Human Placental Morphology, Function, and Pathology: Relationship to Environmental Exposures and Newborn and Child Health

A. PA项目摘要ES 029 9281（PI：CM SALAFIA，RK米勒） 金属暴露是常见的，其对人类健康的有害影响也是常见的。更令人担忧的是， 对脆弱的发育中的胎儿的影响然而，即使胎盘可从每个 交付，很少进行常规评估。因此，我们仍然缺乏关于 产前金属暴露损害胎儿的机制，沿着通往早期的道路的关键步骤， 识别有风险的胎儿，并进行干预，以优化儿童和终身福祉。人们越来越 子宫内环境影响胎盘发育和功能的证据， 后代肥胖的风险。儿童期超重和肥胖是肥胖的常见和重要的预测因子。 发病率和死亡率。目标是在一个独特的、已建立的队列中确定， 研究了所有胎盘，并将胎盘组织存档，胎盘健康和功能如何受到影响 以及金属暴露和胎盘毒性导致婴儿改变的途径 体细胞生长和代谢。最后，临床结果将通过体外外植体研究进行验证， 人类胎盘，其中可以测试金属暴露对胎盘细胞特异性反应的诱导。 从识别、定量和定位特定细胞类型金属的尖端方法开始， 在整个妊娠期间在胎盘中积累，我们将使用存档的胎盘组织进一步识别胎盘 病理学（包括细胞增殖、凋亡、炎症和内皮或巨噬细胞活化）， 传统的组织学和免疫组织化学方法，配对载玻片数字化和自动定制 软件算法配准连续数字化胎盘组织载玻片，以将胎盘病变与 金属的存在、数量和类型。结合从以下数据中提取的孕产妇、妊娠期和新生儿数据， 电子病历，我们将转移到分析新生儿干血点（DBS）收集， 作为纽约州新生儿筛查计划的一部分存档，以检测以下循环标志物： 炎症，可能导致金属暴露和胎盘毒性，以及代谢概况，我们将 与胎盘大小、新生儿大小和连续儿童体重的长度百分位数和生长轨迹相关， 12个月大。最后，我们的2000个母婴胎盘三联体的大样本量将使我们能够探索 胎盘和儿童中金属毒性的性别依赖性影响。本提案中的方法提供了 对胎盘在金属毒性和发育的胎儿病理生理学中的作用进行了前所未有的研究 肥胖在1岁时的发病率，是健康风险包括肥胖、糖尿病和心血管疾病的强有力预测因素。

A. PARENT PROJECT ABSTRACT ES029 9281 (PIs: CM SALAFIA, RK MILLER) Metal exposures are common as are their pernicious effects on human health. Of greater concern are their actions on the vulnerable developing fetus. However, even though the placenta is available from every delivery, few are routinely evaluated. Therefore, we continue to lack sufficient information regarding the mechanisms by which prenatal metals exposures harm the fetus, key steps along the path towards early identification of the at-risk fetus, and intervention to optimize childhood and lifelong wellbeing. There is growing evidence that the intrauterine environment impacts placental development and function to ultimately influence the risk of obesity in offspring. Childhood overweight and obesity are common and important predictors of morbidity and mortality across the life course. The goal is to determine, in a unique, established cohort in which all-placentas were studied and have placental tissue archived, how placental health and function are affected by metal exposures, and the pathways that lead from metals exposures and placental toxicity to altered infant somatic growth and metabolism. Finally, the clinical results will be validated with in vitro explant studies of human placentas, in which metals exposures can be tested for induction of placental cell specific responses. Starting with cutting edge methods that identify, quantitate and localize to specific cell types metals that accumulate in the placenta across gestation, we will use archived placental tissues further to identify placental pathology (including cell proliferation, apoptosis, inflammation and endothelial or macrophage activation) by traditional histologic and immunohistochemical methods, pairing slide digitization and automated custom software algorithms that register serial digitized placental tissue slides to match placental lesions to the presence, quantity and type of metals. Together with maternal, gestational and neonatal data extracted from the electronic medical record, we will move to analyses of newborn dried blood spots (DBS) collected and archived as part of the Newborn Screening Program of New York State to test for circulating markers of inflammation that may result from metals exposures and placental toxicity, and a metabolic profile that we will correlate with placental size, newborn size, and serial child weight for length centiles and growth trajectory to 12 months of age. Lastly our large sample size of 2000 mother-child-placenta triads will allow us to explore sex-dependent effects of metals toxicity in the placenta and in the child. The methods in this proposal provide unprecedented interrogation of the placenta’s role in fetal pathophysiology of metals toxicity and development of obesity at 1 year, a strong predictor of health risks including obesity, diabetes and cardiovascular disease.