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1 Depatment of Physiology, University of Alberta, Edmonton, AB, Canada
2 Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
* To whom correspondence should be addressed. E-mail: john.greer{at}ualberta.ca.
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 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 rightsided 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. Further, we tested the hypothesis that administration of retinoic acid, 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 supports data from in vitro studies demonstrating a nitrofen-induced suppression of RALDH2.
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