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

描述(申请人提供)：这项拟议的工作调查了砷摄取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由于自然和人为来源而受到慢性砷暴露的影响。长期接触会导致砷中毒，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。没有治疗砷中毒的有效方法，强调预防和/或新的治疗方法的重要性。这项拟议工作的目标是了解(1)环境砷摄取对通过受地质砷污染的水和大米暴露的个人肠道微生物群的影响，以及(2)微生物群对砷在人类宿主中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/公共健康风险评估和可能的干预措施。假说是摄入砷改变了人体肠道微生物群的结构和功能，人体肠道微生物群的变异导致了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、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，被列入2012年NIEHS使命声明--并为影响全球数百万人的砷中毒的新干预措施提供信息。具体目的1.确定外源砷对肠道微生物群的影响，以及在无砷/有砷的情况下利用厌氧生物反应器对砷的转化的影响。未接触砷的健康人(对照组)和长期接触砷的孟加拉人组(+/-砷中毒)都将被使用。具体目的2.研究与砷转化相关的微生物基因在健康非砷暴露人群和暴露于砷中毒/非砷中毒人群肠道微生物群中的频率和多样性。AIM 1的队列将用于AIM 2，并将开发和执行qPCR功能基因分析。探索这些基因丰度的模式将允许健康人类以及长期接触砷和非接触砷的人的活动和基因丰度之间的相关性。具体目标3.研究慢性砷暴露合并和不合并砷中毒患者肠道微生物群落的分类组成和多样性的变化。来自AIM 1的孟加拉队列将用于16S 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.