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. Epub 2022 Apr 4.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arsenic* / toxicity
  • Cognition
  • DNA Methylation*
  • DNA Methyltransferase 3A*
  • Female
  • Fibroblasts / metabolism
  • Humans
  • Mice
  • Pregnancy


  • DNA Methyltransferase 3A
  • Arsenic