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

项目总结 尽管肠道微生物群失调可能带来终生后果，但人们对环境知之甚少 影响其多样性和组成的因素，包括暴露的易感性窗口。胆量 微生物组对人类健康具有重要作用，并通过与神经行为发育有关 内脏-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 流行病学方面，青少年的微生物群没有受到重视，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，内化行为经常出现。建议数 该项目旨在通过检查接触抗菌剂三氯生之间的关系来解决这些差距 以及干扰内分泌的化合物--青春期荷尔蒙、青春期微生物群和神经行为。 这项工作将利用环境研究的健康结果和措施，这是一项纵向分娩 具有丰富数据收集的队列，包括从怀孕早期10次就诊时尿三氯生的定量 通过12Y、青春期激素、血清代谢物和行为。对这个项目至关重要，参与者们 在12岁时提供凳子。在K99阶段，粪便DNA将被测序，以描绘微生物群落， 它将用于确定三氯生的易感窗口(目标1)。劳伊博士将评估 激素在形成微生物组中的作用，包括它们是否调节或修饰三氯生-微生物组 协会(目标2)，并审查青少年微生物群与行为之间的关系(目标3a)。 在R00阶段，18y的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联系(目标3b)。劳伊博士将描述 微生物组-行为关联中的血清代谢组(目标4)，并将决定细菌 特征调节或改变三氯生和青少年行为之间的联系(探索性目标5)。 为了完成这项研究，劳伊博士将补充她在环境流行病学和 在她的指导团队的指导下进行广泛培训的婴儿微生物组(玛格丽特·卡拉加斯博士- 主要导师约瑟夫·布劳恩博士、共同导师朱丽叶·马丹博士、艾比·弗莱施博士顾问、 艾米·威利斯--顾问)。Laue博士将从课程作业、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)多信息者建模等 确定易感窗口的方法，3)因果调解，4)儿科内分泌学，5) 神经行为。这一奖项将使劳伊博士成为一名独立研究员，专门从事 环境流行病学与青少年微生物群。劳伊博士的研究将填补 环境流行病学文献，即青少年微生物组和代谢组在 无处不在的环境毒物(三氯生)与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.