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。在任何给定的生命阶段，儿童都会同时接触到许多化学物质。这种混合物的效果 儿童对化学物质对疾病过程的分子基础，如氧化应激(OS)或功能终点(如认知功能)的影响还不是很清楚。儿童体内的内源性抗氧化剂防御或外源性抗氧化剂的程度也几乎没有被低估 缓冲化学混合物对儿童健康的影响。到目前为止，关于这个主题的少数几项研究是 大部分是横截面的或仅限于少量的化学物质。为了解决这些差距，拟议的研究 将利用乌拉圭的Salud Ambiental Montevia(SAM)队列，该队列在2012-19年期间招收了679名一年级儿童。目前，儿童的年龄在7-15岁之间，并根据入学年份进行了0-5年的跟踪调查。在使用毒死蜱和拟除虫菊酯农药尿代谢物的儿童样本中，暴露于这两种农药的特征已经确定。在这组人群中，对金属的曝险普遍较低。在一项对SAM参与者的横断面先导性研究中，一种金属混合物与更高的 DNA氧化损伤水平较低，在一般认知能力测试中表现较差。这项拟议的研究将包括对SAM儿童进行为期3年的随访，以每年表征儿童体内的金属水平 血液和尿液，以及毒死蜱、拟除虫菊酯和多环芳烃(PAHs)的代谢物 尿液。每年，尿中OS(F2-异前列腺素和8-OHdG)，血清抗氧化酶(GPX)的生物标志物 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)。将会被测量。约100名儿童的子样本将参加为期一年的OS生物标记物的强化(每月)评估，以表征生物标记物及其生物学预测因素的短期波动。孩子们将完成评估 在研究的第二年和第三年的执行功能(EF)。利用在加入SAM(T0，~7y)时收集的数据，将在拟议研究的四个时间点：T0和Y1-3在统计机器学习模型中构建化学混合物。将对这些混合物进行建模，以了解随着时间的推移暴露在混合物中的情况 与操作系统和EF相关联。将测试抗氧化剂的潜在效果修饰。拟开展的活动 与2018-23年NIEHS关于暴露组研究的战略计划保持一致，以通过 环境健康科学的进步。具体地说，他们将：1)推进基本认识 OS和抗氧化剂防御的生物标记物的短期(1年)和中期(3年)波动，这有 没有在儿童中进行研究；2)有助于了解化学混合物在多大程度上 儿童早期和中期影响的分子过程(OS)被认为是慢性疾病发展的基础，也是儿童学习和社会互动的功能终点。

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.