Nitrogenous disinfection by-products and their metabolic impact on human gut microbiota

项目摘要 含氮消毒副产物（N-DBPs）是自来水中普遍存在的污染物， 氯与自来水中的天然有机物发生反应。长期接触这些污染物与 不利的健康后果，包括膀胱癌、流产和低出生体重。然而，N-DBPs是 不受管制比较毒性评估表明，N-DBPs具有遗传毒性和细胞毒性。 然而，标准的毒性评估是有限的，因为动物研究和体外试验不 总是概括人类生物学。人类胃肠道微生物组在以下方面起着重要作用： 人类健康和疾病进展。研究表明，肠道微生物组可以降解 将外源性化合物转化为具有各种毒性作用的生物转化产物。此外， 暴露有可能改变微生物组组成和基因表达，这可能在以下方面发挥作用： 对人类健康的不良影响。为了了解N-DBP暴露对健康的影响， 该项目研究N-DBPs与人类胃肠道微生物组之间的相互作用。的 本研究的中心假设是微生物组和N-DBP相互作用在不良健康影响中发挥作用 暴露后。该项目的长期目标是研究化学和生物相互作用 N-DBPs与人类肠道微生物组之间的关系，以阐明不良反应的潜在机制。的 具体的目标是检验以下假设：（1）肠道微生物群将N-DBPs降解为生物转化产物 环境相关的N-DBP暴露可干扰肠道群落 结构和功能活动。目的1是鉴定N-DBP在肠道中的生物转化产物 微生物群我们将使用液相色谱法测量N-DBP降解和生物转化产物 (LC)- 质谱法（MS）。使用计算毒理学方法，我们将预测生物转化 基于化学结构的产品毒性，以确定肠道微生物群是否改变N-DBP的毒性作用。目的2 将确定N-DBP暴露后肠道微生物群落基因表达的变化。为此 工作，我们将进行元转录组学，以确定差异基因表达的变化后，N-DBP exposure.我们将确定一个亚组的显著上调或下调的基因， 与生物转化或细胞应激有关。为确保项目顺利完成， 密歇根大学的资源、指导和培训将随时可用。这些目标将 提供了一个关键的第一步，在长期目标的定义之间的关系N-DBP暴露，肠道 微生物组和人类健康风险。总体而言，这项跨学科研究将对 了解摄入后N-DBP的毒性机制，以及N-DBP暴露对健康的影响。

PROJECT SUMMARY Nitrogenous disinfection by-products (N-DBPs) are ubiquitous contaminants in tap water, and form when chlorine reacts with natural organic matter in tap water. Chronic exposure to these contaminants is linked with adverse health outcomes, including bladder cancer, miscarriages, and low birthweight. Yet, N-DBPs are unregulated. Comparative toxicity assessments have suggested that N-DBPs are genotoxic and cytotoxic. Nevertheless, standard toxicity assessments are limiting because animal studies and in vitro assays do not always recapitulate human biology. The human gastrointestinal tract microbiome plays an important role in human health and disease progression. Studies have demonstrated that the gut microbiome can degrade xenobiotic compounds into biotransformation products with various toxic effects. Furthermore, xenobiotic exposure has the potential to change microbiome composition and gene expression, which can play a role in adverse health outcomes in humans. In an effort to understand the health effects of N-DBP exposure, this project investigates the interactions between N-DBPs and the human gastrointestinal tract microbiome. The central hypothesis of this study is that microbiome and N-DBP interactions play a role in adverse health effects after exposure. The long-term objective of this project is to investigate the chemical and biological interactions between N-DBPs and the human gut microbiome to elucidate potential mechanisms of adverse effects. The specific aims will test the hypotheses that (1) gut microbiota degrade N-DBPs into biotransformation products with various toxic effects, and (2) environmentally-relevant N-DBP exposure can perturb gut community structures and functional activities. Aim 1 will identify N-DBP biotransformation products in the presence of gut microbiota. We will measure N-DBP degradation and biotransformation products using liquid chromatography (LC) – mass spectrometry (MS). Using a computational toxicology approach, we will predict biotransformation product toxicities based on chemical structure to determine if gut microbiota change N-DBP toxic effects. Aim 2 will determine microbial community gene expression changes in the gut following N-DBP exposure. For this work, we will perform metatranscriptomics to determine differential gene expression changes after N-DBP exposure. We will identify a subset of statistically-significant upregulated or downregulated genes that are relevant to biotransformation or cell stress. To ensure successful completion of this project, state-of-the-art resources, mentorship and training at the University of Michigan will be readily available. These aims will provide a key first step in the long-term goal of defining the relationship between N-DBP exposure, the gut microbiome, and human health risks. Overall, this interdisciplinary study will have a significant impact on understanding N-DBP toxicity mechanisms post-ingestion, and implications of N-DBP exposure on health.