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

人类胎盘形态、功能和病理学：与环境暴露和新生儿和儿童健康的关系

• 批准号: 10457073
• 负责人: Richard Kermit Miller
• 金额: $ 3.02万
• 依托单位: INSTITUTE FOR BASIC RES IN DEV DISABIL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457073
• 关键词: Advisory Committees; Affect; Age-Months; Algorithmic Software; Apoptosis; Archives; Basic Science; Biological Markers; Biometry; Birth; Blood; California; Cardiovascular Diseases; Cell Proliferation; Cells; Chemicals; Child; Child Development; Child Health; Childhood; Clinical; Cohort Studies; Collaborations; Committee Members; Computerized Medical Record; Custom; Data; Decidua; Development; Diabetes Mellitus; Diagnosis; Doctor of Philosophy; Dyes; Early identification; Endothelium; Environmental Exposure; Epidemiologist; Epidemiology; Exposure to; Faculty; Fetal Development; Fetus; Functional disorder; Funding; Gestational Age; Goals; Grant; Growth; Head; Health; Histologic; Histopathology; Human; Immunologic Markers; Immunophenotyping; In Vitro; Infant; Inflammation; Institutes; Intervention; Investigation; Knowledge; Lead; Learning; Length; Lesion; Letters; Life Cycle Stages; Link; Macrophage Activation; Maintenance; Maps; Maternal and Child Health; Measures; Mediating; Mentors; Metabolism; Metal exposure; Metals; Methods; Michigan; Microscopy; Modeling; Morbidity - disease rate; Mothers; Neonatal; Neonatal Screening; Neurodevelopmental Disorder; New York; Newborn Infant; Obesity; Outcome; Parents; Pathologist; Pathology; Perinatal; Perinatal Epidemiology; Personal Satisfaction; Phenotype; Placenta; Placental Biology; Placental Toxicity; Placentation; Pregnancy; Psychologist; Research; Research Personnel; Risk; Role; Sample Size; Sampling; Scholarship; Science; Slide; Source; Spottings; Structure; Testing; Tissues; Training; Translational Research; Triad Acrylic Resin; United States National Institutes of Health; Water; Weight; Work; autism spectrum disorder; boys; career; career development; case control; cell type; circulating biomarkers; cohort; cytokine; design; disorder risk; environmental chemical exposure; experience; exposure pathway; fetal; fetus at risk; girls; immune function; immunoregulation; inflammatory marker; intrauterine environment; member; metabolic profile; metal poisoning; migration; mortality; neonatal health; neurocognitive disorder; neurogenesis; obesity development; obesity risk; offspring; overweight child; parent grant; parent project; placental morphology; prenatal; prenatal exposure; programs; response; screening program; season of birth; sex; skills; tissue archive

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.

A. 母项目摘要 ES029 9281（PI：CM SALAFIA、RK MILLER） 金属接触很常见，它们对人类健康的有害影响也很常见。 然而，尽管每个人都可以获得胎盘。 因此，我们仍然缺乏有关交付的足够信息。 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。 有证据表明宫内环境影响胎盘发育和功能，最终影响 儿童时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的目标是确定在一个独特的、既定的队列中， 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对婴儿的影响途径 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、数量和类型以及从母亲、妊娠和新生儿中提取的数据。 电子病历，我们将转向分析收集的新生儿干血斑 (DBS) 作为纽约州新生儿筛查计划的一部分存档，用于测试循环标记物 可能由金属暴露和胎盘毒性引起的炎症，以及我们将要进行的代谢特征 与胎盘大小、新生儿大小和连续儿童体重的长度百分位和生长轨迹相关 最后，2000 个母子胎盘三联体的大样本量将让我们能够探索。 本提案中的方法提供了金属毒性对胎盘和儿童的性别依赖性影响。 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前所未有的质疑 一年内的肥胖率，是肥胖、糖尿病和心血管疾病等健康风险的有力预测因子。