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.

Public Health Relevance

The human gut microbial consortium-or, the human gut microbiome-serves a variety of functions related to nutrition, immunity, and detoxification of ingested substances. Conventional risk assessment does not place emphasis on the possible microbiome interactions with ingested environmental contaminants, instead relying upon universal dose-response curves. We propose to characterize the effects of chronically ingested arsenic on the gut microbiome, and vice-versa, laying groundwork for the novel field of microbiome-based risk assessment and informing future treatments and interventions in affected communities both in the U.S. and worldwide.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Chadwick, Lisa
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Stanford University
Schools of Medicine
United States
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