• Salomé González-Reyes, Leopoldo Martínez, and Juan A Tovar.
• Department of Pediatric Surgery, Research Laboratory, Hospital Universitario La Paz, 28046 Madrid, Spain.
• J. Pediatr. Surg. 2005 Aug 1; 40 (8): 1269-74.

Background/AimNitrofen 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.Material And MethodsTime-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.ResultsNitrofen 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.ConclusionsAntioxidant 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.

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