Submitted on July 23, 2007
Accepted on August 10, 2007
MECHANISMS OF ACTION OF THE CONGENITAL DIAPHRAGMATIC HERNIA-INDUCING TERATOGEN NITROFEN
B. Rhiannon NOBLE1, RANDAL P BABIUK2, ROBIN CLUGSTON1, T. Michael Underhill3, HUI SUN4, RIKI KAWAGUCHI4, Paul G. Walfish5, RUNE BLOMHOFF6, THOMAS E GUNDERSEN6, and John J. Greer2*
1 PHYSIOLOGY, UNIVERSITY OF ALBERTA, EDMONTON, Canada
2 Dept. of Physiology, University of Alberta, Edmonton, Canada
3 CELLULAR AND PHYSIOLOGICAL SCIENCES, University of British Columbia, VANCOUVER, Canada
4 PHYSIOLOGY, UCLA, LOS ANGELES, California, United States
5 University of Toronto, TORONTO, Canada
6 NUTRITION, UNIVERSITY OF OSLO, OSLO, Norway
* To whom correspondence should be addressed. E-mail: john.greer{at}ualberta.ca.
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. Thirdly, 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.
