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

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. SYNOPSIS Arsenic pollution has been linked to cognitive deficits. This study shows that arsenic binds the DNMT3A protein and disturbs cognition‐related gene expression in mouse brains, which can be rescued by metformin treatment. Developmental arsenic exposure induces genome‐wide DNA hypomethylation in the mouse hippocampus. Arsenic directly binds to DNMT3A and induces DNMT3A degradation through the ubiquitin‐proteasome pathway. Arsenic treatment leads to genome‐wide DNA hypomethylation in mouse embryonic fibroblasts but not in non‐embryonic cell lines. Metformin treatment ameliorates the arsenic‐induced cognitive deficits and normalizes the arsenic‐induced hippocampal DNA hypomethylation. Graphical Abstract Arsenic pollution has been linked to cognitive deficits. This study shows that arsenic binds the DNMT3A protein and disturbs cognition‐related gene expression in mouse brains, which can be rescued by metformin treatment.