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品。在生命的任何特定时期，儿童都会同时接触多种化学物质。此类混合物的影响 化学物质对疾病过程的分子基础（例如氧化应激（OS））或功能终点（例如认知功能）的影响在儿童中尚不清楚。人们也很少低估儿童体内内源性抗氧化防御或外源性抗氧化剂的程度 缓冲化学混合物对儿童健康的影响。迄今为止关于这个主题的少数研究 大多数是横截面的或仅限于少量化学品。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，该队列在 2012-19 年间招收了 679 名一年级儿童。目前，儿童年龄范围为 7-15 岁，并根据入学年份进行了 0-5 年的随访。在使用农药尿液代谢物的儿童子样本中，对毒死蜱和拟除虫菊酯类农药的接触情况进行了表征。该人群接触金属的程度普遍较低。在 SAM 参与者的一项横断面试点研究中，金属混合物与更高的 DNA 氧化损伤水平较低，并且在一般认知能力测试中表现较低。拟议的研究将包括对 SAM 儿童进行为期 3 年的随访，以每年表征体内的金属水平。 血液和尿液以及毒死蜱、拟除虫菊酯和多环芳烃 (PAH) 的代谢物 尿。每年，OS 的尿液生物标志物（F2-异前列腺素和 8-OHdG）、血清抗氧化酶（GPx） 和PON1），以及血清抗氧化维生素（维生素C、类胡萝卜素、视黄醇等）。将被测量。大约 100 名儿童的子样本将参加为期一年的 OS 生物标志物强化（每月）评估，以表征生物标志物及其生物预测因子的短期波动。孩子们将完成评估 研究第二年和第三年的执行功能（EF）。利用 SAM 注册时收集的数据（T0，~7y），将在统计机器学习模型中构建四个时间点的化学混合物：拟议研究的 T0 和 Y1-3。将对这些混合物进行建模，以了解随着时间的推移，接触混合物的情况如何 与 OS 和 EF 相关。将测试抗氧化剂的潜在效果修改。拟议的活动 与 2018-23 NIEHS 暴露组研究战略计划保持一致，通过以下方式促进人类健康 环境健康科学的进步。具体来说，他们将：1）增进基本理解 OS 和抗氧化防御生物标志物的短期（1 年）和中期（3 年）波动， 尚未在儿童中进行过研究； 2) 有助于了解化学混合物在多大程度上 童年早期的影响被认为是慢性疾病发展的分子过程（OS），以及儿童学习和社交互动的功能终点。