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

项目概要 氮消毒副产物 (N-DBP) 是自来水中普遍存在的污染物，在以下情况下形成： 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 不良的健康结果，包括膀胱癌、流产和低出生体重。然而，N-DBP 是 不受监管。比较毒性评估表明 N-DBP 具有遗传毒性和细胞毒性。 然而，标准毒性评估是有限的，因为动物研究和体外测定没有 总是概括人类生物学。人体胃肠道微生物组在以下方面发挥着重要作用： 人类健康和疾病进展。研究表明肠道微生物组可以降解 将外源化合物转化为具有各种毒性作用的生物转化产品。此外，异生素 暴露有可能改变微生物组组成和基因表达，这可以在 对人类产生不良健康后果。为了了解 N-DBP 暴露对健康的影响，本研究 该项目研究 N-DBP 与人类胃肠道微生物群之间的相互作用。的 这项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 曝光后。该项目的长期目标是研究化学和生物相互作用 N-DBP 和人类肠道微生物组之间的关系，以阐明不良影响的潜在机制。的 具体目标将检验以下假设：(1) 肠道微生物将 N-DBP 降解为生物转化产物 具有各种毒性作用，并且 (2) 环境相关的 N-DBP 暴露会扰乱肠道菌群 结构和功能活动。目标 1 将鉴定肠道存在下的 N-DBP 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 (MS)。使用计算毒理学方法，我们将预测生物转化 根据化学结构确定产品毒性，以确定肠道微生物群是否改变 N-DBP 毒性作用。目标2 将确定 N-DBP 暴露后肠道中微生物群落基因表达的变化。为此 工作中，我们将进行宏转录组学来确定 N-DBP 后差异基因表达的变化 曝光。我们将识别统计显着的上调或下调基因的子集，这些基因是 与生物转化或细胞应激有关。为确保该项目的顺利完成，我们采用了最先进的技术 密歇根大学的资源、指导和培训将随时可用。这些目标将 为确定 N-DBP 暴露与肠道之间关系的长期目标迈出了关键的第一步 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 N-DBP 摄入后毒性机制以及 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.