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.父项目摘要ES029 9281（PIS：CM Salafia，RK Miller） 金属暴露是常见的，它们对人类健康的有害影响也是如此。更关心的是他们 对弱势发展胎儿的行动。但是，即使每个人都可以使用plapeta 交付，常规评估很少。因此，我们继续缺乏有关 产前金属暴露于伤害胎儿的机制，沿着早期路径的关键步骤 鉴定处于危险的胎儿以及优化童年和终身健康的干预措施。有增长 内部环境会影响占地发展和功能以最终影响的证据 后代肥胖的风险。童年超重和肥胖是常见的重要预测指标 整个生活过程中的发病率和死亡率。目的是确定一个独特的，建立的队列 全置替代人进行了研究，并具有胎盘组织存档，胎盘健康和功能如何受到影响 通过金属暴露以及从金属暴露和占位毒性导致的途径变化的婴儿 体细胞生长和代谢。最后，将通过体外外植体研究来验证临床结果 人胎盘，其中可以测试金属暴露以诱导位置细胞特异性反应。 首先从识别，定量和本地化到特定的细胞类型金属的尖端方法开始 我们将在妊娠的整个子宫内积聚，我们将进一步使用存档的斑点组织来识别斑点 病理（包括细胞增殖，凋亡，炎症和内皮或巨噬细胞激活） 传统的组织学和免疫组织化学方法，配对幻灯片数字化和自动化习惯 注册串行数字化位置组织幻灯片以匹配lopenal病变的软件算法 金属的存在，数量和类型。与母校一起，从中提取的妊娠和新生儿数据 该电子病历，我们将移至收集新生的干血点（DB）的分析，并 作为纽约州新生儿筛查计划的一部分，以测试循环标记 金属暴露和lopenal毒性可能导致的炎症，以及我们将将其代谢特征 与长度为百分点的斑点大小，新生儿大小和串行儿童体重相关，生长轨迹与 12个月大。最后，我们的2000个母子placeta三合会的大型样本量将使我们能够探索 金属毒性在斑点和儿童中的性别依赖性作用。本提案中的方法提供 对金属金属毒性和发育中胎儿病理生理学作用的前所未有的询问 肥胖1年，这是对健康风险的有力预测指标，包括肥胖，糖尿病和心血管疾病。