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: 10312390
• 负责人: Hollie Adeola Adejumo
• 金额: $ 3.6万
• 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/10312390
• 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