Developmental Origins of Kidney Function in Early Life and Environmental Risks

生命早期肾功能的发育起源和环境风险

• 批准号: 10445341
• 负责人: Laura Malaga-Dieguez
• 金额: $ 70.33万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-02 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10445341
• 关键词: 8-hydroxy-2' -deoxyguanosine; Academic Medical Centers; Actins; Acute; Adolescent; Adoption; Adult; Age; Age-Months; Attention; Biological Markers; Birth; Case-Control Studies; Categories; Cell membrane; Chemicals; Child; Child Health; Childhood; Chronic; Chronic Kidney Failure; Complex; Consumption; Coupling; Cytoskeleton; Data; Development; Developmental Biology; Environment; Environmental Exposure; Environmental Health; Environmental Risk Factor; Epidermal Growth Factor; Exposure to; F2-Isoprostanes; Failure; Fetal Growth; Fetal Growth Retardation; Food; Funding; Growth; Health; Herbicides; ITGB3 gene; Impairment; Incidence; Infant; Inflammation; Inflammatory; Injury; Injury to Kidney; Interleukin-6; Kidney; Laboratories; Life; Low Birth Weight Infant; Measurement; Measures; Medical; Modification; Nephrology; Nephrons; New York; Obesity; Organic Food; Organophosphates; Outcome; Oxidative Stress; Pathogenesis; Patients; Perinatal; Pesticides; Pharmaceutical Preparations; Phenotype; Population; Population Study; Pre-Eclampsia; Pregnancy; Pregnant Women; Prevention; Process; Proteinuria; Renal Mass; Renal function; Renal glomerular disease; Reporting; Risk; Risk Factors; Role; Sampling; Serum; Signal Transduction; Testing; Third Pregnancy Trimester; Toddler; Tubular formation; United States National Institutes of Health; Universities; Urine; Urokinase Plasminogen Activator Receptor; Work; adverse childhood events; base; cardiovascular risk factor; cell motility; cohort; cost efficient; cytokine; diagnostic biomarker; disorder risk; early childhood; environmental chemical; experience; follow-up; glomerular filtration; glyphosate; in utero; infancy; medical schools; modifiable risk; nephrogenesis; nephrotoxicity; oxidant stress; phthalates; podocyte; postnatal; postnatal development; premature; prenatal; prenatal exposure; programs; prospective; rat KIM-1 protein; risk stratification; specific biomarkers; stressor; trend; urinary

Project Summary NYU School of Medicine, Rush University Medical Center and New York State Department of Health respond to PA-19-056, proposing to study developmental origins of kidney function in early life and environmental risks. The incidence of chronic kidney disease (CKD) is steadily rising and synthetic chemicals are increasingly understood to contribute to acute and chronic kidney injury. Case-control studies of populations with high incidence rates have identified pesticide and herbicide exposures as risks, raising the question whether developmental exposures may be even more impactful. Our own studies of children with CKD (R01DK100307) have revealed modest declines in kidney function with increasing phthalate and bisphenol exposures, accompanied by increases in oxidative stress. However, these findings do not contribute to our understanding of the origin of CKD. A major limitation is the failure of our and other studies to account for the developmental biology of the kidney and strong influence of perinatal/infant factors. The premise of the present proposal is that intrauterine inflammatory processes disrupt nephrogenesis and that environmental chemicals also impair renal parenchymal growth longitudinally during gestation and postnatal development via oxidant stress. We further interrogate this hypothesis by examining phthalates, bisphenols, glyphosate and organophosphate (OP) pesticides as modifiable risks. We will test these hypotheses in the New York University Children's Health and Environment Study, one of the participating cohorts in the NIH Environmental Influences and Child Health Outcomes Program (UH3OD023305). The proposed work builds upon our experience with postnatal renal sonographic measurement, which we will add prospectively to the existing, funded follow up. The approach is cost-efficient, leveraging existing measures for three exposure categories in pregnancy and infancy and available biospecimens to measure soluble urokinase-type plasminogen activator receptor, an emerging marker of kidney injury and development, and glyphosate. The MPIs (Trasande and Trachtman) are highly complementary, coupling experts in children's environmental health with nephrology who have a track record of productive MPI partnership in R01DK100307, which produced preliminary data in support of the proposed work. Analyses will be performed by K. Kannan at Wadsworth Laboratories of the New York State Department of Health, who has deep experience with precise measurement of glyphosate and metabolites in urine. In contrast to many known CKD risks which are not amenable to modification or avoidance, pesticides and herbicides can be reduced by consuming organic foods while phthalates and bisphenols can be reduced by avoiding canned and processed foods. The proposed work has the potential to shift the paradigm of origins of CKD to focus needed attention on its developmental origins.

项目摘要 纽约大学医学院、拉什大学医学中心和纽约州卫生部回应 PA-19-056，建议研究生命早期肾功能的发育起源和环境风险。 慢性肾脏病（CKD）的发病率正在稳步上升，合成化学品的使用也越来越多。 被认为是导致急性和慢性肾损伤的原因。高血压人群的病例对照研究 发病率已确定农药和除草剂暴露为风险，提出了一个问题， 发育期的暴露可能更具影响力。我们自己的CKD儿童研究（R 01 DK 100307） 显示随着邻苯二甲酸酯和双酚暴露的增加，肾功能适度下降， 伴随着氧化应激的增加。然而，这些发现无助于我们理解 CKD的起源一个主要的局限性是我们和其他研究未能解释发展中国家的发展， 肾脏的生物学和围产期/婴儿因素的强烈影响。本建议的前提是 子宫内的炎症过程破坏了肾的发生，环境化学物质也损害了 通过氧化应激在妊娠期和出生后发育期间肾实质纵向生长。我们 通过检测邻苯二甲酸盐、双酚、草甘膦和有机磷酸盐（OP），进一步探究这一假设 农药作为可改变的风险。我们将在纽约大学儿童健康和 环境研究，NIH环境影响和儿童健康的参与队列之一 结局计划（UH 3 OD 023305）。拟议的工作建立在我们的经验，产后肾 超声测量，我们将前瞻性地将其添加到现有的资助随访中。该方法是 具有成本效益，利用现有措施，针对妊娠期和婴儿期的三种接触类别， 可用的生物标本来测量可溶性尿激酶型纤溶酶原激活物受体， 肾损伤和发育的标志物，以及草甘膦。MPI（Trasande和Trachtman）高度 互补，将儿童环境健康专家与拥有良好记录的肾脏病学专家结合起来 R 01 DK 100307中的生产性MPI伙伴关系，该伙伴关系产生了初步数据，以支持拟议的 工作分析将由K进行。Kannan在纽约国务院沃兹沃斯实验室 他在精确测量尿液中的草甘膦和代谢物方面拥有丰富的经验。在 与许多已知的CKD风险不同，这些风险不适合改变或避免，农药和 除草剂可以通过食用有机食品来减少，而邻苯二甲酸盐和双酚可以通过 避免罐头和加工食品。拟议的工作有可能改变起源的范式， CKD需要关注其发展起源。