Mechanisms of action of the congenital diaphragmatic hernia-inducing teratogen nitrofen.
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.
Noble
B Rhiannon
BR
Department of Physiology, University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
Babiuk
Randal P
RP
Clugston
Robin D
RD
Underhill
T Michael
TM
Sun
Hui
H
Kawaguchi
Riki
R
Walfish
Paul G
PG
Blomhoff
Rune
R
Gundersen
Thomas E
TE
Greer
John J
JJ
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D045744:Cell Line, Tumor; D004347:Drug Interactions; D004628:Embryonic Structures; D006548:Hernia, Diaphragmatic / Q000139:chemically induced*; D065630:Hernias, Diaphragmatic, Congenital; D051379:Mice; D010647:Phenyl Ethers / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D012176:Retinoids / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013723:Teratogens / Q000494:pharmacology*; D013963:Thyroid Hormones / Q000378:metabolism / Q000494:pharmacology; D014801:Vitamin A / Q000494:pharmacology; D014810:Vitamin E / Q000494:pharmacology
D000975:Antioxidants; D010647:Phenyl Ethers; D011988:Receptors, Thyroid Hormone; D012176:Retinoids; D013723:Teratogens; D013963:Thyroid Hormones; D014801:Vitamin A; D014810:Vitamin E; C007350:nitrofen; D001205:Ascorbic Acid