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: 10768140
• 负责人: Katarzyna Kordas
• 金额: $ 1.16万
• 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/10768140
• 关键词: Address; Administrative Supplement; Adolescence; Adolescent; Affect; Age; All-Trans-Retinol; Anthropometry; Antioxidants; Area; Aromatic Polycyclic Hydrocarbons; Arsenic; Arylesterase; Ascorbic Acid; Behavior; Biological; Biological Markers; Blood; Blood specimen; Buffers; Cadmium; Carotenoids; Characteristics; Chemical Exposure; Chemicals; Child; Child Health; Childhood; Chlorpyrifos; Chronic Disease; Cognition; Communication; Complex; Complex Mixtures; Data; Data Analyses; Dedications; Deoxyguanosine; Development; Disease; Doctor of Philosophy; Enrollment; Environmental Epidemiology; Environmental Exposure; Environmental Health; Epidemiologist; Exposure to; F2-Isoprostanes; Fasting; Funding; Future; Growth; Health; Human; Immunoassay; Income; Inductively Coupled Plasma Mass Spectrometry; Influentials; Knowledge; Lead; Learning; Life; Life Cycle Stages; Link; Measures; Metal exposure; Metals; Methodology; Methods; Mission; Modeling; Modification; Molecular; National Institute of Environmental Health Sciences; Neurocognitive; Nurses; Oxidative Stress; Participant; Performance; Pesticides; Phenotype; Physical activity; Physiological; Pilot Projects; Prevention; Process; Public Health; Qualifying; Questionnaires; Recording of previous events; Research; Research Training; Risk; Sampling; Schools; Serum; Social Interaction; Spottings; Strategic Planning; Students; Testing; Time; Toxic effect; Training; Training Programs; Urine; Uruguay; Visit; Vitamins; Work; antioxidant enzyme; cognitive ability; cognitive function; cognitive performance; cohort; design; environmental chemical; executive function; experience; first grade; follow-up; interest; liquid chromatography mass spectrometry; machine learning model; middle childhood; novel; oxidative DNA damage; pyrethroid; response; sample collection; skills; sociodemographics; statistical and machine learning; summer research; urinary

ABSTRACT In many areas of the world, children are regularly exposed to environmental chemicals. During any given pe- riod 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 func- tional endpoints such as cognitive functions, are not well understood in children. There is also little understat- ing 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 chil- dren 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 charac- terized in a sub-sample of children using urinary metabolites of the pesticides. Exposure to metals in this co- hort 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 pro- posed 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-sam- ple of ~100 children will participate in a year-long intensive (monthly) assessment of OS biomarkers to charac- terize 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, ~7 y), 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 dis- ease, 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pe- 生命的生命，儿童将同时经历许多化学物质。这种混合物的影响 疾病过程的分子基础上的化学物质，例如氧化应激（OS）或Func-上 在儿童中，诸如认知功能之类的端点（例如认知功能）尚未得到很好的理解。也很少低估 - 儿童体内内源性抗氧化剂防御的程度或外源性抗氧化剂 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，该队列已招收679个1年级的Chil- 在2012 - 19年间开发。目前，儿童年龄在7-15岁之间，并已随访0-5 多年，取决于入学年份。暴露于毒性雌雄同体和拟除虫菊酯的农药已经是特征 使用农药的尿代谢物在儿童的子样本中成熟。在此共同体中接触金属 霍特通常很低。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。专业人士 摆姿势的研究将包括3年的SAM儿童随访，以每年表征金属的水平 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。一个亚sam- 约有100名儿童的PLE将参加长达一年的密集（每月）对OS生物标志物的评估 在生物标志物及其生物学预测因子中进行短期波动。孩子们将完成评估 该研究的Y2和Y3中的执行功能（EF）。利用注册时收集的数据（T0，〜7） Y），将在统计机器学习模型中构建化学混合物四个时间点：T0和Y1- 拟议研究的3个。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 NIEHS的战略研究计划有关，以通过 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 早期中间儿童期影响分子过程（OS），这是慢性疾病发展的基础 轻松，以及基于儿童学习和社交互动的功能终点。