽西州和明尼苏达州的环境卫生部门进行了4次更新。 我们未来的工作将涉及干洗溶剂及其对乳腺的发育暴露影响的调查，特别是在男性中，因为这些化合物理论上在出生或成长于美国北卡罗来纳州勒琼营军事基地的男性乳腺癌诊断中发挥作用。 我们还在研究早期大豆婴儿配方奶粉活性成分对男性和女性乳腺发育的影响。