Effect of Complex Mixtures on Oxidative Stress and Cognition in Children

摘要 在世界许多地区，儿童经常接触环境化学品。在任何特定的时间， 在生活的各个阶段，儿童会同时接触到许多化学物质。这种混合物的效果 化学物质对疾病过程的分子基础，如氧化应激（OS）或功能， 诸如认知功能的功能终点在儿童中并不被很好地理解。也有一些小的不足， 儿童体内内源性抗氧化剂防御或外源性抗氧化剂防御的程度 缓解化学混合物对儿童健康的影响。迄今为止，关于这一主题的少数研究是 大多数是跨部门的，或仅限于少数化学品。为了弥补这些差距，拟议的研究 将利用乌拉圭的蒙得维的亚健康环境（SAM）队列，该队列已招募了679名一年级儿童， 2012年至2019年之间的。目前，儿童的年龄范围为7-15岁，并已随访0-5 年，取决于入学的年份。暴露于毒死蜱和拟除虫菊酯农药的特征是， 在使用杀虫剂的尿液代谢物的儿童的子样本中进行了表征。在这种情况下暴露于金属- 一般来说，霍特较低。在SAM参与者的横断面试点研究中，金属混合物与较高的 氧化性DNA损伤水平和一般认知能力测试中的表现较低。亲- 提出的研究将包括对SAM儿童进行3年的随访，以每年表征 血液和尿液，以及毒死蜱，拟除虫菊酯和多环芳烃（PAHs）的代谢物， 尿每年，尿中OS生物标志物（F2-异前列腺素和8-OHdG）、血清抗氧化酶（GPx） 和PON 1）和血清抗氧化维生素（维生素C、类胡萝卜素、视黄醇等）。将被衡量。一个亚萨姆- 大约100名儿童将参加为期一年的OS生物标志物强化（每月）评估，以确定特征， 生物标志物的短期波动及其生物学预测因子。儿童将完成评估 执行功能（EF）在Y2和Y3的研究。将入组时收集的数据用于SAM（T0，~7 y），将在统计机器学习模型中构建四个时间点的化学混合物：T0和Y1- 三是研究建议。将对这些混合物进行建模，以了解随着时间的推移， 与OS和EF相关。将测试抗氧化剂的潜在影响。拟议活动 与2018-23年NIEHS关于麻烦的研究战略计划保持一致，以促进人类健康， 环境健康科学的进步。具体而言，他们将：1）推进基本认识 OS和抗氧化防御生物标志物的短期（1年）和中期（3年）波动， 未在儿童中进行调查; 2）有助于了解化学混合物在多大程度上 早期-中期儿童影响一个分子过程（OS），被认为是慢性疾病发展的基础， 轻松，以及作为儿童学习和社会互动基础的功能性终点。

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.