title: Elevated frequencies of benzo(a)pyrene-induced Hprt mutations in internal tissue of XPA-deficient mice.
abstract: Xeroderma pigmentosum (XP) patients are hypersensitive to sunlight and have a high predisposition to developing cancer. At the cellular level, XP patients are defective in nucleotide excision repair (NER). Recently, mice have been generated via gene targeting that are deficient in the expression of the XPA gene [A. de Vries et al., Nature (Lond.), 377: 169-173, 1995]. We have assessed the consequences of defective NER for mutagenesis in normal and XPA mice exposed to benzo(a)pyrene and 2-acetylaminofluorene. To study mutagenesis, mature T lymphocytes were isolated from the spleen and stimulated to proliferate in vitro to select for mutants at the endogenous Hprt locus. Background mutant frequencies in normal and XPA mice were very similar and not influenced by age. Single doses of benzo(a)pyrene administered i.p. resulted in a dose-dependent increase of the Hprt mutant frequency in normal mice. In addition, after chronic exposure to benzo(a)pyrene, Hprt mutants were readily detectable in XPA mice at an early onset of treatment but only at a later stage in normal mice. In contrast, chronic treatment of either normal or XPA mice with 2-acetylaminofluorene did not increase Hprt mutant frequency above the background frequency. This absence of significant induction of Hprt mutants can be entirely attributed to the low frequency of 2-acetylaminofluorene-induced DNA adducts in lymphoid tissue. These results provide the first direct evidence in mammals that deficient NER leads to enhanced mutagenesis in endogenous genes in internal tissue after exposure to relevant environmental mutagens, such as benzo(a)pyrene.
authors.affiliation: J.A. Cohen Institute, Inter-University Institute for Radiopathology and Radiation Protection, Leiden, The Netherlands.
authors.forename: S A
authors.initials: SA
authors.lastname: Bol
authors.forename: H
authors.initials: H
authors.lastname: van Steeg
authors.forename: J G
authors.initials: JG
authors.lastname: Jansen
authors.forename: C
authors.initials: C
authors.lastname: Van Oostrom
authors.forename: A
authors.initials: A
authors.lastname: de Vries
authors.forename: A J
authors.initials: AJ
authors.lastname: de Groot
authors.forename: A D
authors.initials: AD
authors.lastname: Tates
authors.forename: H
authors.initials: H
authors.lastname: Vrieling
authors.forename: A A
authors.initials: AA
authors.lastname: van Zeeland
authors.forename: L H
authors.initials: LH
authors.lastname: Mullenders
mesh_terms: D015073:2-Acetylaminofluorene / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism / Q000633:toxicity; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins; D005347:Fibroblasts / Q000187:drug effects; D007041:Hypoxanthine Phosphoribosyltransferase / Q000187:drug effects* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016296:Mutagenesis / Q000235:genetics*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology; D051760:Xeroderma Pigmentosum Group A Protein
chemical_list: D002273:Carcinogens; D018736:DNA Adducts; D004268:DNA-Binding Proteins; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; D001564:Benzo(a)pyrene; D015073:2-Acetylaminofluorene; D007041:Hypoxanthine Phosphoribosyltransferase