Homocysteine induces congenital defects of the heart and neural tube: effect of folic acid.
The biological basis or mechanism whereby folate supplementation protects against heart and neural tube defect is unknown. It has been hypothesized that the amino acid homocysteine may be the teratogenic agent, since serum homocysteine increases in folate depletion; however, this hypothesis has not been tested. In this study, avian embryos were treated directly with D,L-homocysteine or with L-homocysteine thiolactone, and a dose response was established. Of embryos treated with 50 microliters of the teratogenic dose (200 mM D,L-homocysteine or 100 mM L-homocysteine thiolactone) on incubation days 0, 1, and 2 and harvested at 53 h (stage 14), 27% showed neural tube defects. To determine the effect of the teratogenic dose on the process of heart septation, embryos were treated during incubation days 2, 3, and 4; then they were harvested at day 9 following the completion of septation. Of surviving embryos, 23% showed ventricular septal defects, and 11% showed neural tube defects. A high percentage of the day 9 embryos also showed a ventral closure defect. The teratogenic dose was shown to raise serum homocysteine to over 150 nmol/ml, compared with a normal level of about 10 nmol/ml. Folate supplementation kept the rise in serum homocysteine to approximately 45 nmol/ml, and prevented the teratogenic effect. These results support the hypothesis that homocysteine per se causes dysmorphogenesis of the heart and neural tube, as well as of the ventral wall.
Rosenquist
T H
TH
Department of Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha 68198-6395, USA.
Ratashak
S A
SA
Selhub
J
J
D000818:Animals; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000187:drug effects*; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005492:Folic Acid / Q000494:pharmacology*; D005775:Gastrula / Q000187:drug effects; D006330:Heart Defects, Congenital / Q000139:chemically induced* / Q000517:prevention & control; D006710:Homocysteine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051379:Mice; D009436:Neural Tube Defects / Q000139:chemically induced* / Q000517:prevention & control; D013723:Teratogens / Q000633:toxicity*
D013723:Teratogens; D006710:Homocysteine; D005492:Folic Acid; C007957:homocysteine thiolactone