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
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). "
ABSTRACT: Arsenic and atrazine are common environmental contaminants probably due to their extensive use as pesticides on agricultural farmlands. In this study, zebrafish embryos were exposed to 0.8 mM arsenic, 0.1 mM atrazine or mixture of both for 96 h, and various indices which are indicative of teratogenicity (egg coagulation, growth retardation, edema formation, hatching success, scoliosis), genotoxicity (DNA tail moments) and oxidative stress (lipid peroxidation and reduced glutathione (GSH) levels, catalase and glutathione peroxidase activities) were determined. The negative control were exposed to 0.5% DMSO while the positive control group were exposed to 4 mg/L 3,4 dichloroaniline. Egg coagulation was highest in the positive control (85%), followed by thegroup that was exposed to mixture of arsenic and atrazine (30%) and least in the arsenic-exposed group (20%). The incidences of edema (59%) and growth retardation (35.2%) were more frequent in the group that was exposed to contaminant mixture and least in atrazine-exposed group where incidences of both edema and growth retardation were 15%. The incidence of scoliosis ranged between 20% in arsenic-exposed group and 10% in atrazine-exposed group. Hatching success was generally high in all the groups ranging between 95% in atrazine-exposed group and 88% in the group that was exposed to mixture of arsenic and atrazine. There was no evidence of teratogenic effect in the negative control group. DNA tail moments and lipid peroxidation levels increased significantly while GSH levels and catalase activity decreased significantly in contaminant-exposed groups, especially the mixture compared to the negative control. There was no significant change in GPx activity in the exposed groups compared to the negative control. The results of this study demonstrate that both arsenic and atrazine are potentially teratogenic and genotoxic, and can cause oxidative stress in zebrafish embryos, and these effects are potentiated by toxic interactions between the two contaminants.
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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 . 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 . These enriched pathways and transcription factors suggest that the disruption of retinoid family signaling is a cadmium specific mechanism. "
ABSTRACT: Many heavy metals, including nickel (Ni), cadmium (Cd), and chromium (Cr) are toxic industrial chemicals with an exposure risk in both occupational and environmental settings that may cause harmful outcomes. While these substances are known to produce adverse health effects leading to disease or health problems, the detailed mechanisms remain unclear. To elucidate the processes involved in the toxicity of nickel, cadmium, and chromium at the molecular level and to perform a comparative analysis, H4-II-E-C3 rat liver-derived cell lines were treated with soluble salts of each metal using concentrations derived from viability assays, and gene expression patterns were determined with DNA microarrays. We identified both common and unique biological responses to exposure to the three metals. Nickel, cadmium, chromium all induced oxidative stress with both similar and unique genes and pathways responding to this stress. Although all three metals are known to be genotoxic, evidence for DNA damage in our study only exists in response to chromium. Nickel induced a hypoxic response as well as inducing genes involved in chromatin structure, perhaps by replacing iron in key proteins. Cadmium distinctly perturbed genes related to endoplasmic reticulum stress and invoked the unfolded protein response leading to apoptosis. With these studies, we have completed the first gene expression comparative analysis of nickel, cadmium, and chromium in H4-II-E-C3 cells.
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- "[50,51]). Like stress-induced signal transduction pathways, also the enriched Vitamin A (retinoid) metabolism can be related to apoptosis  by retinoic acid mediated transcriptional activity . "
ABSTRACT: To incorporate genomics data into environmental assessments a mechanistic perspective of interactions between chemicals and induced biological processes needs to be developed. Since chemical compounds with structural similarity often induce comparable biological responses in exposed animals, gene expression signatures can serve as a starting point for the assessment of chemicals and their toxicity, but only when relevant and stable gene panels are available. To design such a panel, we isolated differentially expressed gene fragments from the soil arthropod Folsomia candida, a species often used for ecotoxicological testing. Animals were exposed to two chemically distinct compounds, being a metal (cadmium) and a polycyclic aromatic hydrocarbon (phenanthrene). We investigated the affected molecular responses resulting from either treatment and developed and validated 44 qPCR assays for their responses using a high throughput nano-liter RT-qPCR platform for the analysis of the samples. Suppressive subtractive hybridization (SSH) was used to retrieve stress-related gene fragments. SSH libraries revealed pathways involved in mitochondrial dysfunction and protein degradation for cadmium and biotransformation for phenanthrene to be overrepresented. Amongst a small cluster of SSH-derived cadmium responsive markers were an inflammatory response protein and an endo-glucanase. Conversely, cytochrome P450 family 6 or 9 was specifically induced by phenanthrene. Differential expressions of these candidate biomarkers were also highly significant in the independently generated test sample set. Toxicity levels in different training samples were not reflected by any of the markers' intensity of expressions. Though, a model based on partial least squares differential analysis (PLS-DA) (with RMSEPs between 9 and 22% and R(2)s between 0.82 and 0.97) using gene expressions of 25 important qPCR assays correctly predicted the nature of exposures of test samples. For the application of molecular bio-indication in environmental assessments, multivariate analyses obviously have an added value over univariate methods. Our results suggest that compound discrimination can be achieved by PLS-DA, based on a hard classification of the within-class rankings of samples from a test set. This study clearly shows that the use of high throughput RT-qPCR could be a valuable tool in ecotoxicology combining high throughput with analytical sensitivity.
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