Background To explore the possible mechanism of action of folic acid in the prevention of arse-nic-induced congenital heart disease in fetal mice about the SMAD4/PI3K/AKT/GSK-3β pathway.Methods Thirty Sprague-Dawley rats were randomly divided into control group,arsenic exposure group and folate+arsenic intervention group.Fetal hearts were collected and cardiac pathological injury were observed by H-E staining.Apoptosis/proliferation status of cardiomyocytes was detected by TUNEL reagent and immunohistochemical staining with ki67.The expression levels of Smad4、Gata4、Nkx2.5 and PI3K/AKT/GSK-3β pathways in heart tissue were determined by RT-PCR and WB.CO-IP explores the interaction relationship between SMAD 4 and NKX 2.5.Results The incidence of congenital heart disease in the arsenic-exposed mice was 13.3％,and 0％in both the control group and the folate+arsenic intervention group.Apoptotic car-diomyocytes were significantly increased in the arsenic-exposed group compared with the control group and the folate+arsenic intervention group,while the proliferating cardiomyocytes were significantly reduced(P＜0.05).The levels of Smad4,Gata4,Nkx2.5 mRNA and protein in the heart tissue of the arsenic-exposed group were significantly downregulated compared with the control group and folate+arsenic intervention group(P＜0.05).SMAD4 interact with NKX2.5.The protein expression lev-els of total PI3K,total AKT,and total GSK-3β of the arsenic-exposed group were not significantly different from the control group(P＞0.05),but the protein expression levels of p-PI3K,p-AKT,and p-GSK-3β were significantly lower than the control group and folate+arsenic intervention group(P＜0.05).Conclusion Perinatal folic acid supplementation can alleviate the de-creased proliferation and increased apoptosis of fetal mice caused by arsenic exposure,reverse the downregulation of Smad4 expression caused by arsenic exposure,repair the damage of PI3K/AKT/GSK-3β pathway,and reduce the occurrence of arse-nic-induced congenital heart disease.
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