Maternal folate deficiency affects proliferation, but not apoptosis, in embryonic mouse heart.
Low dietary folate and deficiency of methylenetetrahydrofolate reductase (Mthfr) were reported to increase the risk for congenital heart defects, but contributory mechanisms have not been elucidated. Because low folate and absent MTHFR activity were shown to affect proliferation and apoptosis in developing neural tissue, we examined these processes in the myocardium of embryos from Mthfr +/+ and Mthfr +/- mice fed control diets (CD) or folic acid-deficient diets (FADD). Mice consumed the designated diets for 8 wk, from weaning and through pregnancy until they were killed. Embryos were assessed on gestational day 12.5 for myocardial proliferation by 5-bromo-2'-deoxyuridine (BrdU) labeling and for apoptosis by TdT-mediated dUTP nick end labeling staining and caspase 3/7 activity assays. FADD-treated dams had significantly higher resorption rates than CD-treated dams. Embryonic lengths and weights from FADD-treated dams were significantly lower than those from CD-treated dams; the smallest embryos were those of the Mthfr +/- dams that consumed the FADD, with effect of genotype tending to be significant (P = 0.09). The thickness of cardiac ventricular compact walls of embryos from FADD-treated dams was significantly reduced, and embryonic myocardium from FADD-treated dams had significantly fewer BrdU-labeled cells compared with CD-treated dams, with no differences in apoptosis due to the diets. Genotype did not affect proliferation or apoptosis. Our results suggest that proliferation of embryonic myocardium is sensitive to maternal dietary folate and that folate supplementation during pregnancy is important for normal heart development and prevention of heart defects.
Li
Deqiang
D
Departments of Human Genetics, Pediatrics, and Biology, McGill University-Montreal Children's Hospital Research Institute, Montreal, PQ, Canada.
Rozen
Rima
R
D000818:Animals; D000963:Antimetabolites / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000302:isolation & purification; D049109:Cell Proliferation / Q000187:drug effects; D004032:Diet; D047108:Embryonic Development; D005260:Female; D005492:Folic Acid / Q000097:blood; D005494:Folic Acid Deficiency / Q000150:complications* / Q000378:metabolism; D005838:Genotype; D006330:Heart Defects, Congenital / Q000209:etiology* / Q000473:pathology; D006397:Hematinics / Q000097:blood; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D011247:Pregnancy
D000963:Antimetabolites; D006397:Hematinics; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D001973:Bromodeoxyuridine