Carcinogenic lead chromate induces DNA double-strand breaks in human lung cells

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

Goodale

et al. 2007

Self Cite

Particulate hexavalent chromium [Cr(VI)] compounds are well-established human carcinogens. Cr (VI)-induced tumors are characterized by chromosomal instability (CIN); however, the mechanisms of this effect are unknown. We investigated the hypothesis that homologous recombination (HR) repair of DNA double strand breaks protect cells from Cr(VI)-induced CIN by focusing on the XRCC3 and RAD51C genes, which play an important role in cellular resistance to DNA double strand breaks. We used Chinese hamster cells defective in each HR gene (irs3 for RAD51C and irs1SF for XRCC3) and compared with their wildtype parental and cDNA-complemented controls. We found that the intracellular Cr ion levels varied among the cell lines after particulate chromate treatment. Importantly, accounting for differences in Cr ion levels, we discovered that XRCC3 and RAD51C cells treated with lead chromate had increased cytotoxicity and chromosomal aberrations, relative to wild-type and cDNA-complimented cells. We also observed the emergence of high levels of chromatid exchanges in the two mutant cell lines. For example, 1 ug/cm 2 lead chromate induced 20 and 32 exchanges in XRCC3-and RAD51C-deficient cells, respectively, whereas no exchanges were detected in the wildtype and cDNA-complemented cells. These observations suggest that HR protects cells from Cr(VI)-induced CIN, consistent with the ability of particulate Cr(VI) to induce double strand breaks.

Section: Discussionmentioning

confidence: 99%

Homologous recombination repair protects against particulate chromate-induced chromosome instability in Chinese hamster cells

Stackpole

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

Goodale

et al. 2007

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“…The major health concern for exposure to Cr(VI) compounds is inhalation exposure leading to lung cancer, though other cancer and respiratory effects can occur, and potential reproductive effects [Costa, 1997]. DNA damage, such as chromosomal abnormalities [Wise et al, 2002;Wise et al, 2004], DNA strand breaks [Xie et al, 2005], and oxidative damage [Bagchi et al, 2001], is considered to be the underlying causes of these toxic effects. Cr(VI) is considered the most toxic form because it is readily absorbed by the cells.…”

Section: Introductionmentioning

confidence: 99%

“…Particulate Cr(VI) is genotoxic to human cells, inducing chromosomal aberrations and DNA double strand breaks [Wise et al, 2002;Wise et al, 2004;Xie et al, 2005]. The potential toxicity of particulate Cr(VI) has not been assessed in any marine mammal.…”

Section: Introductionmentioning

confidence: 99%

Particulate hexavalent chromium is cytotoxic and genotoxic to the North Atlantic right whale (Eubalaena glacialis) lung and skin fibroblasts

Chen

Environ and Mol Mutagen

Kraus

et al. 2009

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Hexavalent chromium compounds are present in the atmosphere and oceans and are established mutagens and carcinogens in human and terrestrial mammals. However, the adverse effects of these toxicants in marine mammals are uncertain. Previously, we reported that North Atlantic right whales, one of the most endangered great whales, have tissue chromium levels that are high, levels that may pose a risk to the whale's health. Furthermore, the study suggested that inhalation may be an important exposure route. Exposure to chromium through inhalation is mainly because of particulate compounds. However, the toxicity of particulate chromium compounds in marine mammal cells is unknown. Accordingly, in this study, we tested the cytotoxic and genotoxic effects of particulate hexavalent chromium in primary cultured lung and skin fibroblasts from the endangered North Atlantic right whale. Cytotoxicity was measured by clonogenic survival assay, and genotoxicity was measured as production of chromosome aberrations. Particulate hexavalent chromium induced cytotoxicity and genotoxicity in a concentration‐dependent manner in both right whale lung and skin fibroblasts. Lung fibroblasts were more resistant to chromium cytotoxicity, but presented with more chromosome damage than skin fibroblasts. These data further support the hypothesis that chromium may be a health concern for the endangered North Atlantic right whale. Environ. Mol. Mutagen. 2009. © 2009 Wiley‐Liss, Inc.

“…DNA double strand breaks were measured using our published methods (9,18). Briefly, 80,000 cells were seeded into a 6 well plate and treated with lead chromate.…”

Section: Neutral Comet Assaymentioning

confidence: 99%

“…Immunofluorescence was done based on our previous publication (9). Logarithmic growing cells were grown on 8 well chamber slides.…”

Section: Immunofluorescence For Gamma-h2ax Foci Formationmentioning

confidence: 99%

Deficient repair of particulate hexavalent chromium-induced DNA double strand breaks leads to neoplastic transformation

Xie

Mutation Research/Genetic Toxicology and Environmental Mutagene

2008

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Hexavalent chromium (Cr(VI)) is a potent respiratory toxicant and carcinogen. The most carcinogenic forms of Cr(VI) are the particulate salts such as lead chromate, which deposit and persist in the respiratory tract after inhalation. We demonstrate here that particulate chromate induces DNA double strand breaks in human lung cells with 0.1, 0.5, and 1 ug/cm 2 lead chromate inducing 1.5, 2 and 5 relative increases in the percent of DNA in the comet tail, respectively. These lesions are repaired within 24 h and require Mre11 expression for their repair. Particulate chromate also caused Mre11 to co-localize with gamma-H2A.X and ATM. Failure to repair these breaks with Mre11 induced neoplastic transformation including loss of cell contact inhibition and anchorage independent growth. A 5-day exposure to lead chromate induced loss of cell contact inhibition in a concentrationdependent manner with 0, 0.1, 0.5 and 1 ug/cm 2 lead chromate inducing 1, 78 and 103 foci in 20 dishes, respectively. These data indicate that Mre11 is critical to repairing particulate Cr(VI)-induced double strand breaks and preventing Cr(VI)-induced neoplastic transformation.