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

项目概要/摘要 金属接触很常见，它们对人类健康的有害影响也很常见。更令人担忧的是他们 对脆弱的发育中胎儿采取行动。然而，尽管胎盘可以从各个地方获得 交付，很少进行常规评估。因此，我们仍然缺乏足够的信息 产前金属暴露对胎儿造成伤害的机制、早期接触金属的关键步骤 识别有风险的胎儿，并进行干预以优化童年和终生福祉。有不断增长的 有证据表明宫内环境影响胎盘发育和功能，最终影响 后代肥胖的风险。儿童期超重和肥胖是常见且重要的预测因素 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存档胎盘组织，了解胎盘健康和功能如何受到影响 金属暴露以及金属暴露和胎盘毒性导致婴儿改变的途径 体细胞生长和新陈代谢。最后，临床结果将通过体外外植体研究进行验证 人类胎盘，可以测试金属暴露是否诱导胎盘细胞特异性反应。 从识别、定量和定位特定细胞类型金属的尖端方法开始 整个妊娠期在胎盘中积累，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、炎症和内皮细胞或巨噬细胞激活） 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化定制 软件算法可记录连续数字化胎盘组织切片，以将胎盘病变与胎盘组织相匹配 金属的存在、数量和类型。连同从以下来源提取的孕产妇、妊娠和新生儿数据 电子病历，我们将转向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，用于测试可能会导致炎症的血清标志物 金属暴露和胎盘毒性的结果，以及我们将与胎盘相关的代谢特征 尺寸、新生儿尺寸和连续儿童体重（长度百分位数）以及 12 个月大的生长轨迹。最后 我们的 2000 个母子胎盘三联体的大样本量将使我们能够探索性别依赖性影响 金属对胎盘和儿童的毒性。 该提案中的方法对胎盘在胎儿发育中的作用提供了前所未有的质疑 金属毒性的病理生理学，以及 1 岁时肥胖的发展，这是其他疾病的有力预测因素 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.