Low-Dose Cd Induces Hepatic Gene Hypermethylation, along with the Persistent Reduction of Cell Death and Increase of Cell Proliferation in Rats and Mice

Abstract

BackgroundCadmium (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 FindingsRats 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/SignificanceThese 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.

Cadmium and Its Epigenetic Effects

“…With the liver tissue the gene methylation was analyzed at the 48 th week 4-week Cd exposure with methylated DNA immunoprecipitation-CpG island microarray, which revealed 1,629 genes with promoter CpG islands methylation changes. Specifically there were 675 (41.44 %) genes for which all CpG islands in the promoter were hypermethylated, 899 (55.19 %) genes for which all CpG islands in the promoter were hypomethylated, and 55 (3.38 %) genes for which CpG islands in the promoter were mixed with hypermethylated and hypomethylated [54]. Our studies suggest that global hyper-or hypo-methylation may reflect a mixed outcome of different gene methylation status.…”

“…For instance, caspase-8 gene promoter CGIs and TNF gene promoter CGIs were hypermethylated and hypomethylated, respectively, which was accompanied with decreased expression of cleaved caspase-8 and increased expression of TNF-α proteins, respectively [54]. The decreased caspase-8 function resulted in persistent decrease of cell death and increase of cell proliferation in the liver of Cd-treated rats [54]. To establish the role of caspase-8 promoter CpG island hypermethylation in these pathological changes, mice were given chronic exposure to low-dose Cd with and without methylation inhibitor 5-aza.…”

Effect of chronic heroin and cocaine administration on global DNA methylation in brain and liver

“…Hypo-methylation has also been reported as a result of exposure to furan and has been linked to tumors induced by this carcinogen (Chen et al, 2012). On the other hand, cadmium has been found to increase global gene methylation in the liver of rats and this effect has been linked to increased apoptosis and the onset of neoplastic lesions (Wang et al, 2012). Another environmental pollutant, perfluorooctanoic acid, has been found to cause dose-dependent hyper-methylation of the glutathione-Stransferase Pi promoter in human liver cells (Tian et al, 2012a).…”

Distinct genotype-dependent differences in transcriptome responses in humans exposed to environmental carcinogens

“…Two of these, NOTCH1 resp. ITGB3, are also known as genes that are responsive to PCBs and cadmium chloride exposure in rodents, respectively to lead in humans (21)(22)(23).…”