title: Fanconi anemia complementation group A cells are hypersensitive to chromium(VI)-induced toxicity.
abstract: Fanconi anemia (FA) is an autosomal recessive disorder characterized by diverse developmental abnormalities, progressive bone marrow failure, and a markedly increased incidence of malignancy. FA cells are hypersensitive to DNA cross-linking agents, suggesting a general defect in the repair of DNA cross-links. Some forms of hexavalent chromium [Cr(VI)] are implicated as respiratory carcinogens and induce several types of DNA lesions, including ternary DNA-Cr-DNA interstrand cross-links (Cr-DDC). We hypothesized that human FA complementation group A (FA-A) cells would be hypersensitive to Cr(VI) and Cr(VI)-induced apoptosis. Using phosphatidylserine translocation and caspase-3 activation, human FA-A fibroblasts were found to be markedly hypersensitive to chromium-induced apoptosis compared with CRL-1634 cells, which are normal human foreskin fibroblasts (CRL). The clonogenicity of FA-A cells was also significantly decreased compared with CRL cells after Cr(VI) treatment. There was no significant difference in either Cr(VI) uptake or Cr-DNA adduct formation between FA-A and CRL cells. These results show that FA-A cells are hypersensitive to Cr(VI) and Cr-induced apoptosis and that this hypersensitivity is not due to increased Cr(VI) uptake or increased Cr-DNA adduct formation. The results also suggest that Cr-DDC may be proapoptotic lesions. These results are the first to show that FA cells are hypersensitive to an environmentally relevant DNA cross-linking agent.
authors.affiliation: Department of Pharmacology, Program in Molecular and Cellular Oncology, The George Washington University Medical Center, 2300 Eye Street NW, Washington, DC 20037, USA.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Vilcheck
authors.forename: Travis J
authors.initials: TJ
authors.lastname: O'Brien
authors.forename: Daryl E
authors.initials: DE
authors.lastname: Pritchard
authors.forename: Linan
authors.initials: L
authors.lastname: Ha
authors.forename: Susan
authors.initials: S
authors.lastname: Ceryak
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Fornsaglio
authors.forename: Steven R
authors.initials: SR
authors.lastname: Patierno
mesh_terms: D017209:Apoptosis; D002274:Carcinogens, Environmental / Q000633:toxicity*; D053148:Caspase 3; D020169:Caspases / Q000494:pharmacology; D018929:Cell Culture Techniques; D002857:Chromium / Q000633:toxicity*; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D004260:DNA Repair; D005199:Fanconi Anemia / Q000235:genetics* / Q000503:physiopathology*; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D008297:Male; D010413:Penis / Q000166:cytology; D010770:Phosphotransferases / Q000494:pharmacology
chemical_list: D002274:Carcinogens, Environmental; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D002857:Chromium; C074702:chromium hexavalent ion; D010770:Phosphotransferases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases