Indirect mechanism of lead-induced genotoxicity in cultured mammalian cells.

The data concerning the mutagenic, clastogenic and carcinogenic properties of inorganic lead compounds have been conflicting. To investigate whether the genotoxicity of lead is due to indirect effects such as interference with DNA-repair processes, the induction of mutations, sister-chromatid exchanges and strand breaks by lead ions alone as well as in combination with UV light as a standard mutagen were determined. Lead acetate alone does not induce DNA-strand breaks in HeLa cells or mutations at the HPRT locus and sister-chromatid exchanges in V79 Chinese hamster cells. However, at all endpoints tested, lead ions interfere with the processing of UV-induced DNA damage. They inhibit the closing of DNA-strand breaks after UV irradiation and enhance the number of UV-induced mutations and sister-chromatid exchanges, indicating an inhibition of DNA repair. These data point out the necessity to consider such indirect effects when assessing the genotoxicity of metal compounds. As possible mechanisms of repair inhibition we suggest either the interaction with repair enzymes such as polymerase or ligase or else the interaction with calcium-regulated processes, for example with calmodulin.

[1]  L Alessio,et al.  Chromosome and biochemical studies in women occupationally exposed to lead. , 1980, Archives of environmental health.

[2]  S. Paillet,et al.  Induction of trifluorothymidine-resistant mutants by metal ions in L5178Y/TK+/- cells. , 1980, Mutation research.

[3]  J. O’Neill,et al.  Utilization of a quantitative mammalian cell mutation system, CHO/HGPRT, in experimental mutagenesis and genetic toxicology , 1977 .

[4]  A. B. Fischer.  Factors influencing cadmium uptake and cytotoxicity in cultured cells. , 1985, Xenobiotica; the fate of foreign compounds in biological systems.

[5]  G. Frenkel,et al.  Effects of lead acetate on DNA and RNA synthesis by intact HeLa cells, isolated nuclei and purified polymerases. , 1987, Biochemical pharmacology.

[6]  Anne E. Willis,et al.  DNA ligase I deficiency in Bloom's syndrome , 1987, Nature.

[7]  L. Loeb,et al.  Infidelity of DNA synthesis in vitro: screening for potential metal mutagens or carcinogens. , 1976, Science.

[8]  I. Dingwall-Fordyce,et al.  A Follow-up Study of Lead Workers , 1963, British journal of industrial medicine.

[9]  R. L. Carter,et al.  IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans , 1980, IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans.

[10]  J. Pounds.  Effect of lead intoxication on calcium homeostasis and calcium-mediated cell function: a review. , 1984, Neurotoxicology.

[11]  P. Cook,et al.  Detection and repair of single-strand breaks in nuclear DNA , 1976, Nature.

[12]  J. H. Li,et al.  Genetic toxicology of lead compounds. , 1988, Carcinogenesis.

[13]  J. Regan,et al.  Inhibition of DNA repair by trifluoperazine. , 1985, Biochimica et biophysica acta.

[14]  A. Means,et al.  Potentiation of bleomycin lethality by anticalmodulin drugs: a role for calmodulin in DNA repair. , 1984, Science.

[15]  M. Bender,et al.  Effects of inhibitors of DNA synthesis on spontaneous and ultraviolet light-induced sister-chromatid exchanges in Chinese hamster cells. , 1980, Mutation research.

[16]  L. Beckman,et al.  Occupational and environmental risks in and around a smelter in northern Sweden. VII. Reanalysis and follow-up of chromosomal aberrations in workers exposed to arsenic. , 2008, Hereditas.

[17]  A. Hartwig,et al.  Enhancement of UV-induced mutagenesis and sister-chromatid exchanges by nickel ions in V79 cells: evidence for inhibition of DNA repair. , 1989, Mutation research.

[18]  S. Nordström,et al.  Occupational and environmental risks in and around a smelter in northern Sweden. I. Variations in birth weight. , 2009, Hereditas.

[19]  M. Lipsky,et al.  Effect of lead acetate on N-(4'-fluoro-4-biphenyl)acetamide-induced renal carcinogenesis in the rat. , 1984, Carcinogenesis.

[20]  M. Schmaeler,et al.  Interaction of human DNA polymerase β with ions of copper, lead, and cadmium☆☆☆ , 1979 .

[21]  G. Stotzky,et al.  The mediation of mutagenicity and clastogenicity of heavy metals by physicochemical factors. , 1985, Environmental research.

[22]  The human leukocyte test system , 1976 .

[23]  M. Mr..  The relation of three-dimensional DNA structure to DNA repair as studied by nucleoid sedimentation. , 1984 .

[24]  W. Gaffey,et al.  Mortality of lead workers. , 1975, Journal of occupational medicine. : official publication of the Industrial Medical Association.

[25]  M. Holmberg.  The effect of deoxynucleosides on repair of DNA breaks in UVC-irradiated human lymphocytes. , 1989, Mutation research.

[26]  H. Vrieling,et al.  DNA strand specificity for UV-induced mutations in mammalian cells , 1989, Molecular and cellular biology.

[27]  L. Thompson,et al.  Repair of (6-4)photoproducts correlates with split-dose recovery in UV-irradiated normal and hypersensitive rodent cells. , 1988, Mutation research.