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.
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.
|Ding, Guolian; Gong, Yingyun; Eckel-Mahan, Kristin L et al. (2018) Central Circadian Clock Regulates Energy Metabolism. Adv Exp Med Biol 1090:79-103|
|Koerner, Martha V; FitzPatrick, Laura; Selfridge, Jim et al. (2018) Toxicity of overexpressed MeCP2 is independent of HDAC3 activity. Genes Dev 32:1514-1524|
|Cui, Chang; Jiang, Xiaohong; Ju, Weizhu et al. (2018) Atrial remodeling and metabolic dysfunction in idiopathic isolated fibrotic atrial cardiomyopathy. Int J Cardiol 265:155-161|
|Zhao, Na; Cao, Jin; Xu, Longyong et al. (2018) Pharmacological targeting of MYC-regulated IRE1/XBP1 pathway suppresses MYC-driven breast cancer. J Clin Invest 128:1283-1299|
|Song, Shiyang; Wen, Yefei; Tong, Hui et al. (2018) The HDAC3 Enzymatic Activity Regulates Skeletal Muscle Fuel Metabolism. J Mol Cell Biol :|
|Gong, Yingyun; Cao, Rui; Ding, Guolian et al. (2018) Integrated omics approaches to characterize a nuclear receptor corepressor-associated histone deacetylase in mouse skeletal muscle. Mol Cell Endocrinol 471:22-32|
|Bai, Shun; Fu, Kaiqiang; Yin, Huiqi et al. (2018) Sox30 initiates transcription of haploid genes during late meiosis and spermiogenesis in mouse testes. Development 145:|
|Zhang, Yuxiang; Papazyan, Romeo; Damle, Manashree et al. (2017) The hepatic circadian clock fine-tunes the lipogenic response to feeding through ROR?/?. Genes Dev 31:1202-1211|