Folic acid alleviates gestational arsenic exposure-induced spatial learning and memory impairment in mice offspring via consuming SAM-mediated DNA hypomethylation in the developing brain.

Arsenic is ubiquitously distributed in the environment and substantially threatens human health; however, the mechanism underlying gestational arsenic exposure-induced impairment of neural development in offspring is unclear. Herein, the impact of arsenic exposure during pregnancy on spatial learning and memory was evaluated using a mouse model. The findings indicated that adult offspring exhibited cognitive disorders due to intrauterine arsenic exposure, which correlated with diminished S-adenosylmethionine (SAM) and folic acid (FA) levels in fetuses. Subsequent analysis confirmed that intrauterine arsenic exposure downregulated the DNA methylation, leading to a reduction in the expression of genes related to cognition in the fetal hippocampus, such as breast cancer susceptibility protein 1 (Brca1), c-Fos, activity-regulated cytoskeleton-associated protein (Arc), and Foxg1. We then established a mouse model with FA intervention and discovered that supplementing with FA prevented the arsenic-induced reduction of SAM and 5-methylcytosine (5mC) levels, and restored DNA methylation and genes associated with cognition, thereby mitigating spatial learning and memory impairments in adult offspring. This study demonstrates that FA supplementation alleviates gestational arsenic exposure-induced spatial learning and memory deficits, at least partially, by increasing SAM levels in the developing brain. Our findings identify potential targets and strategies for preventing cognitive impairments in offspring due to gestational arsenic exposure.