PEDIGREE: Prenatal Environmental Determinants of InterGenerational Risk

描述(由申请人提供)：研究人员提出了一项关于人类在两个关键的乳房暴露窗口中暴露于有机氯的独特研究：1)怀孕时，准备哺乳使母亲的乳房面临致癌风险；2)产前，当乳房分化使母亲的乳房面临致癌风险时。很少有人类研究可以直接测量在这些关键时期暴露于内分泌活性化合物与随后的乳腺癌风险的关系。拟议的研究解决了这一差距，并代表了一个新的和独特的机会，有效地利用了跨越两代人的现有队列。研究人员还将发展队列成员作为正式研究伙伴参与的能力，加强持续乳腺癌研究在这一独特研究群体中的相关性和成功。这项研究是通过对儿童健康和发育研究怀孕队列(CHDS)长达50年的跟踪研究而实现的。孕妇妊娠血清样本是在20世纪60年代S时期有机氯农药和多氯联苯暴露高峰期收集的，当时这些化学物质还没有被禁止。拟议的研究资金用于为最近诊断的母亲乳腺癌病例进行有机氯血清检测，以扩大先前发表的母亲乳腺癌研究的样本规模，为被诊断为乳腺癌的母亲的女儿收集200张乳房X光照片，分析400名成年女儿的DNA甲基化，支持新的数据分析，以1)测试一项新的假设，即母亲在关键窗口(14岁之前)接触会增加胎儿对子宫内环境暴露的影响的易感性；2)测试一个公认的假设，在此之前没有数据可用；患乳腺癌的妇女的女儿在子宫中更容易受到环境暴露的影响；3)检查孕激素暴露在解释观察到的有机氯与母亲乳腺癌及其女儿初潮年龄、乳房X光密度和DNA甲基化之间的关系的作用。

DESCRIPTION (provided by applicant): The investigators propose a unique study of human exposure to organchlorines during two critical windows of exposure for the breast: 1) pregnancy when preparation for lactation places the breast at risk for carcinogenesis in the mother and 2) the prenatal period when breast differentiation places the breast at risk for carcinogenesis in the daughter. There are few human studies where exposure to endocrine active compounds during these critical periods can be measured directly in relation to subsequent breast cancer risk. The proposed research addresses this gap and represents a novel and unique opportunity, efficiently using an existing cohort that spans two generations. The investigators will also develop the capacity for cohort members to participate as full research partners, enhancing the relevance and success of continuing breast cancer research in this unique study population. This study is made possible by a 50-year follow-up of the Child Health and Development Studies Pregnancy Cohort (CHDS). Maternal pregnancy serum samples were collected during peak exposure to organochlorine pesticides and polychlorinated biphenyls in the 1960's, prior to the ban on these chemicals. The proposed research funds organochlorine serum assays for recently diagnosed cases of breast cancer in mothers to extend the sample size for a prior published study of maternal breast cancer, collects 200 mammograms for daughters of mothers who have been diagnosed with breast cancer, assays 400 adult daughter specimens for DNA methylation, supports new data analysis to 1) test a novel hypothesis that maternal exposure during a critical window (prior to age 14) increases susceptibility of the fetus to the effects of environmental exposures in the womb; 2) test a well accepted hypothesis where data have not heretofore been available; that daughters of women who developed breast cancer are more susceptible to environmental exposures in the womb; and 3) examine the role of pregnancy hormone exposures in explaining observed organochlorine associations with breast cancer in mothers and age at menarche, mammographic density and DNA methylation of their daughters.