Mitochondrial dysfunction is implicated in retinoic acid-induced spina bifida aperta in rat fetuses.

Neural tube defects (NTDs) are the most common and severe congenital malformations, which result from failure of the neural tube to close during embryonic development. The etiology of NTDs is complex, caused by interactions between genetic defects and environmental factors, but the exact mechanisms of this disease are still not fully understood. We herein employ a Seahorse Bioscience microplate-based extracellular flux (XF) analyzer to determine mitochondrial function and quantify respiratory coupling to various bioenergetic functions using specific pharmacological inhibitors of bioenergetic pathways. We demonstrate that changes in coupling between ATP turnover and proton leak are correlated with NTDs. Further, we determined that the ATP content and oxidative stress levels in posterior spinal cords of rat embryos with NTDs between E11 and E14 was lower than that of normal controls. The present study reveals that mitochondrial dysfunction is associated with all-trans retinoic acid (atRA)-induced NTDs in rat embryos. Oxidative stress results from decreased antioxidant enzyme activity. This study provides a novel viewpoint for exploring the embryonic pathogenesis of atRA-induced NTDs.