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: 8149121
• 负责人: Suzanne Fenton
• 金额: $ 204.06万
• 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/8149121
• 关键词: Endocrine Disruptors; Mammary gland

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 two other 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。使用动物模型研究人类疾病使我们能够评估不同的接触途径、试验化学品的内部剂量，以及对啮齿动物产生的与人类健康有关的各种影响。在过去一年中，我们制定了许多重要文件，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。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DE-71大鼠的研究表明，这种亲脂阻燃混合物可以通过胎盘和哺乳期从母体传递给后代。雌性后代在出生时表现出正常的MG发育，但在哺乳整个哺乳期后，表现出剂量反应性MG发育受损。溴化阻燃剂具有生物蓄积性，其亲脂性使其可通过牛奶大量接触。在这项研究中，其他生殖组织和激素也受到了影响，但雌性的MG似乎是最敏感的组织之一。国家毒理学规划还在研究高用途和新兴阻燃剂，我们的专业知识已用于这些研究。