Triclosan, pubertal hormones, and the gut microbiome: implications for neurobehavior

项目摘要 尽管肠道微生物组生态失调可能导致终身后果，但对环境因素知之甚少。 影响其多样性和组成的因素，包括易受照射的窗口。肠道 微生物组对人类健康起着至关重要的作用，并通过以下途径与神经行为发育有关： 肠脑轴虽然一些研究已经在环境背景下检查了婴儿/成人微生物组， 流行病学，青少年微生物组没有得到关注，即使它发生在一个快速增长的时期， 当荷尔蒙环境发生变化时，往往会出现内化行为。拟议 该项目旨在通过研究接触三氯生（一种抗菌剂） 以及内分泌干扰化合物-青春期激素、青少年微生物组和神经行为。 这项工作将利用环境研究的健康成果和措施， 收集了丰富数据的队列，包括妊娠早期10次访视时的尿三氯生定量 到12岁，青春期激素，血清代谢组和行为。对这个项目至关重要的是，参与者 在12岁时提供粪便。在K99阶段，将对粪便DNA进行测序，以分析微生物群落， 将用于确定三氯生敏感性的窗口（目标1）。劳厄博士将评估 激素在塑造微生物组中的作用，包括它们是否介导或改变三氯生微生物组 关联（目标2），并检查青少年微生物组与行为之间的关系（目标3a）。 在R 00阶段，在18岁时进行微生物组和行为评估，以告知我们对 微生物组与行为之间的纵向关联（目标3b）。劳厄博士将描述的作用， 微生物组-行为关联中的血清代谢组（目标4），并将确定细菌是否 特征介导或改变三氯生与青少年行为之间的关联（探索性目标5）。 为了完成这项研究，劳厄博士将补充她在环境流行病学和环境卫生方面的专业知识。 在她的导师团队的指导下，通过广泛的培训（Margaret Karagas博士， 主要导师，Joseph Braun博士共同导师，Juliette Madan博士顾问，Abby Fleisch博士顾问， 艾米·威利斯顾问）。劳埃将从课程作业，研讨会和个性化培训中学习1） 处理微生物组数据和微生物组测量误差，2）多个信息建模和其他 确定易感性窗口的方法，3）因果中介，4）儿科内分泌学，和5） 神经行为该奖项将准备劳厄博士是一个独立的研究人员，专门从事 环境流行病学和青少年微生物组。劳厄博士的研究将填补一个关键的空白， 环境流行病学文献，即青少年微生物组和代谢组在其中发挥的作用 普遍存在的环境毒物（三氯生）和神经行为之间的关系。

PROJECT SUMMARY Despite potential lifelong consequences of gut microbiome dysbiosis, little is known about environmental factors that influence its diversity and composition, including windows of susceptibility to exposure. The gut microbiome performs essential functions for human health, and is related to neurobehavioral development via the gut-brain axis. While a few studies have examined the infant/adult microbiome in the context environmental epidemiology, the adolescent microbiome has not received attention, even though it occurs in a period of rapid development when the hormonal milieu is changing, and internalizing behaviors often emerge. The proposed project aims to address these gaps by examining the relations between exposure to triclosan—an antimicrobial and endocrine disrupting compound—pubertal hormones, the adolescent microbiome, and neurobehavior. This work will leverage the Health Outcomes and Measures of the Environment Study, a longitudinal birth cohort with rich data collection including quantification of urinary triclosan at 10 visits from early gestation through 12Y, pubertal hormones, the serum metabolome, and behavior. Crucial to this project, participants provided stools at 12Y. During the K99 phase, fecal DNA will be sequenced to profile microbial communities, which will be used to identify windows of susceptibility to triclosan (Aim 1). Dr. Laue will assess the role of hormones in shaping the microbiome, including whether they mediate or modify the triclosan-microbiome association (Aim 2), and examine the relationship between the adolescent microbiome and behavior (Aim 3a). During the R00 phase, microbiome and behavioral assessment at 18Y to inform our understanding of the longitudinal association between the microbiome and behavior (Aim 3b). Dr. Laue will characterize the role of the serum metabolome in the microbiome-behavior association (Aim 4) and will determine whether bacterial features mediate or modify the association between triclosan and adolescent behavior (Exploratory Aim 5). To complete this research, Dr. Laue will complement her expertise in environmental epidemiology and the infant microbiome with extensive training under the guidance of her mentorship team (Dr. Margaret Karagas— primary mentor, Dr. Joseph Braun—co-mentor, Dr. Juliette Madan—advisor, Dr. Abby Fleisch—advisor, Dr. Amy Willis—advisor). Dr. Laue will learn from coursework, workshops, and individualized trainings in 1) processing microbiome data and microbiome measurement error, 2) multiple informant modeling and other methods for identifying windows of susceptibility, 3) causal mediation, 4) pediatric endocrinology, and 5) neurobehavior. This award will prepare Dr. Laue to be an independent researcher specializing in environmental epidemiology and the adolescent microbiome. Dr. Laue’s research will fill a critical gap in the environmental epidemiological literature, namely what role the adolescent microbiome and metabolome play in the relationship between a ubiquitous environmental toxicant (triclosan) and neurobehavior.