Congenital heart disease (CHD) is an abnormality in morphological structure and functional metabolism caused by abnormal development of the heart and large blood vessels during the embryonic period or a congenital deformity in which the orifices that are present during the fetal period and are used for blood circulation remain open after birth. Common types of CHD include atrial septal defect, ventricular septal defect, tetralogy of Fallot and complete transposition of the main arteries. In China, approximately 900,000 new cases of birth defects occur each year, and the incidence rate is as high as 5.6%. CHD has the highest incidence of all birth defects, and the incidence is increasing year to year [
1]. CHD seriously harms the health of infants and young children and presents a large economic burden to families and society. Therefore, it is of great significance to explore the pathogenesis of and preventive measures for CHD.
At present, the pathogenesis of CHD is not clear, and it is mainly thought to be caused by environmental factors, genetic factors and the interaction between the two [
2,
3]. Relevant data show that only 40% of CHD cases can be explained by genetic abnormalities and chromosomal abnormalities and that the majority are caused by the combined actions of genetic factors and environmental factors [
4]. At the early stage of development, fetuses are highly sensitive to environmental factors. Changes in the external environment, such as a lack of essential nutrients, exposure to toxic substances, infection with viruses, and unhealthy lifestyles, such as smoking and drinking during pregnancy, can affect the formation and development of the embryonic heart. The development of the heart is delicate and complex, requiring accurate expression of related genes in different locations and at different times. Any small interference can affect the normal formation and development of the heart, which leads to the occurrence of CHD [
5]. There is increasing evidence that in addition to genetic factors, epigenetic inheritance also plays a key role in the precise expression of genes involved in cardiac development. The main components of epigenetics include DNA methylation, histone modification, noncoding RNA regulation and chromatin remodeling. Among histone modifications, the earliest known transcription-related acetylation modification plays an important role in regulating gene transcription. The acetylation of histone H3 lysine 9 (H3K9) plays an important role in gene transcription and expression [
6]. Myocyte enhancer factor-2C (Mef2C) is a core transcription factor during cardiac development, and the abnormal expression of Mef2C can cause abnormal cardiac development and lead to the occurrence of congenital heart disease. A previous study found that [
7] histone acetylation may be an important factor that regulates the expression of the Mef2C gene. Arsenic is a toxic metal that is widely found in nature. Inorganic arsenic can interfere with DNA methylation, histone modification, and noncoding RNA expression [
8,
9]. Our preliminary study showed as exposure to NaAsO
2 increases, the incidence of CHD in fetal rats increases. At the same time, arsenic exposure in fetal rats increases the acetylation levels of histone H3K9 in the myocardium and the expression levels of Mef2C compared to those in the control group. This suggests that arsenic may induce cardiac malformation through epigenetic action.
Folic acid is an essential nutrient for the human body. Folic acid deficiency or the inhibition of biological activities can lead to birth defects such as neural tube defects, CHD, cleft lip and palate deformity [
10,
11]. If folic acid is taken during pregnancy, it can effectively reduce the incidence of premature birth and low birth weight [
12,
13]. At present, research on the mechanism by which folic acid prevents birth defects mainly focuses on folate deficiency and one-carbon metabolism disorders, and there are few reports on epigenetic mechanisms. Studies have shown that folate metabolism can increase the level of NAD-dependent histone deacetylase sirtuins (SIRTs) by increasing the level of nicotinamide adenine dinucleotide coenzyme (NAD) [
14], resulting in changes in histone acetylation levels and thus affecting cell survival, aging and apoptosis. In this study, female rats exposed to arsenic during the periconception period were fed chow containing folic acid to observe the development of the fetal heart, and the effects of different doses of folic acid on developmental toxicity in fetal rats induced by arsenic were investigated. The possible mechanism of the intervention was explored to provide a theoretical basis for supplementation with folic acid during pregnancy to prevent CHD.