Environmental arsenic contamination poses a major threat to public health, affecting over 140 million people in the US and worldwide. Epidemiological studies show a link between arsenic exposure and the development of type 2 diabetes mellitus (T2DM), yet the molecular and genetic mechanisms underlying this link remain poorly understood. At the cellular level, arsenic induces adaptive changes known as the ER (endoplasmic reticulum) stress response. The ER stress response is critically implicated in insulin dysregulation and impaired glucose homeostasis that are key hallmarks of T2DM. The overarching hypothesis of this project is that arsenic exposures cause diabetes by inducing the cellular ER stress response. To test this hypothesis and to elucidate the molecular and genetic mechanisms of arsenic-induced ER stress, we propose a multidisciplinary study with the following specific aims: 1) to perform genome-wide functional genetic screens to discover a comprehensive map of genes and genetic pathways that are critically involved in arsenic-induced ER stress, 2) to test the hypothesis that arsenic impacts glucose homeostasis (i.e. insulin production in pancreatic beta cells and glucose utilization in fat cells) through its functional modulation of ER stress genes, and 3) to identify genetic variants in the arsenic-specific ER stress genes and assess their association with T2DM in a human population. This integrative and multidisciplinary study will advance our understanding of the well-established yet poorly understood diabetogenic effects of arsenic exposure. The research will further strengthen the link between a widespread environmental toxin contaminant (arsenic) and T2DM--an increasingly prevalent and devastating human disease. Mechanistic insights gained from the study may ultimately lead to better strategies for the diagnosis, prevention and alleviation of T2DM caused by exposure to arsenic in the environment. Furthermore, our study on ER stress response will contribute to the understanding of other human diseases, in which etiology resides at gene-environment interactions that cause cellular stress and adaptive responses.

Public Health Relevance

Exposure to arsenic contamination in the environment is associated with the development of type 2 diabetes. We propose a multidisciplinary study to discover and assess the roles of genes that mediates a cellular adaptive response critically implicated in diabetes. This study will advance our understanding of the well-established yet poorly understood diabetogenic effects of arsenic exposure and may ultimately lead to better strategies for the diagnosis, prevention and alleviation of type 2 diabetes caused by exposure to arsenic in the environment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES022230-02
Application #
8607184
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Mcallister, Kimberly A
Project Start
2013-02-01
Project End
2017-10-31
Budget Start
2013-11-01
Budget End
2014-10-31
Support Year
2
Fiscal Year
2014
Total Cost
$327,038
Indirect Cost
$124,538
Name
Harvard University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Pan, Wen-Chi; Kile, Molly L; Seow, Wei Jie et al. (2013) Genetic susceptible locus in NOTCH2 interacts with arsenic in drinking water on risk of type 2 diabetes. PLoS One 8:e70792