Homocysteine induces congenital defects of the heart and neural tube: Effect of folic acid
Homocysteine induces congenital defects of the heart and neural tube: Effect of folic acid
复制标题
DOI：
10.1073/pnas.93.26.15227
复制
发表时间：
1996-12-24
影响因子：
11.1
通讯作者：
Selhub, J
中科院分区：
文献类型：
--
作者：
Rosenquist, TH;Ratashak, SA;Selhub, J
叶酸补充剂保护心脏和神经管缺陷的生物学基础或机制尚不清楚。有人假设，氨基酸同型半胱氨酸可能是致畸剂，因为血清同型半胱氨酸增加叶酸消耗;然而，这一假设尚未得到验证，在这项研究中，禽胚胎直接与D，L-同型半胱氨酸或与L-同型半胱氨酸硫内酯，并建立了剂量反应。50 μ l致畸剂量处理的胚胎（200 mM D，L-高半胱氨酸或100 mM L-高半胱氨酸硫内酯），并在第53 h收获为确定致畸剂量对心脏分隔过程的影响，在孵育第2、3和4天处理胚胎;在存活的胚胎中，23%表现出室间隔缺损，11%表现出神经管缺损，高百分比的第9天胚胎还表现出腹侧闭合缺损，显示致畸剂量使血清同型半胱氨酸升高至超过150 nmol/ml，而正常水平为约10 nmol/ml，补充叶酸可使血清高半胱氨酸升高至约45 nmol/ml，并防止致畸作用。这些结果支持了高半胱氨酸本身会导致心脏和神经管以及腹壁畸形的假设。
The biological basis or mechanism whereby folate supplementation protects against heart and neural tube defects 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 mu l 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 approximate to 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.