Developmental arsenic exposure impairs cognition, directly targets DNMT3A, and reduces DNA methylation

  • EMBO Rep. 2022 Jun 7;23(6):e54147. doi: 10.15252/embr.202154147.
Ni Yan   #  1  2 ,  Yuntong Li   #  1  3 ,  Yangfei Xing  1 ,  Jiale Wu  1 ,  Jiabing Li  1 ,  Ying Liang  1 ,  Yigang Tang  1 ,  Zhengyuan Wang  1 ,  Huaxin Song  1 ,  Haoyu Wang  1 ,  Shujun Xiao  1  2 ,  Min Lu  1
Affiliations
  • 1. Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2. School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
  • 3. Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • # Contributed equally.
PMID: 35373418 DOI: 10.15252/embr.202154147
Abstract

Developmental arsenic exposure has been associated with cognitive deficits in epidemiological studies, but the underlying mechanisms remain poorly understood. Here, we establish a mouse model of developmental arsenic exposure exhibiting deficits of recognition and spatial memory in the offspring. These deficits are associated with genome-wide DNA hypomethylation and abnormal expression of cognition-related genes in the hippocampus. Arsenic atoms directly bind to the cysteine-rich ADD domain of DNA Methyltransferase 3A (DNMT3A), triggering ubiquitin- and proteasome-mediated degradation of DNMT3A in different cellular contexts. DNMT3A degradation leads to genome-wide DNA hypomethylation in mouse embryonic fibroblasts but not in non-embryonic cell lines. Treatment with metformin, a first-line antidiabetic agent reported to increase DNA methylation, ameliorates the behavioral deficits and normalizes the aberrant expression of cognition-related genes and DNA methylation in the hippocampus of arsenic-exposed offspring. Our study establishes a DNA hypomethylation effect of developmental arsenic exposure and proposes a potential treatment against cognitive deficits in the offspring of pregnant women in arsenic-contaminated areas.

Keywords
DNA methylation; DNMT3A; arsenic; cognition; metformin.
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