González-Reyes Salomé, Martínez Leopoldo, Tovar Juan A
Department of Pediatric Surgery, Research Laboratory, Hospital Universitario La Paz, 28046 Madrid, Spain.
J Pediatr Surg. 2005 Aug;40(8):1269-74. doi: 10.1016/j.jpedsurg.2005.05.009.
BACKGROUND/AIM: Nitrofen induces heart hypoplasia together with congenital diaphragmatic hernia (CDH) in rats. Intracellular oxidative stress might be one of the mechanisms of action of the teratogen, and vitamin A has been shown to reverse in part these effects when administered simultaneously or shortly after it. This study aims at testing the hypothesis that vitamin A and other antioxidant vitamins, such as E and C, could improve myocardial development even when administered late in gestation, a likely useful period for prenatal medication.
Time-mated Sprague-Dawley female rats were exposed to either vehicle (control) or 100 mg of nitrofen (experimental) on day 9.5 of gestation. In 3 additional groups, the animals were exposed to vitamin A (total 15000 IU), vitamin E (total 150 IU), or vitamin C (total 150 IU) on days 16, 17, and 18. The fetuses were recovered on day 21, and randomly selected hearts of those with CDH were processed for histologic studies (hematoxylin-eosin and periodic acid-Schiff stainings), DNA and protein contents, and ki-67 (proliferation) and terminal deoxynucleotidyl transferase-mediated dUTP-biotin end labeling (apoptosis) studies. The differences among groups were assessed by analysis of variance with Bonferroni/Dunn post hoc tests and a threshold of significance of P < .05.
Nitrofen induced heart hypoplasia in terms of decreased heart/body weight, cell mass (less DNA and protein), and proportion of proliferating cells with increased apoptosis. Vitamin C alleviated weight hypoplasia and the 3 vitamins were able to restore cell mass and to reestablish near-normal figures of proliferation and apoptosis.
Antioxidant vitamins A, E, and C given late in gestation alleviate heart hypoplasia that accompanies CDH in the rat model. This timing suggests that the beneficial effects are exerted on the maturational phase of development.
背景/目的：在大鼠中，除草醚可导致心脏发育不全并伴有先天性膈疝（CDH）。细胞内氧化应激可能是这种致畸剂的作用机制之一，并且已表明维生素A在同时或在其之后不久给药时可部分逆转这些效应。本研究旨在验证这一假设：即使在妊娠后期给药，维生素A以及其他抗氧化维生素（如维生素E和维生素C）也可改善心肌发育，这可能是产前用药的一个有用时期。
将定时交配的斯普拉格-道利雌性大鼠在妊娠第9.5天暴露于赋形剂（对照组）或100 mg除草醚（实验组）。在另外3组中，动物在第16、17和18天分别暴露于维生素A（总量15000 IU）、维生素E（总量150 IU）或维生素C（总量150 IU）。在第21天取出胎儿，随机选择患有CDH的胎儿的心脏进行组织学研究（苏木精-伊红染色和过碘酸-希夫染色）、DNA和蛋白质含量测定以及ki-67（增殖）和末端脱氧核苷酸转移酶介导的dUTP-生物素末端标记（凋亡）研究。通过方差分析和Bonferroni/Dunn事后检验评估组间差异，显著性阈值为P < 0.05。
除草醚导致心脏发育不全，表现为心脏/体重降低、细胞量减少（DNA和蛋白质含量降低）、增殖细胞比例降低以及凋亡增加。维生素C减轻了体重发育不全，这3种维生素能够恢复细胞量，并使增殖和凋亡数据重新接近正常水平。
在大鼠模型中，妊娠后期给予抗氧化维生素A、E和C可减轻伴有CDH的心脏发育不全。这一时机表明有益作用是在发育的成熟阶段发挥的。
