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

项目摘要/摘要 金属暴露是常见的，对人类健康的有害影响也是如此。更令人担忧的是他们的 对脆弱的发育中胎儿采取的行动。然而，即使胎盘在每个地方都有 在交付过程中，很少对其进行例行评估。因此，我们仍然缺乏关于 产前金属暴露损害胎儿的机制，在通往早期的道路上的关键步骤 识别高危胎儿，并进行干预，以优化童年和终身幸福。有越来越多的 宫内环境影响胎盘发育和功能最终影响的证据 后代肥胖的风险。儿童超重和肥胖是常见的和重要的预测因素 整个生命过程中的发病率和死亡率。目标是在一个独特的、既定的队列中确定 对所有胎盘进行研究，并将胎盘组织存档，胎盘健康和功能如何受到影响 通过金属暴露，以及金属暴露和胎盘毒性对改变的婴儿导致的途径 体细胞生长和代谢。最后，临床结果将通过体外外植体研究得到验证。 人类胎盘，其中金属暴露可以被测试以诱导胎盘细胞特异性反应。 从识别、定量和定位到特定细胞类型的金属的尖端方法开始 在妊娠期间在胎盘中积聚，我们将使用存档的胎盘组织进一步识别胎盘 病理(包括细胞增殖、凋亡、炎症和内皮细胞或巨噬细胞激活) 传统的组织学和免疫组织化学方法，将幻灯片数字化和自动化定制相结合 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。连同从以下来源提取的母亲、妊娠和新生儿数据 电子病历，我们将对收集和存档的新生儿干血点进行分析 纽约州新生儿筛查计划的一部分，用于检测炎症的血清标志物 由金属暴露和胎盘毒性造成的，以及我们将与胎盘相关的代谢谱 大小，新生儿的大小，和儿童体重系列的长度百分位数和生长轨迹到12个月大。最后一点 我们的2000个母婴胎盘三联症的大样本将使我们能够探索 胎盘和儿童体内的金属毒性。 这项提案中的方法对胎盘在胎儿中的作用提供了前所未有的询问 金属毒性的病理生理学，以及1岁时肥胖的发展，是其他 健康风险包括肥胖、糖尿病和心血管疾病。

PROJECT SUMMARY/ABSTRACT 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 collected and archived as part of the Newborn Screening Program of New York State to test for serum 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 the development of obesity at age 1 year, a strong predictor of other health risks including obesity, diabetes and cardiovascular disease.