Effect of complex mixtures on oxidative stress and cognition in children

复杂混合物对儿童氧化应激和认知的影响

• 批准号: 10663185
• 负责人: Katarzyna Kordas
• 金额: $ 58.1万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-18 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663185
• 关键词: Address; Affect; Age; All-Trans-Retinol; Antioxidants; Area; Aromatic Polycyclic Hydrocarbons; Ascorbic Acid; Behavior; Behavioral; Biological; Biological Factors; Biological Markers; Biological Process; Blood; Body mass index; Brain; Buffers; Carotenoids; Chemicals; Child; Child Health; Childhood; Chlorpyrifos; Chronic; Chronic Disease; Cognition; Communication; Communities; Complex; Complex Mixtures; Data; Development; Disease; Enrollment; Environmental Exposure; Environmental Health; Environmental Risk Factor; Exposure to; F2-Isoprostanes; Foundations; Funding; Future; Goals; Growth; Health; Human; Income; Infrastructure; Knowledge; Learning; Life; Life Cycle Stages; Link; Literature; Measures; Mediation; Memory; Metal exposure; Metals; Mission; Modeling; Modification; Molecular; National Institute of Environmental Health Sciences; Neurocognitive; Outcome; Oxidative Stress; Participant; Performance; Pesticides; Pilot Projects; Play; Prevention; Process; Public Health; Regulation; Research; Risk; Risk Assessment; Role; Schools; Serum; Social Interaction; Strategic Planning; Testing; Time; Tocopherols; Urine; Uruguay; Vitamins; Work; aged; antioxidant enzyme; aryldialkylphosphatase; cognitive ability; cognitive function; cognitive performance; cohort; early adolescence; environmental chemical; enzyme activity; executive function; experience; first grade; follow-up; glutathione peroxidase; improved; individual variation; machine learning model; middle childhood; oxidative DNA damage; pyrethroid; response; sample collection; sex; statistical and machine learning; success; urinary

ABSTRACT In many areas of the world, children are regularly exposed to environmental chemicals. During any given period of life, children will experience exposure to many chemicals at the same time. The effects of such mixtures of chemicals on the molecular underpinnings of the disease process, such as oxidative stress (OS) or on functional endpoints such as cognitive functions, are not well understood in children. There is also little understating of the extent to which endogenous antioxidant defenses in children's bodies or exogenous antioxidants buffer the effects of chemical mixtures on children's health. The few studies on this topic to date have been mostly cross-sectional or limited to small numbers of chemicals. To address these gaps, the proposed study will leverage the Salud Ambiental Montevideo (SAM) cohort in Uruguay, which has enrolled 679 1st-grade children between years 2012-19. Currently, children range in age 7-15 years and have been followed-up for 0-5 years, depending on year of enrollment. Exposure to chlorpyrifos and pyrethroids pesticides has been characterized in a sub-sample of children using urinary metabolites of the pesticides. Exposure to metals in this cohort is generally low. In a cross-sectional pilot study of SAM participants, a metal mixture was linked to higher levels of oxidative DNA damage and with lower performance on a test of general cognitive abilities. The proposed study will consist of 3 years of follow-up of SAM children to annually characterize the levels of metals in blood and urine, and metabolites of chlorpyrifos, pyrethroids, and polycyclic aromatic hydrocarbons (PAHs) in urine. Each year, urinary biomarkers of OS (F2-isoprostane and 8-OHdG), serum antioxidant enzymes (GPx and PON1), and serum antioxidant vitamins (vitamin C, carotenoids, retinol, etc). will be measured. A sub-sample of ~100 children will participate in a year-long intensive (monthly) assessment of OS biomarkers to characterize short-term fluctuations in biomarkers and their biological predictors. Children will complete assessments of executive functions (EF) in Y2 and Y3 of the study. Leveraging data collected at enrollment into SAM (T0, ~7y), chemical mixtures will be constructed in statistical machine learning models for four time points: T0 and Y1-3 of the proposed study. These mixtures will be modeled to understand how exposure to mixtures over time is associated with OS and EF. Potential effect modification by antioxidants will be tested. The proposed activities align with the 2018-23 NIEHS strategic plan of research on the exposome to promote human health through the advancement of environmental health sciences. Specifically, they will: 1) advance the basic understanding of short (1 yr) and medium-term (3 yrs) fluctuations in biomarkers of OS and antioxidant defenses, which have not been investigated in children; 2) contribute to understanding of the extent to which chemical mixtures in early-middle childhood affect a molecular process (OS) thought to underlie the development of chronic disease, as well as functional endpoints that underlie children's learning and social interactions.

抽象的 在世界许多地区，儿童经常接触环境化学物质。在任何给定的生命时期，儿童都会同时经历许多化学物质。这种混合物的影响 在儿童中，疾病过程的分子基础上的化学物质（例如氧化应激（OS））或功能性终点（例如认知功能）在儿童中尚未得到充分了解。在儿童体内或外源性抗氧化剂中内源性抗氧化剂防御的程度也很少低估 缓冲化学混合物对儿童健康的影响。迄今为止有关此主题的少数研究是 主要是横截面或限于少量化学物质。为了解决这些差距，拟议的研究 将利用乌拉圭的Salud Ambiental Montevideo（SAM）队列，该队在2012 - 19年间招募了679名1年级的儿童。目前，儿童在7-15岁之间的范围为0-5岁，具体取决于入学年份。使用农药的尿代谢产物，在儿童的子样本中表征了暴露于毒性雌雄同体和拟除虫菊酯的农药。在该队列中接触金属通常很低。在SAM参与者的横断面试验研究中，金属混合物与较高 在一般认知能力的测试中，氧化DNA损伤水平较低。拟议的研究将包括3年的SAM儿童随访，以每年表征金属水平 血液和尿液，以及毒性雌雄同体，拟除虫菊酯和多环芳烃的代谢产物（PAHS） 尿。每年，OS（F2-异丙烷和8-OHDG）的尿液标志物，血清抗氧化剂（GPX） 和PON1）和血清抗氧化剂维生素（维生素C，类胡萝卜素，视黄醇等）。将测量。一个约100名儿童的子样本将参与对OS生物标志物的长期密集（每月）评估，以表征生物标志物及其生物学预测因子的短期波动。孩子们将完成评估 该研究的Y2和Y3中的执行功能（EF）。将入学时收集到SAM（T0，〜7Y）收集的数据，将在统计机器学习模型中构建化学混合物四个时间点：拟议研究的T0和Y1-3。这些混合物将被建模，以了解随着时间的流逝如何暴露于混合物 与OS和EF相关。将测试抗氧化剂的潜在效应修饰。拟议的活动 与2018 - 23年NIEHS关于外交部研究的战略研究计划，以促进人类健康 环境健康科学的进步。具体来说，他们将：1）提高基本理解 在具有OS和抗氧化剂防御的生物标志物中的短期（1年）和中期（3年）的波动中 没有在儿童中进行调查； 2）有助于理解化学混合物的程度 早期中间的童年影响分子过程（OS）是慢性疾病发展的基础，以及基于儿童学习和社交互动的功能性终点。