Epigenetic implications in maternal diabetes and metabolic syndrome-associated risk of orofacial clefts

Abstract

Orofacial clefts (OFCs) are one of the most common types of structural birth defects. The etiologies are complicated, involving with genetic, epigenetic, and environmental factors. Studies have found that maternal diabetes and metabolic syndrome are associated with a higher risk of OFCs in offspring. Metabolic syndrome is a clustering of several disease risk factors, including hyperglycemia, dyslipidemia, obesity, and hypertension. Metabolic disease during pregnancy can increase risk of adverse outcomes and significantly influence fetal development, including orofacial formation and fusion. An altered metabolic state may contribute to developmental disorders or congenital defects including OFCs, potentially through epigenetic modulations, such as histone modification, DNA methylation, and noncoding RNA expression to alter activities of critical morphogenetic signaling or related developmental genes. This review summarizes the currently available evidence and underlying mechanisms of how the maternal metabolic syndrome is associated with OFCs in mostly human and some animal studies. It may provide a better understanding of the interactions between intrauterine metabolic status and fetal orofacial development which might be applied toward prevention and treatments of OFCs.

Keywords: diabetes; dyslipidemia; epigenetics; hypertension; maternal metabolic syndrome; obesity; orofacial clefts.

Figure 1.. Epigenetic mechanisms implicated in orofacial clefts associated with maternal metabolic disorders.

Maternal metabolic disorders or syndromes can alter fetal epigenome, including DNA methylation, histone modifications, and microRNA productions which may further affect expression activities of critical signaling genes, such as Wnt and other morphogenetic signaling pathways that are required for orofacial development, leading to orofacial clefts. CLO, cleft lip only; CLP, cleft lip with cleft palate; CPO, cleft palate only; GDM, gestational diabetes; N, nose; P, palate; PGDM, pregestational diabetes; T, tongue; UL, upper lip. Cleft lip (CLO or CLP) can be unilateral or bilateral, only the latter is shown in the diagram.