Cipollone Daria, Carsetti Rita, Tagliani Angela, Rosado Maria Manuela, Borgiani Paola, Novelli Giuseppe, D'Amati Giulia, Fumagalli Lorenzo, Marino Bruno, Businaro Rita
Department of Biopathology and Diagnostic Imaging, University "Tor Vergata," Rome, Italy.
Cardiovasc Pathol. 2009 Mar-Apr;18(2):100-9. doi: 10.1016/j.carpath.2008.02.007. Epub 2008 Apr 15.
Periconceptional supplementation with multivitamins containing folic acid reduces the risk of congenital malformations. We have previously investigated the effect on the murine development of a multiple retinoic acid competitive antagonist, Bristol-Myers-Squibb 189453, showing that treated fetuses were affected with heart defects, thymus aplasia or hypoplasia, and severe anomalies of the central nervous system. Hereby, we analyzed the effects of nutritive therapy involving folic acid and methionine on teratogen-induced congenital defects in mice.
A total of 132 outbred CD1 litters were studied. Pregnant mice were divided into four experimental groups, and an oral supplementation of H(2)O or folic acid, or methionine, or folic acid+methionine was administered from 0.5 days postcoitum until the end of pregnancy. At 7.5 days postcoitum, mice from all these groups were administered Bristol-Myers-Squibb 189453 to induce the teratogenic effect. At the end of pregnancy, fetuses were dissected and tissues were analyzed by histology and flow cytometric assays.
Folic acid reduces congenital heart diseases from 81.3% to 64.8%, neural tube defects from 20.3% to 3.7%, and thymus abnormalities from 98.4% to 27.8%, restoring a normal number of differentiated thymus cells. Methionine is less effective in contrasting congenital heart diseases and neural tube defects, and induces thymus cell proliferation but not differentiation. Folic acid+methionine weakly reduce congenital heart diseases and neural tube defects, but consistently reduce the incidence of fetuses affected with thymus pathologies from 98.4% to 67.7%.
Our results suggest that folic acid and methionine periconceptional supplementations may influence the incidence of congenital defects and may probably induce negative selection of embryos presenting developmental anomalies.
孕期补充含叶酸的多种维生素可降低先天性畸形的风险。我们之前研究了一种多重视黄酸竞争性拮抗剂百时美施贵宝189453对小鼠发育的影响，结果显示，接受治疗的胎儿出现心脏缺陷、胸腺发育不全或发育不良以及严重的中枢神经系统异常。在此，我们分析了叶酸和蛋氨酸营养疗法对致畸剂诱导的小鼠先天性缺陷的影响。
共研究了132窝远交群CD1小鼠。将怀孕小鼠分为四个实验组，从交配后0.5天至妊娠结束，分别口服补充水、叶酸、蛋氨酸或叶酸+蛋氨酸。在交配后7.5天，给所有这些组的小鼠施用百时美施贵宝189453以诱导致畸作用。妊娠结束时，解剖胎儿，并通过组织学和流式细胞术分析组织。
叶酸可将先天性心脏病的发生率从81.3%降至64.8%，神经管缺陷的发生率从20.3%降至3.7%，胸腺异常的发生率从98.4%降至27.8%，使分化的胸腺细胞数量恢复正常。蛋氨酸在对抗先天性心脏病和神经管缺陷方面效果较差，可诱导胸腺细胞增殖但不能诱导分化。叶酸+蛋氨酸对先天性心脏病和神经管缺陷的降低作用较弱，但可将受胸腺病变影响的胎儿发生率从98.4%持续降至67.7%。
我们的结果表明，孕期补充叶酸和蛋氨酸可能会影响先天性缺陷的发生率，并且可能会对出现发育异常的胚胎进行负向选择。
