Mechanism Of DNA Methylation And Atherosclerosis In The Male Offspring Induced By Gestational Arsenic Exposure

Background/aims:Exposure to the environmental toxicants poses a serious threat to human health.Early life exposure to arsenic can significantly increase the risk of serious diseases in adulthood.DNA methylation is one of the main mechanisms of epigenetics.Studies have shown that ABCA1methylation can increase the risk of atherosclerosis,but the role of ABCA1 in arsenic-induced atherosclerosis is unclear.In this study,Apo E knockout(Apo E^-/-)mice were used to explore the relationship between atherosclerosis and ABCA1 methylation in male offspring exposed to arsenic during pregnancy.Methods:From the GEO public database,we used the bioinformatics method to analyze the gene expression profile of neonate mouse epidermis stem cell after in utero exposure to ingonre arsenic in drinking water.After screening and analyzing the DEGs by R tool,we found that the expression level of many ABC family members have changed.Then the pregnant mice were randomly assigned to control and arsenic-treated group according to be maintained on tap water with or without 85ppm NaAsO₂ from gestation day（GD）8 to GD15.Arsenic-contaminated drinking water were refreshed every 2-3 days to minimize oxidation.After parturition,the pups were weaned at birth 21 days of age and maintained on a standard chow diet.At 8 and 24 weeks of age,Oil red O staining,HE and Masson staining were used to detect the formation of aortic plaques and the content lipid in liver;Elisa was used to detect serum lipid levels;radioactive element[³H]was labeled with peritoneal macrophages,and liquid scintillation counters were detected.Biochemical colorimetric was used to examine oxidative stress.Global DNA methylation was measured by MethylFlash^TM Methylated DNA Quantification Kit;BSP was used to measure methylation status of hepatic ABCA1 gene promoter.Results:Results indicated that in utero arsenic exposure could cause dyslipidemia in male offspring both at 8 and 24 weeks.And arsenic could induce lipid accumulation in liver,increased the area of plaque,inhibite cholesterol efflux of macrophages and downregulate hepatic ABCA1 gene expression at week 24,which accelerate the formation of atherosclerosis.Further,we found that arsenic exposure during pregnancy could cause oxidative stress and global DNA hypermethylation in male offspring.However,arsenic had no effect on the methylation status of ABCA1 gene promoter.Conclusion:1.Arsenic exposure during pregnancy can promote Global DNA hypermethylation and increase the risk of atherosclerosis by enhancing oxidative stress in male offspring.2.Arsenic exposure during pregnancy can down-regulate the expression of ABCA1 in the liver of male offspring,inhibit cholesterol outflow,cause lipid metabolism disorder,and finally lead to the formation of atherosclerosis.