Effects of cadmium(II) on (+/-)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide-induced DNA damage response in human fibroblasts and DNA repair: a possible mechanism of cadmium's cogenotoxicity.
Cadmium, a widespread environmental pollutant and a cigarette smoke constituent, enhances the genotoxicity of benzo[a]pyrene (BP). The mechanism(s) underlying the potentiation of BP-induced genotoxicity by Cd2+ is not clearly understood. Our studies of the effects of noncytotoxic concentrations of Cd2+ on the levels of p53 and p21 in (+/-)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE)-treated human fibroblasts showed that Cd2+ decreased BPDE-induced p21 levels in a dose-dependent manner whereas p53 accumulation is attenuated only at higher noncytotoxic concentrations of cadmium. These findings suggest that both the activity and the accumulation of p53 in response of BPDE treatment are inhibited by Cd2+ although the possibility of p53-independent p21 transactivation cannot be ruled out. Exposure of synchronized human fibroblast cells to 0.5 microM of BPDE caused 72% of the cells remaining in G1 phase as compared to 52% in the case of untreated cells. Treatment of the cells with CdCl2 prior to exposing them to BPDE caused a decrease in the G1 population (72 to 54%) in a dose-dependent manner. An in vitro repair assay of BPDE-damaged pUC18 plasmid DNA using untreated and cadmium-treated nucleotide excision repair (NER) proficient HeLa extract showed that cadmium impaired the ability of HeLa cell extract to repair BPDE-damaged pUC18 DNA. Our findings indicate that cadmium not only inhibits NER pathway-dependent repair of BPDE-damaged DNA but also impairs p53 and p21 responses and overrides BPDE-induced G1-S cell cycle arrest. The effect of cadmium on these processes may explain, at least partly, the potentiating effect of the metal on the genotoxicity of BP.
Mukherjee
Jagat J
JJ
Environmental Toxicology and Chemistry Laboratory, Great Lakes Center, State University of New York College at Buffalo, 1300 Elmwood Avenue, Buffalo, New York 14222, USA.
Gupta
Suresh K
SK
Kumar
Subodh
S
Sikka
Harish C
HC
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000633:toxicity*; D002104:Cadmium / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004785:Environmental Pollutants / Q000633:toxicity*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007399:Interphase / Q000187:drug effects; D009153:Mutagens / Q000633:toxicity*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004785:Environmental Pollutants; D009153:Mutagens; D016159:Tumor Suppressor Protein p53; D002104:Cadmium; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D004247:DNA