Abstract 13595: Folic Acid Protects Embryo From Environmental Effects on Lipid Metabolism During Cardiac and Placental Development

Abstract

Introduction: Congenital heart defects (CHDs) are the most prevalent of human birth defects with males exhibiting more severe types of CHDs. Cardiac cell and placental trophoblast differentiation are two embryonic processes occurring early between E6.5-E8.0 of mouse gestation (16-19 days of human pregnancy) that can be interfered with by environmental factors to induce anomalies. Objective: To determine the predominant pathway(s) targeted by exposures to lithium (Li+), homocysteine (HCys) , or alcohol (ethanol, EtOH) that result in CHDs and that can be protected by high dose folic acid (FA) supplementation. Method: On morning of conception, pregnant mice were placed on a protective, high FA diet (10 mg/kg) or on a health maintenance FA diet (3.3 mg/kg) that did not prevent CHDs. At gastrulation (E6.75) the mice received an i.p. injection of Li, HCys, or EtOH. Pregnant control groups received either the protective high FA or the normal FA maintenance diet and an i.p. injection of physiological saline only. Echocardiography on E15.5 determined embryos with abnormal cardiac function. All abnormal hearts and normal control hearts were removed, total RNA extracted. Microarrays were used to evaluate gene changes. Results: Significant expression changes among 12 treatment groups with Li and HCys exposures indicated that Gene Ontology (GO) categories involving lipid metabolism were chiefly altered. When the GO sets were sorted according to gender, male embryos displayed greater changes in lipid-related categories than the female. Validation studies demonstrated that Acyl CoA dehydrogenase medium length chain (Acadm) and its protein product important in fatty acid oxidation were modulated by the exposures, including by alcohol. Oil Red O (ORO) localization of neutral lipids in the heart and placenta demonstrated that lipids are highly altered possibly related to altered umbilical blood flow seen with embryos showing abnormal cardiac function. High FA restored normal ORO patterns, placental blood flow, and heart function. Conclusions: Li, HCys and alcohol exposed embryos display altered lipid metabolism. Early gestational supplementation with high-dose FA protects lipid metabolism at control levels, maintains placental physiology, and prevents CHDs.