PEDIGREE: Prenatal Environmental Determinants of InterGenerational Risk

描述（由申请人提供）：研究者提出了一项独特的研究，研究人类在乳房暴露的两个关键窗口期暴露于有机氯：1)怀孕时，准备哺乳使母亲的乳房处于致癌风险中；2)产前期间，乳房分化使女儿的乳房处于致癌风险中。很少有人体研究可以直接测量在这些关键时期接触内分泌活性化合物与随后乳腺癌风险的关系。拟议的研究解决了这一差距，并代表了一个新颖而独特的机会，有效地利用了跨越两代人的现有队列。研究人员还将开发队列成员作为全面研究伙伴参与的能力，增强在这一独特研究人群中继续进行乳腺癌研究的相关性和成功。这项研究是通过对儿童健康与发育研究妊娠队列（CHDS）进行50年的随访而得以实现的。在禁止使用有机氯农药和多氯联苯之前的20世纪60年代，孕妇的妊娠血清样本是在有机氯农药和多氯联苯暴露高峰时期收集的。拟议的研究资助对最近诊断为乳腺癌的母亲进行有机氯血清检测，以扩大先前发表的一项关于母亲乳腺癌的研究的样本量，收集200张诊断为乳腺癌的母亲的女儿的乳房x光照片，检测400个成年女儿的DNA甲基化样本，支持新的数据分析，以验证一个新的假设，即母亲在一个关键窗口期（14岁之前）暴露于环境中会增加胎儿对子宫内环境暴露影响的易感性；2)在尚未获得数据的情况下检验一个广为接受的假设；患乳腺癌妇女的女儿在子宫内更容易受到环境暴露的影响；3)检查妊娠激素暴露在解释观察到的有机氯与母亲乳腺癌、初潮年龄、乳房x线摄影密度和女儿DNA甲基化之间的关联中的作用。

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.