Folate protection from congenital heart defects linked with canonical Wnt signaling and epigenetics

Abstract

Purpose of review-Environmental factors, such as drugs, chemicals, or abnormal concentrations of natural metabolites induce birth defects. Environmental effects on cardiogenesis have been little studied in contrast to neurogenesis. This review presents evidence on three environmental factors, alcohol, the drug lithium (Li), and the metabolite homocysteine (HCy), impacting the Wnt/β-catenin pathway during cardiac development and folate (FA) protection.Recent findings-Animal and epidemiological studies have shown that FA protects the embryo from birth defects. New animal studies demonstrate that FA prevents cardiovascular defects induced by Li, HCy, or alcohol, but protection occurs at a higher concentration than currently used in vitamin supplements. The data indicate that FA in combination with myo-inositol may further reduce the risk of birth defects. Discussion is presented of the cell specification stages that are impacted resulting in cardiac defects, how Wnt/β-catenin signaling is involved, and how FA and myo-inositol additively may protect embryonic pathways. The possible epigenetic role of folate in Wnt/β-catenin signaling is described.Summary-This review will enable better counseling of women by defining, during early pregnancy, a susceptible window of embryonic exposure leading to a high risk of cardiac defects, and provides a therapeutic means and the necessary timing for prevention of environmentally induced birth defects.

Connecting teratogen‐induced congenital heart defects to neural crest cells and their effect on cardiac function

“…Too low or too high levels of retinoic acid (RA) signaling are known to cause cardiac and other effects very similar to those observed after neural crest ablation (Sinning, ; Zile, ; Pan and Baker, ). Lithium, elevated homocysteine, and ethanol may work through a common pathway, the one carbon cycle, that is rescued by folate and other compounds (Linask and Laties, ; Han et al, ; Linask and Huhta, and reviewed in van Gelder et al, ; Rosenquist, ). This link to a common pathway suggests that an understanding of how one teratogen causes defects may elucidate a general mechanism that might be activated by other teratogens.…”

Protective effects of folic acid on PM2.5-induced cardiac developmental toxicity in zebrafish embryos by targeting AhR and Wnt/β-catenin signal pathways

“…Our previous observations suggested that EOM from PM2.5 induced heart defects in zebrafish embryos, which could be prevented either by CH223191 (an AhR inhibitor) or by CHIR99021 (a Wnt activator). Since FA has been reported to be involved in the canonical Wnt/β‐catenin pathway to rescue lithium‐induced vertebrate cardiac anomalies, we hypothesized that FA may also prevent PM2.5‐induced heart defects by interfering AhR and Wnt/β‐catenin signaling pathways.…”

Epigenetics in the development, modification, and prevention of cardiovascular disease

“…People who consume low levels of folate or who have low folate concentrations in their blood, have a significantly increased risk of developing CV disease [59], despite the confusion regarding possible lack of value, or even harm, from direct supplementation with folate combined with vitamins B6 and B12 [45]. On the other hand, folate in the early pregnancy of a mother-to-be, in combination with myo-inositol, may favorably modify epigenetics to help prevent environmentally induced birth defects associated with congenital heart disease [73].…”