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Low-dose Cd induces hepatic gene hypermethylation, along with the persistent reduction of cell death and increase of cell proliferation in rats and mice
- Source :
- PLoS ONE, PLoS ONE, Vol 7, Iss 3, p e33853 (2012)
- Publication Year :
- 2011
-
Abstract
- Background Cadmium (Cd) is classified as a human carcinogen probably associated with epigenetic changes. DNA methylation is one of epigenetic mechanisms by which cells control gene expression. Therefore, the present study genome-widely screened the methylation-altered genes in the liver of rats previously exposed to low-dose Cd. Methodology Principal Findings Rats were exposed to Cd at 20 nmol/kg every other day for 4 weeks and gene methylation was analyzed at the 48th week with methylated DNA immunoprecipitation-CpG island microarray. Among the 1629 altered genes, there were 675 genes whose promoter CpG islands (CGIs) were hypermethylated, 899 genes whose promoter CGIs were hypomethylated, and 55 genes whose promoter CGIs were mixed with hyper- and hypo-methylation. Caspase-8 gene promoter CGIs and TNF gene promoter CGIs were hypermethylated and hypomethylated, respectively, along with a low apoptosis rate in Cd-treated rat livers. To link the aberrant methylation of caspase-8 and TNF genes to the low apoptosis induced by low-dose Cd, mice were given chronic exposure to low-dose Cd with and without methylation inhibitor (5-aza-2′-deoxyctidene, 5-aza). At the 48th week after Cd exposure, livers from Cd-treated mice displayed the increased caspase-8 CGI methylation and decreased caspase-8 protein expression, along with significant increases in cell proliferation and overexpression of TGF-β1 and cytokeratin 8/18 (the latter is a new marker of mouse liver preneoplastic lesions), all which were prevented by 5-aza treatment. Conclusion/Significance These results suggest that Cd-induced global gene hypermethylation, most likely caspase-8 gene promoter hypermethylation that down-regulated its expression, leading to the decreased hepatic apoptosis and increased preneoplastic lesions.
- Subjects :
- Programmed cell death
Pollutants
lcsh:Medicine
Apoptosis
Gastroenterology and Hepatology
Biology
Toxicology
03 medical and health sciences
Mice
0302 clinical medicine
Model Organisms
Gene expression
Animals
Environmental Chemistry
Epigenetics
lcsh:Science
Promoter Regions, Genetic
Gene
Carcinogen
030304 developmental biology
Cell Proliferation
0303 health sciences
Caspase 8
Multidisciplinary
Dose-Response Relationship, Drug
Cell growth
Tumor Necrosis Factor-alpha
Liver Diseases
Cancer Risk Factors
lcsh:R
Animal Models
DNA Methylation
Molecular biology
3. Good health
Rats
Chemistry
Liver
Oncology
030220 oncology & carcinogenesis
DNA methylation
Medicine
lcsh:Q
CpG Islands
Cell Division
Cadmium
Research Article
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 7
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- PloS one
- Accession number :
- edsair.doi.dedup.....e3822eb9adbc9365a9a731e21cb5dc4a