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Elevated Frequencies of Benzo(a)pyrene-induced Hprt Mutations in Internal Tissue of XPA-deficient Mice¹

Department of Radiation Genetics and Chemical Mutagenesis-MGC, Leiden University Medical Centre, 2333 AL Leiden [J. G. J., A. J. L. d. G., A. D. T., H. V., A. A. v. Z., L. H. F. M.]; National Institute of Public Health and the Environment, Department of Carcinogenesis, Mutagenesis and Genetics, 3720 BA Bilthoven [H. v. S., C. V. O., A. d. V.]; and J. A. Cohen Institute, Inter-University Institute for Radiopathology and Radiation Protection, 2333 AL Leiden [S. A. M. B., A. D. T., H. V., A. A. v. Z., L. H. F. M.], the Netherlands

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.

¹ This study was supported by Dutch Foundation for Scientific Research Grant 900-501-093 and European Communities Projects EV5V-CT93-0246 and EV5V-CT94-0397.

² Present address: Nestlé Research Centre, Nestec Ltd., Vers-chez-les-Blanc, 1000 Lausanne 26, Switzerland.

³ To whom requests for reprints should be addressed, at Department of Radiation Genetics and Chemical Mutagenesis-MGC, Leiden University Medical Centre, P.O. Box 9503, 2300 RA Leiden, the Netherlands. Phone: 31(0)715276126; Fax: 31(0)715221615; E-mail: MULLENDERS@RULFF2.MedFac.LeidenUniv.nl.

Received 10/17/97. Accepted 4/30/98.

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