Metal mixtures, children's cognition, and sensitive developmental windows

描述(由申请人提供) 混合物是一种常见的暴露情景，但很少被研究。金属包括一类共同暴露的化学品，其神经毒性效应尤其严重，使它们成为混合物研究的潜在范例类化学品。对铅等单一金属的研究一直很活跃，但对金属混合物的研究却很匮乏。阻碍混合物研究进展的主要挑战包括缺乏足够的多种金属暴露数据。即使收集了多个金属暴露生物标志物，仍然缺乏分析工具来充分评估相互作用。在Coull博士和Lucchini博士的指导下，Claus Henn博士(首席研究员)将利用尖端的统计学习方法，结合宿主接触混合金属的可靠数据，克服混合物研究中的障碍。通过这样做，她将评估多种金属对神经发育的联合影响。这款K99/R00应用程序以Claus Henn博士在环境流行病学和暴露科学方面的经验为基础，对她进行儿童发育和生物统计学方面的交叉培训，并为她成为一名专门从事化学混合物和儿科环境健康的独立研究员做好准备。在该奖项的K99阶段，Claus Henn博士将利用教程、教学指导和研讨会/会议接受以下方面的培训：1)用于分析综合暴露的先进定量方法；2)从产前到青春期的儿童神经发育。这些培训领域代表了克劳斯·亨恩博士的一个新的跨学科目标。随后，她的培训将应用于混合元素暴露对公共健康影响(PHIME)研究的750名意大利青少年的现有队列中。克劳斯·亨恩博士将应用结构方程模型、随机森林和核回归机器来研究同时接触金属组合对认知的影响。在R00阶段，Claus Henn博士将评估暴露在金属组合中的认知影响是否取决于暴露时间。使用墨西哥早期暴露于环境神经毒物(元素)纵向出生队列的数据，她将在多个暴露时间点应用上述方法，跨越产前和童年。这项跨学科的建议是以创新但具有成本效益的方式有效利用现有数据的独特机会。这个 拟议的培训和研究将为克劳斯·亨恩博士提供技能，在未来的研究中研究多种化学物质和多个时间点对神经发育的联合影响。这项研究将1)解决关于化学混合物对健康影响的巨大数据差距，以及2)帮助确定神经毒物易感性的关键窗口；两者都是NIEHS的战略目标和公共卫生优先事项。

DESCRIPTION (provided by applicant) Mixtures are a common exposure scenario but are rarely studied. Metals comprise a class of chemicals to which co-exposure is common and whose neurotoxic effects, particularly, can be severe, making them a potentially paradigm class of chemicals for mixtures research. Research on individual metals, such as lead, has been robust; but research on metal mixtures is lacking. Major challenges impeding progress in mixtures research include the lack of sufficient exposure data for multiple metals. Even when multiple metal exposure biomarkers are collected, there remains a lack of analytical tools to fully evaluate interactions. Under the mentorship of Drs. Coull and Lucchini, Dr. Claus Henn (principal investigator) will overcome barriers in mixtures research by using cutting-edge statistical learning methods, combined with robust data on host exposure to mixed metals. By doing so, she will evaluate the joint effects of multiple metals on neurodevelopment. This K99/R00 application builds upon Dr. Claus Henn's experience in environmental epidemiology and exposure science to cross train her in child development and biostatistics and prepare her to become an independent investigator specializing in chemical mixtures and pediatric environmental health. In the K99 phase of the award, Dr. Claus Henn will use tutorials, didactic instruction, and seminars/conferences to receive training in: 1) advanced quantitative methods for use in analyzing combined exposures, and 2) childhood neurodevelopment from the prenatal period through adolescence. These areas of training represent a new cross-disciplinary goal for Dr. Claus Henn. Her training will subsequently be applied in an existing cohort of 750 Italian adolescents in the Public Health Impact of Mixed Element exposure (PHIME) study. Dr. Claus Henn will apply structural equation models, random forests, and kernel regression machines to examine cognitive effects of concurrent exposure to combinations of metals. In the R00 phase, Dr. Claus Henn will evaluate whether cognitive effects of exposure to combinations of metals depend on exposure timing. Using data from the Early Life Exposure in Mexico to Environmental NeuroToxicants (ELEMENT) longitudinal birth cohort, she will apply the aforementioned methods at multiple exposure time points, across the prenatal period and childhood. This cross-disciplinary proposal represents a unique opportunity to efficiently use existing data in an innovative yet cost-effective manner. The proposed training and research will provide Dr. Claus Henn with the skills to study the joint effects of multiple chemicals and multiple time points on neurodevelopment in future research. This research will 1) address the large data gap on health effects of chemical mixtures, and 2) help characterize critical windows of susceptibility to neurotoxicants; both are NIEHS strategic goals and public health priorities.