Cadmium induces retinoic acid signaling by regulating retinoic acid metabolic gene expression.
The transition metal cadmium is an environmental teratogen. In addition, cadmium and retinoic acid can act synergistically to induce forelimb malformations. The molecular mechanism underlying the teratogenicity of cadmium and the synergistic effect with retinoic acid has not been addressed. An evolutionarily conserved gene, beta,beta-carotene 15,15'-monooxygenase (BCMO), which is involved in retinoic acid biosynthesis, was studied in both Caenorhabditis elegans and murine Hepa 1-6 cells. In C. elegans, bcmo-1 was expressed in the intestine and was cadmium inducible. Similarly, in Hepa 1-6 cells, Bcmo1 was induced by cadmium. Retinoic acid-mediated signaling increased after 24-h exposures to 5 and 10 microm cadmium in Hepa 1-6 cells. Examination of gene expression demonstrated that the induction of retinoic acid signaling by cadmium may be mediated by overexpression of Bcmo1. Furthermore, cadmium inhibited the expression of Cyp26a1 and Cyp26b1, which are involved in retinoic acid degradation. These results indicate that cadmium-induced teratogenicity may be due to the ability of the metal to increase the levels of retinoic acid by disrupting the expression of retinoic acid-metabolizing genes.
Cui
Yuxia
Y
Comparative Genomics Group, Laboratory of Molecular Toxicology, NIEHS, National Institutes of Health, Durham, North Carolina 27709, USA.
Freedman
Jonathan H
JH
D000818:Animals; D030801:Animals, Genetically Modified; D002104:Cadmium / Q000378:metabolism*; D017173:Caenorhabditis elegans; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D000072516:Retinoic Acid 4-Hydroxylase; D013997:Time Factors; D014212:Tretinoin / Q000378:metabolism*; D050559:beta-Carotene 15,15'-Monooxygenase / Q000378:metabolism
D002104:Cadmium; D049452:Green Fluorescent Proteins; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; C493359:Bco1 protein, mouse; C000607080:Cyp26a1 protein, mouse; C000607081:Cyp26b1 protein, mouse; D000072516:Retinoic Acid 4-Hydroxylase; D050559:beta-Carotene 15,15'-Monooxygenase