Cadmium Induces Retinoic Acid Signaling by Regulating Retinoic Acid Metabolic Gene Expression

Comparative Genomics Group, Laboratory of Molecular Toxicology, NIEHS, National Institutes of Health, Durham, North Carolina 27709, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 07/2009; 284(37):24925-32. DOI: 10.1074/jbc.M109.026609
Source: PubMed


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.

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    • "In vertebrates, the retinoic acid acts as a signaling molecule that guides the development of the posterior portion of a developing embryo. The induction of teratogenesis involving the retinoic acid signaling pathway could be due to the ability of the contaminants to increase the levels of retinoic acid by disrupting the expression of retinoic acid-metabolizing genes (Cui and Freedman, 2009). "
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    • "Retinoic acid is a hormone-like molecule that is involved in the regulation of cell differentiation and proliferation whose effects are mediated by retinoic acid receptors [44]. It has been suggested that cadmium acts as an environmental teratogen by increasing the amount of retinoic acid through interference with the retinoic acid metabolizing genes [45]. These enriched pathways and transcription factors suggest that the disruption of retinoid family signaling is a cadmium specific mechanism. "
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