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

含氮消毒副产物及其对人体肠道微生物群的代谢影响

• 批准号: 10468671
• 负责人: Hollie Adeola Adejumo
• 金额: $ 3.67万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468671
• 关键词: Acute; Adverse effects; Animals; Automobile Driving; Biological; Cellular Stress; Chemical Structure; Chemicals; Chlorine; Chronic; Communities; Complex; Computer software; Coupled; Disease; Disease Progression; Disinfectants; Disinfection; Ensure; Equilibrium; Exposure to; Gastrointestinal tract structure; Gene Expression; Genes; Genomics; Goals; Growth; Health; Health Benefit; Human; Human Biology; Ingestion; Interdisciplinary Study; Investigation; Link; Liquid Chromatography; Literature; Love; Low Birth Weight Infant; Malignant neoplasm of urinary bladder; Mass Fragmentography; Mass Spectrum Analysis; Measures; Mentorship; Messenger RNA; Metabolic; Metabolic Biotransformation; Metabolism; Methods; Michigan; Microbe; Modeling; Outcome; Outcome Study; Parents; Phase; Play; Proliferating; Reporting; Research; Residual state; Resolution; Resources; Risk; Role; Solid; Spontaneous abortion; Structure; System; Techniques; Testing; Tissue-Specific Gene Expression; Toxic effect; Toxicology; Training; Transcript; Universities; Water; Water Pollutants; Water consumption; Work; Xenobiotics; analytical method; base; carcinogenicity; chlorination; comparative; computational toxicology; cytotoxic; detection method; digital; drinking water; genotoxicity; gut microbiome; gut microbiota; in vitro Assay; in vitro Model; insight; liquid chromatography mass spectrometry; metatranscriptomics; microbial; microbial community; microbiome; microbiome composition; pathogen; response; toxicant; transcriptomics; water sampling; waterborne illness

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.

项目总结 含氮消毒副产物(N-DBPs)是自来水中普遍存在的污染物，当 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-DBP是 不受监管。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能。 总是重述人类生物学。人体胃肠道微生物群在 人类健康和疾病进展。研究表明，肠道微生物群可以降解 异源生物化合物转化为具有各种毒性作用的生物转化产品。此外，异种生物 暴露有可能改变微生物群的组成和基因表达，这可能在 对人类的不利健康后果。为了了解接触N-DBP对健康的影响，这项研究 该项目研究N-二氯苯酚与人体胃肠道微生物群之间的相互作用。这个 这项研究的中心假设是微生物组和N-DBP的相互作用在不利的健康影响中发挥作用 曝光后。这个项目的长期目标是研究化学和生物的相互作用。 N-二苯基苯并苯和人体肠道微生物组之间的关系，以阐明不良反应的潜在机制。这个 特定的目标将检验以下假设：(1)肠道微生物区系将N-DBPs降解为生物转化产物 具有各种毒性作用，以及(2)与环境相关的N-DBP暴露可扰乱肠道群落 结构和功能活动。目标1将在肠道存在的情况下鉴定N-DBP生物转化产物 微生物区系。我们将用高效液相色谱法测定N-DBP的降解和生物转化产物 (LC)-质谱仪(MS)。使用计算机毒理学方法，我们将预测生物转化 产品毒性基于化学结构，以确定肠道微生物区系是否改变N-DBP的毒性效应。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。为了这个 我们将进行元翻译以确定N-DBP后差异基因表达的变化 曝光。我们将确定具有统计学意义的上调或下调基因的子集 与生物转化或细胞压力有关的。为了确保这个项目的成功完成，最先进的 密歇根大学的资源、指导和培训将随时可用。这些目标将 在确定N-DBP暴露与肠道之间关系的长期目标中迈出关键的第一步 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摄入后的毒性机制，以及N-DBP暴露对健康的影响。