Prenatal arsenic exposure causes cognitive dysfunction in offspring through KDM5-regulated reprogramming of autophagy in developing brain, an effect attenuated by alpha-ketoglutarate

Prenatal exposure to arsenic has lasting health effects on the developing fetus, including an increased risk of neurological damage in the offspring during adulthood. Epigenetics may be involved in the pathogenic process, but the underlying mechanisms remain unclear. Autophagy, which is involved in nearly all steps of neurodevelopment, is regulated by histones and can be inherited across generations. In the study, we investigated the effects of prenatal arsenic exposure on cognitive function in offspring mice. Dams were exposed to 0, 0.2, 2, or 20 ppm arsenic or to a mixture of 20 ppm arsenic and 1 % α-ketoglutatate (α-KG) through drinking water during pregnancy. Our data showed that prenatal arsenic exposure led to memory impairment in adult male offspring, but not in females. RNA sequencing (RNA-seq) was used to explore differences in gene expression. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses highlighted changes in the activity of lysine demethylase 5 (KDM5) and autophagy pathways. Subsequent experiments revealed that arsenic downregulated the levels of α-KG, reduced the levels of KDM5 activity in the brains of male offspring at postnatal day (PND) 1, and led to elevated levels of trimethylation marks on histone 3 lysine 4 (H3K4me3). Furthermore, H3K4me3 facilitated the transcription of Beclin1 mRNA and increased its expression, resulting in excessive neuronal autophagy. As a cofactor required for KDM5 activity, α-KG, supplemented prenatally, restored KDM5 activity in the brains of offspring and reversed these changes. The results show that supplementation with α-KG during pregnancy, via restoring KDM5 activity, blocks prenatal arsenic exposure-induced cognitive dysfunction in adult male offspring through reprogramming of autophagic processes in developing brain. Our findings provide new insights into the neurodevelopmental damage caused by prenatal arsenic exposure.