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. 1994 Oct;102(Suppl 4):135–138. doi: 10.1289/ehp.94102s4135

Mutations induced in the hypoxanthine phosphoribosyl transferase gene by three urban air pollutants: acetaldehyde, benzo[a]pyrene diolepoxide, and ethylene oxide.

B Lambert 1, B Andersson 1, T Bastlova 1, S M Hou 1, D Hellgren 1, A Kolman 1
PMCID: PMC1566944  PMID: 7821287

Abstract

Provisional mutational spectra at the hypoxanthine phosphoribosyl transferase (HPRT) locus in vitro have been worked out for acetaldehyde (AA) and benzo[a]pyrene diolepoxide (BPDE) in human (T)-lymphocytes and for ethylene oxide (EtO) in human diploid fibroblasts using Southern blotting and polymerase chain reaction (PCR)-based DNA sequencing techniques. The results indicate that large genomic deletions are the predominating hprt mutations caused by AA and EO, whereas BPDE induces point mutations that are mainly GC > TA transversions. The mutational spectra induced by the three agents are clearly different from the background spectrum in human T-cells. Thus, the hprt locus is a useful target for the study of chemical-specific mutational events that may help identify causes of background mutation in human cells in vivo.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Albertini R. J., Castle K. L., Borcherding W. R. T-cell cloning to detect the mutant 6-thioguanine-resistant lymphocytes present in human peripheral blood. Proc Natl Acad Sci U S A. 1982 Nov;79(21):6617–6621. doi: 10.1073/pnas.79.21.6617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Albertini R. J. Somatic gene mutations in vivo as indicated by the 6-thioguanine-resistant T-lymphocytes in human blood. Mutat Res. 1985 Jun-Jul;150(1-2):411–422. doi: 10.1016/0027-5107(85)90138-1. [DOI] [PubMed] [Google Scholar]
  3. Andersson B., Fält S., Lambert B. Strand specificity for mutations induced by (+)-anti BPDE in the hprt gene in human T-lymphocytes. Mutat Res. 1992 Sep;269(1):129–140. doi: 10.1016/0027-5107(92)90168-2. [DOI] [PubMed] [Google Scholar]
  4. Andersson B., Lambert B. Mutations induced by benzo[a]pyrene diolepoxide at the hprt locus in human T-lymphocytes in vitro. Mutat Res. 1990 Oct;245(2):75–82. doi: 10.1016/0165-7992(90)90003-3. [DOI] [PubMed] [Google Scholar]
  5. Bastlová T., Andersson B., Lambert B., Kolman A. Molecular analysis of ethylene oxide-induced mutations at the HPRT locus in human diploid fibroblasts. Mutat Res. 1993 Jun;287(2):283–292. doi: 10.1016/0027-5107(93)90021-7. [DOI] [PubMed] [Google Scholar]
  6. Bohr V. A., Phillips D. H., Hanawalt P. C. Heterogeneous DNA damage and repair in the mammalian genome. Cancer Res. 1987 Dec 15;47(24 Pt 1):6426–6436. [PubMed] [Google Scholar]
  7. Brookes P., Osborne M. R. Mutation in mammalian cells by stereoisomers of anti-benzo[a] pyrene-diolepoxide in relation to the extent and nature of the DNA reaction products. Carcinogenesis. 1982;3(10):1223–1226. doi: 10.1093/carcin/3.10.1223. [DOI] [PubMed] [Google Scholar]
  8. Cariello N. F., Keohavong P., Kat A. G., Thilly W. G. Molecular analysis of complex human cell populations: mutational spectra of MNNG and ICR-191. Mutat Res. 1990 Aug;231(2):165–176. doi: 10.1016/0027-5107(90)90023-w. [DOI] [PubMed] [Google Scholar]
  9. Chen R. H., Maher V. M., McCormick J. J. Effect of excision repair by diploid human fibroblasts on the kinds and locations of mutations induced by (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10- tetrahydrobenzo[a]pyrene in the coding region of the HPRT gene. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8680–8684. doi: 10.1073/pnas.87.21.8680. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cole J., Green M. H., James S. E., Henderson L., Cole H. A further assessment of factors influencing measurements of thioguanine-resistant mutant frequency in circulating T-lymphocytes. Mutat Res. 1988 Mar;204(3):493–507. doi: 10.1016/0165-1218(88)90044-4. [DOI] [PubMed] [Google Scholar]
  11. Dellarco V. L. A mutagenicity assessment of acetaldehyde. Mutat Res. 1988 Jan;195(1):1–20. doi: 10.1016/0165-1110(88)90013-9. [DOI] [PubMed] [Google Scholar]
  12. Dellarco V. L., Generoso W. M., Sega G. A., Fowle J. R., 3rd, Jacobson-Kram D. Review of the mutagenicity of ethylene oxide. Environ Mol Mutagen. 1990;16(2):85–103. doi: 10.1002/em.2850160207. [DOI] [PubMed] [Google Scholar]
  13. Edwards A., Voss H., Rice P., Civitello A., Stegemann J., Schwager C., Zimmermann J., Erfle H., Caskey C. T., Ansorge W. Automated DNA sequencing of the human HPRT locus. Genomics. 1990 Apr;6(4):593–608. doi: 10.1016/0888-7543(90)90493-e. [DOI] [PubMed] [Google Scholar]
  14. Gibbs R. A., Caskey C. T. Identification and localization of mutations at the Lesch-Nyhan locus by ribonuclease A cleavage. Science. 1987 Apr 17;236(4799):303–305. doi: 10.1126/science.3563511. [DOI] [PubMed] [Google Scholar]
  15. Gibbs R. A., Nguyen P. N., Edwards A., Civitello A. B., Caskey C. T. Multiplex DNA deletion detection and exon sequencing of the hypoxanthine phosphoribosyltransferase gene in Lesch-Nyhan families. Genomics. 1990 Jun;7(2):235–244. doi: 10.1016/0888-7543(90)90545-6. [DOI] [PubMed] [Google Scholar]
  16. Gibbs R. A., Nguyen P. N., McBride L. J., Koepf S. M., Caskey C. T. Identification of mutations leading to the Lesch-Nyhan syndrome by automated direct DNA sequencing of in vitro amplified cDNA. Proc Natl Acad Sci U S A. 1989 Mar;86(6):1919–1923. doi: 10.1073/pnas.86.6.1919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. He S. M., Holmberg K., Lambert B., Einhorn N. Hprt mutations and karyotype abnormalities in T-cell clones from healthy subjects and melphalan-treated ovarian carcinoma patients. Mutat Res. 1989 Feb;210(2):353–358. doi: 10.1016/0027-5107(89)90097-3. [DOI] [PubMed] [Google Scholar]
  18. He S. M., Lambert B. Acetaldehyde-induced mutation at the hprt locus in human lymphocytes in vitro. Environ Mol Mutagen. 1990;16(2):57–63. doi: 10.1002/em.2850160202. [DOI] [PubMed] [Google Scholar]
  19. Hemminki K., Randerath K., Reddy M. V., Putman K. L., Santella R. M., Perera F. P., Young T. L., Phillips D. H., Hewer A., Savela K. Postlabeling and immunoassay analysis of polycyclic aromatic hydrocarbons--adducts of deoxyribonucleic acid in white blood cells of foundry workers. Scand J Work Environ Health. 1990 Jun;16(3):158–162. doi: 10.5271/sjweh.1798. [DOI] [PubMed] [Google Scholar]
  20. Hou S. M., Steen A. M., Fält S., Andersson B. Molecular spectrum of background mutation at the hprt locus in human T-lymphocytes. Mutagenesis. 1993 Jan;8(1):43–49. doi: 10.1093/mutage/8.1.43. [DOI] [PubMed] [Google Scholar]
  21. Hovig E., Smith-Sørensen B., Brøgger A., Børresen A. L. Constant denaturant gel electrophoresis, a modification of denaturing gradient gel electrophoresis, in mutation detection. Mutat Res. 1991 Jan;262(1):63–71. doi: 10.1016/0165-7992(91)90108-g. [DOI] [PubMed] [Google Scholar]
  22. Kolman A., Bohusová T., Lambert B., Simons J. W. Induction of 6-thioguanine-resistant mutants in human diploid fibroblasts in vitro with ethylene oxide. Environ Mol Mutagen. 1992;19(2):93–97. doi: 10.1002/em.2850190203. [DOI] [PubMed] [Google Scholar]
  23. Lambert B., Andersson B., He S. M., Marcus S., Steen A. M. Molecular analysis of mutation in the human gene for hypoxanthine phosphoribosyltransferase. Mol Genet Med. 1992;2:161–188. doi: 10.1016/b978-0-12-462002-5.50011-x. [DOI] [PubMed] [Google Scholar]
  24. Lambert B., Marcus S., Andersson B., Hou S. M., Steen A. M., Hellgren D. Missense mutations and evolutionary conserved amino acids at the human hypoxanthine phosphoribosyl-transferase locus. Pharmacogenetics. 1992 Dec;2(6):329–336. doi: 10.1097/00008571-199212000-00012. [DOI] [PubMed] [Google Scholar]
  25. Mohrenweiser H. W., Jones I. M. Review of the molecular characteristics of gene mutations of the germline and somatic cells of the human. Mutat Res. 1990 Jul;231(1):87–108. doi: 10.1016/0027-5107(90)90179-8. [DOI] [PubMed] [Google Scholar]
  26. Morley A. A., Trainor K. J., Seshadri R., Ryall R. G. Measurement of in vivo mutations in human lymphocytes. Nature. 1983 Mar 10;302(5904):155–156. doi: 10.1038/302155a0. [DOI] [PubMed] [Google Scholar]
  27. Muir P., Osborne Y., Morley A. A., Turner D. R. Karyotypic abnormality of the X chromosome is rare in mutant HPRT-lymphocyte clones. Mutat Res. 1988 Jan;197(1):157–160. doi: 10.1016/0027-5107(88)90152-2. [DOI] [PubMed] [Google Scholar]
  28. Nicklas J. A., Hunter T. C., O'Neill J. P., Albertini R. J. Molecular analyses of in vivo hprt mutations in human T-lymphocytes. III. Longitudinal study of hprt gene structural alterations and T-cell clonal origins. Mutat Res. 1989 Dec;215(2):147–160. doi: 10.1016/0027-5107(89)90178-4. [DOI] [PubMed] [Google Scholar]
  29. Nicklas J. A., O'Neill J. P., Albertini R. J. Use of T-cell receptor gene probes to quantify the in vivo hprt mutations in human T-lymphocytes. Mutat Res. 1986 Jan;173(1):67–72. doi: 10.1016/0165-7992(86)90013-8. [DOI] [PubMed] [Google Scholar]
  30. O'Neill J. P., Hunter T. C., Sullivan L. M., Nicklas J. A., Albertini R. J. Southern-blot analyses of human T-lymphocyte mutants induced in vitro by gamma-irradiation. Mutat Res. 1990 Feb;240(2):143–149. doi: 10.1016/0165-1218(90)90018-w. [DOI] [PubMed] [Google Scholar]
  31. O'Neill J. P., Sullivan L. M., Albertini R. J. In vitro induction, expression and selection of thioguanine-resistant mutants with human T-lymphocytes. Mutat Res. 1990 Feb;240(2):135–142. doi: 10.1016/0165-1218(90)90017-v. [DOI] [PubMed] [Google Scholar]
  32. Recio L., Cochrane J., Simpson D., Skopek T. R., O'Neill J. P., Nicklas J. A., Albertini R. J. DNA sequence analysis of in vivo hprt mutation in human T lymphocytes. Mutagenesis. 1990 Sep;5(5):505–510. doi: 10.1093/mutage/5.5.505. [DOI] [PubMed] [Google Scholar]
  33. Rossi A. M., Thijssen J. C., Tates A. D., Vrieling H., Natarajan A. T., Lohman P. H., van Zeeland A. A. Mutations affecting RNA splicing in man are detected more frequently in somatic than in germ cells. Mutat Res. 1990 Aug;244(4):353–357. doi: 10.1016/0165-7992(90)90084-w. [DOI] [PubMed] [Google Scholar]
  34. Tates A. D., Grummt T., Törnqvist M., Farmer P. B., van Dam F. J., van Mossel H., Schoemaker H. M., Osterman-Golkar S., Uebel C., Tang Y. S. Biological and chemical monitoring of occupational exposure to ethylene oxide. Mutat Res. 1991 Sep-Oct;250(1-2):483–497. doi: 10.1016/0027-5107(91)90205-3. [DOI] [PubMed] [Google Scholar]
  35. Tates A. D., van Dam F. J., van Mossel H., Schoemaker H., Thijssen J. C., Woldring V. M., Zwinderman A. H., Natarajan A. T. Use of the clonal assay for the measurement of frequencies of HPRT mutants in T-lymphocytes from five control populations. Mutat Res. 1991 Oct;253(2):199–213. doi: 10.1016/0165-1161(91)90133-s. [DOI] [PubMed] [Google Scholar]
  36. Vrieling H., Simons J. W., van Zeeland A. A. Nucleotide sequence determination of point mutations at the mouse HPRT locus using in vitro amplification of HPRT mRNA sequences. Mutat Res. 1988 Mar;198(1):107–113. doi: 10.1016/0027-5107(88)90046-2. [DOI] [PubMed] [Google Scholar]
  37. Vrieling H., Venema J., van Rooyen M. L., van Hoffen A., Menichini P., Zdzienicka M. Z., Simons J. W., Mullenders L. H., van Zeeland A. A. Strand specificity for UV-induced DNA repair and mutations in the Chinese hamster HPRT gene. Nucleic Acids Res. 1991 May 11;19(9):2411–2415. doi: 10.1093/nar/19.9.2411. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Yang T. P., Patel P. I., Chinault A. C., Stout J. T., Jackson L. G., Hildebrand B. M., Caskey C. T. Molecular evidence for new mutation at the hprt locus in Lesch-Nyhan patients. Nature. 1984 Aug 2;310(5976):412–414. doi: 10.1038/310412a0. [DOI] [PubMed] [Google Scholar]

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