Microbiome-Based Risk Assessment: Reciprocal Effects of Arsenic on Environmental

描述（由申请人提供）：这项拟议的工作调查砷摄入对环境和人类健康的相互影响，因为美国和世界各地数百万人因自然发生和人为来源而受到慢性砷暴露。长期接触砷会导致砷中毒，包括黑变病、角化病以及肺癌、膀胱癌、肾癌和皮肤癌。慢性砷暴露也会影响儿童的智力功能和发育。砷中毒没有有效的治疗方法，强调预防和/或新的治疗方法的重要性。拟议工作的目标是了解（1）环境砷摄入对通过地质砷污染的水和大米暴露的个人肠道微生物组的影响，以及（2）微生物组对人类宿主中砷的命运和毒性的影响。这项研究结合了基因组学、人类微生物生态学、实验环境微生物学和生物化学，推进了环境/公共卫生风险评估和可能的干预措施。该假设是砷摄入改变了人类肠道微生物组的结构和功能，人类肠道微生物组的变化有助于观察到的砷中毒存在/不存在的差异。这一多学科项目的广泛的长期目标是为微生物组相关风险评估奠定基础，这是一个新兴领域，被纳入2012年NIEHS使命声明，并为砷中毒提供新的干预措施，砷中毒是一种影响全球数百万人的疾病。具体目标1。确定外源性砷对肠道微生物组的影响，以及在不存在/存在砷修正培养基的情况下使用厌氧生物反应器对砷转化的影响。将采用未暴露的健康人个体（对照组）和长期砷暴露的孟加拉国组（+/-砷中毒）。具体目标2。描述未暴露于砷的健康人以及有/无砷中毒的暴露个体的肠道微生物组中与砷转化相关的微生物基因的频率和多样性。目标1的队列将用于目标2，并将开发和进行qPCR功能基因分析。探索这些基因的丰度模式将允许健康人以及长期砷暴露和非暴露个体的活性和基因丰度之间的相关性。具体目标3。描述慢性砷暴露个体（有砷中毒和无砷中毒）肠道微生物组分类组成和多样性的变化。来自Aim 1的孟加拉国队列将用于该16 S rRNA基因序列分析。

DESCRIPTION (provided by applicant): This proposed work investigates the reciprocal effects of arsenic ingestion upon both environmental and human health, as millions of people both in the U.S. and worldwide are subject to chronic arsenic exposure due to naturally-occurring and anthropogenic sources. Chronic exposure leads to arsenicosis, which includes melanosis, keratosis, as well as lung, bladder, kidney, and skin cancer. Chronic arsenic exposure can also affect childhood intellectual function and development. There is no effective therapy for arsenicosis, emphasizing the importance of prevention and/or novel therapeutic approaches. The goal of the proposed work is to understand both (1) the effects of environmental arsenic ingestion upon the human gut microbiome of individuals exposed through geogenic arsenic-contaminated water and rice, and (2) the effects of the microbiome on the fate and toxicity of arsenic in the human host. This research couples genomics, human microbial ecology, experimental environmental microbiology, and biochemistry, advancing environmental/public health risk assessment and possible interventions. The hypothesis is that arsenic ingestion alters the structure and function of the human gut microbiome and that variation in the human gut microbiome contribute to the observed differences in presence/absence of arsenicosis. The broad, long-term objectives of this multidisciplinary project are to lay groundwork for microbiome-related risk assessment-an emerging field recognized by its inclusion in the 2012 NIEHS Mission Statement-and to inform novel interventions for arsenicosis, a disease affecting millions worldwide. Specific Aim 1. To determine the effects of exogenous arsenic on the gut microbiome and on the resulting transformation of arsenic using anaerobic bioreactors in the absence/presence of arsenic-amended media. Both non-exposed healthy human individuals (control group) and chronically arsenic exposed Bangladeshi groups (+/- arsenicosis) will be employed. Specific Aim 2. To characterize the frequency and diversity of microbial genes related to arsenic transformation in the gut microbiome of healthy humans with no arsenic exposure, as well as exposed individuals with/without arsenicosis. The cohorts of Aim 1 will be used for Aim 2, and a qPCR functional gene analysis will be developed and performed. Exploring patterns of abundance of these genes will allow for correlations between activity and gene abundance in healthy humans, as well as both chronically arsenic exposed and non-exposed individuals. Specific Aim 3. To characterize variations in taxonomic composition and diversity of the gut microbiomes of chronic arsenic-exposed individuals with and without arsenicosis. The Bangladeshi cohorts from Aim 1 will be employed for this 16S rRNA gene sequence analysis.