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Reductions in the incidence of nitrofen-induced diaphragmatic hernia by vitamin A and retinoic acid

¹Department of Physiology, ²Department of Pediatrics, Perinatal Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2

Submitted 21 November 2003 ; accepted in final form 2 January 2004

Congenital diaphragmatic hernia (CDH) is a serious medical condition in which the developing diaphragm forms incompletely, leaving a hole through which the abdominal contents can enter the thoracic space and interfere with lung growth. A perturbation of the retinoid system has been linked to the etiology of CDH. This includes findings that nitrofen, which induces CDH in rodents, inhibits the key enzyme for retinoic acid (RA) production, retinaldehyde dehydrogenase-2 (RALDH2) in vitro. Published studies indicate that antenatal vitamin A administration on gestational day (D) 12 in the nitrofen model of CDH reduced the severity and incidence of right-sided defects and lung hypoplasia. In this study, we administered nitrofen on D8, to include the induction of clinically more prevalent left-sided defects, and examined the efficacy of several vitamin A administration paradigms to gain insights into the developmental stage of susceptibility. Furthermore, we tested the hypothesis that administration of RA, the product of RALDH2 activity, is more potent than administering the substrate, vitamin A, in reducing the incidence of CDH. The incidence of CDH was reduced from 54% (nitrofen alone) to 32% with vitamin A treatment. The efficacy of RA treatment was very marked, with a reduction in the incidence of CDH to 15%. Administration of vitamin A or RA on D10 was most effective. These data lend further support for the potential involvement of retinoid signaling pathways and the etiology of CDH and support data from in vitro studies demonstrating a nitrofen-induced suppression of RALDH2.

retinoids; congenital diaphragmatic hernia; neonate diaphragm; respiration; newborn; lung

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