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This Article Full Text Full Text (PDF) All Versions of this Article: 293/4/L1079    most recent 00286.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Noble, B. R. Articles by Greer, J. J. Search for Related Content PubMed PubMed Citation Articles by Noble, B. R. Articles by Greer, J. J.

Mechanisms of action of the congenital diaphragmatic hernia-inducing teratogen nitrofen

¹Department of Physiology, University of Alberta, Edmonton, Alberta; ²Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia; ³Department of Physiology, David Geffen School of Medicine at University of California Los Angeles; ⁴Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada; and ⁵Institute of Basic Medical Sciences, Department of Nutrition, University of Oslo, Oslo, Norway

Submitted 23 July 2007 ; accepted in final form 10 August 2007

Congenital diaphragmatic hernia (CDH) is a developmental anomaly that results in significant mortality and morbidity. The underlying etiology is poorly understood. Insights will arise from an understanding of the mechanisms by which the teratogen nitrofen induces CDH in rodent models. In this study, we use in vitro cell assays in conjunction with whole animal rodent studies to test hypotheses regarding nitrofen's mechanism of action. The first component examined the interaction of nitrofen with various aspects of the retinoid signaling pathway including uptake proteins, binding proteins, receptors, conversion, and degradation enzymes. The second component examined the interactions of nitrofen and vitamins A, C, and E to test the hypothesis that nitrofen was functioning as an antioxidant to interfere with retinoid signaling. Third, we performed a series of experiments examining the interaction of nitrofen and thyroid signaling. Collectively, the data suggest that the primary aspect of retinoid signaling affected by nitrofen is via inhibition of the rate-limiting enzymes controlling retinoic acid synthesis. Retinoid signaling perturbations do not appear to involve oxidative effects of nitrofen. Any substantial roles of nitrofen-induced perturbations of thyroid hormone signaling or receptor function are not supported.

retinoid signaling