title: 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: 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.
  
  
  RESULTS
  Rats were exposed to Cd at 20 nmol/kg every other day for 4 weeks and gene methylation was analyzed at the 48(th) 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 48(th) 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pathophysiology, Prostate Diseases Prevention and Treatment Research Center, Norman Bethune College of Medicine, Jilin University, Changchun, Jilin, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Yi
authors.initials: Y
authors.lastname: Tan
authors.forename: Xiao
authors.initials: X
authors.lastname: Miao
authors.forename: Xu-Dong
authors.initials: XD
authors.lastname: Liu
authors.forename: Chen
authors.initials: C
authors.lastname: Shao
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Yang
authors.forename: Subat
authors.initials: S
authors.lastname: Turdi
authors.forename: Li-Jie
authors.initials: LJ
authors.lastname: Ma
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
authors.forename: Lu
authors.initials: L
authors.lastname: Cai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002104:Cadmium / Q000633:toxicity*; D053181:Caspase 8 / Q000235:genetics; D002455:Cell Division / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D018899:CpG Islands; D019175:DNA Methylation; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D011401:Promoter Regions, Genetic; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D014409:Tumor Necrosis Factor-alpha; D002104:Cadmium; D053181:Caspase 8