Children's Exposure to Metals, MicroRNAs and Biomarkers of Renal Health

项目摘要 有毒金属，包括镉（Cd）、汞（Hg）和铅（Pb），是已知的成人肾脏毒物; 然而，它们对发育中儿童的肾毒性研究不足。产前和幼儿期是潜在的 肾毒性金属的敏感窗口，因为这些生命阶段与发育有关， 肾过滤、分泌和重吸收系统的分化。本研究的目的是确定 生命早期暴露于重金属是否会导致儿童肾毒性，以及miRNAs是否 介导金属肾毒性。为了实现我们的目标，我们将利用已建立的纵向出生队列 在墨西哥城-肥胖、增长环境和社会压力规划研究（PROGRESS） 这项研究纵向测量了血液、头发和指甲中的肾毒性金属（镉、汞、铅）水平， 以及血压，并在每次访视时收集尿液。除了儿童血压， 研究将检查肾功能不全的三个独立区域的临床前指标： 肾小球、近端小管和远端肾单位（即远端小管和集合管）。桑德斯医生将收到 肾脏发育生理学的培训，以及先进的生物统计方法，以解决创新 关于儿童毒性肾编程起源的假设， 环境卫生。指导团队包括国际公认的科学家，他们的专业是 肾脏学、生物统计学、金属毒理学、流行病学和表观遗传学，包括丽莎萨特林博士、克里斯 Gennings，Robert Wright博士，Andrea Baccarelli博士和Stephanie Engel博士。此K99/R 00提案 利用桑德斯博士以前在暴露科学，流行病学和表观遗传学方面的培训， 专业从事肾脏生理学和生物统计学; Sanders博士还将受益于补充毒理学 临床培训。将实现以下目标：1）确定产前/生命早期金属 暴露可预测儿童期血压或特定肾脏区域的功能性生物标志物。2)施加 新的生物统计学方法，能够“检测”金属相关的肾毒性，这是全球或网站， 特定. 3)检查尿miRNA作为金属-肾脏健康关系的生物标志物/介质的作用。 这些发现将推动儿童肾脏健康领域的发展，并产生新的假设， 金属和可能导致不良肾脏结局的病理生理学的特定机制。的 拟议的培训和研究活动将为桑德斯博士提供成为独立专家的技能。 在未来流行病学或毒理学中研究生命早期金属暴露和肾脏发育的研究者 研究活动。

PROJECT SUMMARY Toxic metals including cadmium (Cd), mercury (Hg), and lead (Pb) are known renal toxicants in adults; however, their renal toxicity in developing children is understudied. Prenatal and early childhood are potential susceptibility windows for renal toxic metals as these life stages are associated with development and differentiation of renal filtration, secretion, and reabsorptive systems. The aim of this study is to determine whether exposure to heavy metals early in life contributes to renal toxicity in children and whether miRNAs mediate metal nephrotoxicity. To accomplish our goals, we will leverage an established longitudinal birth cohort in Mexico City - the Programming Research in Obesity, GRowth Environment and Social Stress (PROGRESS) study, which has measured levels of renal toxic metals (Cd, Hg, Pb) longitudinally in blood, hair, and nails as well as blood pressure, and collected urine at each visit. In addition to childhood blood pressure, the proposed research will examine preclinical indicators of renal dysfunction in three discrete regions of the kidney: the glomerulus, proximal tubule and distal nephron (i.e. distal tubule and collecting duct). Dr. Sanders will receive training in renal developmental physiology, as well as advanced biostatistical methods to address innovative hypotheses regarding the origins of toxic renal programming in children, an understudied aspect of environmental health. The mentoring team includes internationally recognized scientists with specializations in nephrology, biostatistics, metals toxicology, epidemiology, and epigenetics, including Dr. Lisa Satlin, Dr. Chris Gennings, Dr. Robert Wright, Dr. Andrea Baccarelli, and Dr. Stephanie Engel. This K99/R00 proposal leverages Dr. Sanders' previous training in exposure science, epidemiology, and epigenetics with new specialization in renal physiology and biostatistics; Dr. Sanders will also benefit from supplemental toxicology and clinical training. The following aims will be accomplished: 1) Determine whether prenatal/early life metal exposure predicts childhood blood pressure or functional biomarkers in specific kidney regions. 2) Apply a novel biostatistical approach to enable “detection” of metal-associated renal toxicity that is global or site- specific. 3) Examine the role of urinary miRNAs as biomarkers/mediators of metal-renal health relationships. These findings will advance the field of children's renal health as well as generate new hypotheses about metals and specific mechanisms that may contribute to the pathophysiology of adverse renal outcomes. The proposed training and research activities will provide Dr. Sanders with the skills to become an independent investigator studying early life metal exposure and renal development in future epidemiologic or toxicologic research activities.