Inorganic arsenic (iAs) is the top chemical on the ATSDR priority list of hazardous substances. Its role in carcinogenesis has been studied extensively, whereas its role in metabolic disorders has not. Recent human epidemiology studies have identified correlation between type 2 diabetes (T2D) and arsenic exposure. We found that the effect of iAs on metabolism shows sexual dimorphism in mice, with male mice more susceptible to glucose intolerance and female mice more susceptible to changes in hepatic lipid accumulation. We hypothesize that the metabolic and transcriptomic effect of iAs is modulated by estrogen through estrogen receptor (ER) and its co-repressor complex containing histone deacetylase 3 (HDAC3), which accounts for gender-specific effects of iAs in diabetes. We will determine whether loss of estrogen receptor (ER) increases susceptibility to iAs-induced diabetes; whether gain-of-function of ER through genetic manipulation of HDAC3 protects against iAs-induced diabetes; how ER modulates iAs-induced transcriptomic changes, and whether such modulation can be mimicked by HDAC inhibitors (HDIs). Our study addresses the knowledge gap in gender-specific susceptibility to diseases or environmental toxins, and has obvious translational value in prevention and treatment against environmental hazards in both genders, given the availability of selective estrogen receptor modulators (SERMs) and epigenome-modifying HDIs.

Public Health Relevance

The proposed project will address the gender difference in diabetes development due to exposure to inorganic arsenic. We will examine the role of estrogen and estrogen receptor in the process, and test whether modulating these molecules could protect the body from arsenic toxicity. The project is highly relevant to public health because arsenic and diabetes are widespread environmental hazard or human disease, and recent human studies identified correlation between the two.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES027544-01
Application #
9231112
Study Section
Special Emphasis Panel (ZES1-JAB-D (R1))
Program Officer
Schug, Thaddeus
Project Start
2017-03-01
Project End
2022-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
1
Fiscal Year
2017
Total Cost
$593,675
Indirect Cost
$143,675
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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