Project 3: Placental Biomarkers of Exposure and Outcome (Marsit)

有强有力的证据表明，子宫内经历的环境有助于儿童和成年期间的心血管，代谢，免疫和神经系统健康。在生命早期确定儿童处于危险之中对改善健康结果至关重要;暴露和结果的生物标志物是用于风险识别的有力工具，并提供了一个机会，为疾病的发育起源所涉及的机制提供信息。来自我们自己实验室和其他实验室的新证据表明，胎盘作为宫内环境和胎儿发育的主要调节器，在健康和疾病的发育起源中起着关键作用。因此，胎盘是一种理想的组织，在其中鉴定介导胎儿健康编程的功能性生物标志物。在已发表的和初步的研究中，我们已经证明，暴露，如砷，可以改变原代人类胎盘组织中的DNA甲基化和基因表达的模式，我们已经证明，这种改变与胎儿生长和新生儿神经行为的措施。我们的目标是开发新的 通过检查孕妇所遇到的环境暴露影响婴儿胎盘的表观遗传和基因表达谱以及这些功能改变与儿童健康状况不佳相关的假设，确定暴露和结果的生物标志物。我们将利用正在进行的新罕布什尔州出生队列研究的现有资源及其已建立的胎盘组织生物储存库，结合婴儿和母亲砷暴露的生物标志物，对基因表达和全基因组DNA甲基化进行敏感和可靠的评估。我们建议使用最先进的基因组技术来鉴定和验证人类胎盘中易受环境暴露影响的DNA甲基化和基因表达的新谱，并检查它们与新生儿结局的关联，包括项目1和项目2中评估的生长、感染和神经发育。 方案的2。这些检查将为终身健康的发育起源机制提供重要的见解，突出受驱动儿童健康的暴露影响的新途径，并确定新的生物标志物，可用于在生命的最早阶段发现处于危险中的儿童，以便尽快采取必要的干预措施以预防未来的疾病。

There is strong evidence that the environment experienced in utero contributes to cardiovascular, metabolic, immunologic, and nervous system health during both childhood and adulthood. Defining children at-risk early in life is critical to improving health outcomes; biomarkers of exposure and outcome are powerful tools to use in risk identification and offer an opportunity to inform the mechanisms involved in the developmental origins of disease. Emerging evidence, from our own laboratories and others, suggests that the placenta, as a master regulator of the intrauterine environment and of fetal development, plays a critical role in the developmental origins of health and disease. Thus, the placenta is an ideal tissue in which to identify functional biomarkers that mediate fetal programming of health. In published and preliminary studies we have demonstrated that exposures, such as arsenic, can alter the patterns of DNA methylation and of gene expression in primary human placental tissue, and we have demonstrated that such alterations are associated with fetal growth and newborn neurobehavioral measures. We aim here to develop novel biomarkers of exposure and outcome by examining the hypothesis that environmental exposures encountered by a pregnant woman impact the epigenetic and gene expression profiles of the infant's placenta and these functional alterations are associated with poor-health outcomes in the children. We will employ the existing resources of the ongoing New Hampshire Birth Cohort Study, and its established biorepository of placental tissues, to allow sensitive and robust assessment of gene expression and genomewide DNA methylation in combination with infant and maternal biomarkers of arsenic exposure. We propose to use state-of-the-art genomic technologies to identify and validate novel profiles of DNA methylation and gene expression susceptible to environmental exposure in human placenta and to examine their association with newborn outcomes including growth, infection and neurodevelopment being assessed in Projects 1 and 2 of the Program. These examinations will provide critical insight into the mechanisms of the developmental origins of lifelong health, highlight novel pathways affected by exposures that drive children's health, and identify novel biomarkers which can be used to find at the earliest points of life, children at-risk so necessary interventions can be employed soon enough to prevent future disease.