Affiliations
- Center for Global Health, China International Cooperation Center for Environment and Human Health, Jiangsu Safety Assessment and Research Center for Drug, Pesticide, and Veterinary Drug, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China.
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 550025, Guizhou, People's Republic of China.
- Suzhou Center for Disease Control and Prevention, Suzhou Institute of Public Health, Gusu School, Nanjing Medical University, Suzhou 215004, Jiangsu, People's Republic of China.
- Institute of Physical and Chemical Testing, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing 210009, Jiangsu, People's Republic of China.
- Medical Research Centre, Liaquat University of Medical & Health Sciences, Jamshoro 76090, Sindh, Pakistan.
- Center for Global Health, China International Cooperation Center for Environment and Human Health, Jiangsu Safety Assessment and Research Center for Drug, Pesticide, and Veterinary Drug, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China. Electronic address: jingshuzh@njmu.edu.cn.
- Center for Global Health, China International Cooperation Center for Environment and Human Health, Jiangsu Safety Assessment and Research Center for Drug, Pesticide, and Veterinary Drug, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; Suzhou Center for Disease Control and Prevention, Suzhou Institute of Public Health, Gusu School, Nanjing Medical University, Suzhou 215004, Jiangsu, People's Republic of China. Electronic address: drqzliu@hotmail.com.
PMID: 38185084 DOI: 10.1016/j.jhazmat.2023.133405
Abstract
Exposure to arsenic during gestation has lasting health-related effects on the developing fetus, including an increase in the risk of metabolic disease later in life. Epigenetics is a potential mechanism involved in this process. Ten-eleven translocation 2 (TET2) has been widely considered as a transferase of 5-hydroxymethylcytosine (5hmC). Here, mice were exposed, via drinking water, to arsenic or arsenic combined with ascorbic acid (AA) during gestation. For adult offspring, intrauterine arsenic exposure exhibited disorders of glucose metabolism, which are associated with DNA hydroxymethylation reprogramming of hepatic nuclear factor 4 alpha (HNF4α). Further molecular structure analysis, by SEC-UV-DAD, SEC-ICP-MS, verified that arsenic binds to the cysteine domain of TET2. Mechanistically, arsenic reduces the stability of TET2 by binding to it, resulting in the decrease of 5hmC levels in Hnf4α and subsequently inhibiting its expression. This leads to the disorders of expression of its downstream key glucose metabolism genes. Supplementation with AA blocked the reduction of TET2 and normalized the 5hmC levels of Hnf4α, thus alleviating the glucose metabolism disorders. Our study provides targets and methods for the prevention of offspring glucose metabolism abnormalities caused by intrauterine arsenic exposure.
Keywords: Ascorbic acid; Glucose metabolism disorders; Hepatic nuclear factor 4 alpha; Intrauterine arsenic exposure; Ten-eleven translocation 2.
