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. 2003 Jun;60(6):403–409. doi: 10.1136/oem.60.6.403

DNA–protein crosslinks and p53 protein expression in relation to occupational exposure to formaldehyde

J Shaham 1, Y Bomstein 1, R Gurvich 1, M Rashkovsky 1, Z Kaufman 1
PMCID: PMC1740563  PMID: 12771391

Abstract

Background: Formaldehyde (FA) is classified as a probable human carcinogen.

Aims: To examine DNA protein crosslinks (DPC) and p53, which are generally known to be involved in carcinogenesis, in peripheral blood lymphocytes of workers exposed to FA.

Methods: DPC and p53 ("wild type" and mutant) were examined in peripheral blood lymphocytes of 186 workers exposed to FA (mean years of exposure = 16) and 213 unexposed workers. Every worker completed a questionnaire on demographic data, occupational and medical history, smoking, and hygiene.

Results: The adjusted mean level of DPC in the exposed and the unexposed workers differed significantly. Adjustment was made for age, sex, years of education, smoking, and origin. Exposure to FA increased the risk of having a higher level of pantropic p53 above 150 pg/ml (OR 1.6, 95% CI 0.8 to 3.1). A significant positive correlation was found between the increase of pantropic p53 protein and mutant p53 protein, as well as between pantropic p53 >150 pg/ml and mutant p53 protein. In the exposed group a significantly higher proportion of p53 >150 pg/ml was found among workers with DPC >0.187 (55.7%) (0.187 = median level of DPC) than among workers with DPC ⩽0.187 (33.3%). The risk of having pantropic p53 protein >150 pg/ml was determined mainly by levels of DPC. Workers with DPC above the median level had a significantly higher risk of having pantropic p53 >150 pg/ml (adjusted OR 2.5, 95% CI 1.2 to 5.4).

Conclusions: Results suggest that DPC and mutation in p53 may represent steps in FA carcinogenesis and a possible causal relation between DPC and mutation in p53. These biomarkers can be applied in the assessment of the development of cancer due to FA exposure.

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Selected References

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  1. Audrézet M. P., Robaszkiewicz M., Mercier B., Nousbaum J. B., Bail J. P., Hardy E., Volant A., Lozac'h P., Charles J. F., Gouéron H. TP53 gene mutation profile in esophageal squamous cell carcinomas. Cancer Res. 1993 Dec 1;53(23):5745–5749. [PubMed] [Google Scholar]
  2. Beall J. R., Ulsamer A. G. Formaldehyde and hepatotoxicity: a review. J Toxicol Environ Health. 1984;14(1):1–21. doi: 10.1080/15287398409530560. [DOI] [PubMed] [Google Scholar]
  3. Bennett W. P., Hollstein M. C., He A., Zhu S. M., Resau J. H., Trump B. F., Metcalf R. A., Welsh J. A., Midgley C., Lane D. P. Archival analysis of p53 genetic and protein alterations in Chinese esophageal cancer. Oncogene. 1991 Oct;6(10):1779–1784. [PubMed] [Google Scholar]
  4. Blair A., Saracci R., Stewart P. A., Hayes R. B., Shy C. Epidemiologic evidence on the relationship between formaldehyde exposure and cancer. Scand J Work Environ Health. 1990 Dec;16(6):381–393. doi: 10.5271/sjweh.1767. [DOI] [PubMed] [Google Scholar]
  5. Bodner S. M., Minna J. D., Jensen S. M., D'Amico D., Carbone D., Mitsudomi T., Fedorko J., Buchhagen D. L., Nau M. M., Gazdar A. F. Expression of mutant p53 proteins in lung cancer correlates with the class of p53 gene mutation. Oncogene. 1992 Apr;7(4):743–749. [PubMed] [Google Scholar]
  6. Brandt-Rauf P. W., Niman H. L. Serum screening for oncogene proteins in workers exposed to PCBs. Br J Ind Med. 1988 Oct;45(10):689–693. doi: 10.1136/oem.45.10.689. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Brandt-Rauf P. W., Smith S., Niman H. L., Goldstein M. D., Favata E. Serum oncogene proteins in hazardous-waste workers. J Soc Occup Med. 1989 Winter;39(4):141–143. doi: 10.1093/occmed/39.4.141. [DOI] [PubMed] [Google Scholar]
  8. Brandt-Rauf P. W., Smith S., Perera F. P., Niman H. L., Yohannan W., Hemminki K., Santella R. M. Serum oncogene proteins in foundry workers. J Soc Occup Med. 1990 Spring;40(1):11–14. doi: 10.1093/occmed/40.1.11. [DOI] [PubMed] [Google Scholar]
  9. Casanova-Schmitz M., Heck H. D. Effects of formaldehyde exposure on the extractability of DNA from proteins in the rat nasal mucosa. Toxicol Appl Pharmacol. 1983 Aug;70(1):121–132. doi: 10.1016/0041-008x(83)90185-0. [DOI] [PubMed] [Google Scholar]
  10. Casanova M., Deyo D. F., Heck H. D. Covalent binding of inhaled formaldehyde to DNA in the nasal mucosa of Fischer 344 rats: analysis of formaldehyde and DNA by high-performance liquid chromatography and provisional pharmacokinetic interpretation. Fundam Appl Toxicol. 1989 Apr;12(3):397–417. doi: 10.1016/0272-0590(89)90015-8. [DOI] [PubMed] [Google Scholar]
  11. Chang J. C., Gross E. A., Swenberg J. A., Barrow C. S. Nasal cavity deposition, histopathology, and cell proliferation after single or repeated formaldehyde exposures in B6C3F1 mice and F-344 rats. Toxicol Appl Pharmacol. 1983 Apr;68(2):161–176. doi: 10.1016/0041-008x(83)90001-7. [DOI] [PubMed] [Google Scholar]
  12. Chiba I., Takahashi T., Nau M. M., D'Amico D., Curiel D. T., Mitsudomi T., Buchhagen D. L., Carbone D., Piantadosi S., Koga H. Mutations in the p53 gene are frequent in primary, resected non-small cell lung cancer. Lung Cancer Study Group. Oncogene. 1990 Oct;5(10):1603–1610. [PubMed] [Google Scholar]
  13. Conaway C. C., Whysner J., Verna L. K., Williams G. M. Formaldehyde mechanistic data and risk assessment: endogenous protection from DNA adduct formation. Pharmacol Ther. 1996;71(1-2):29–55. doi: 10.1016/0163-7258(96)00061-7. [DOI] [PubMed] [Google Scholar]
  14. Conway K., Costa M. Nonrandom chromosomal alterations in nickel-transformed Chinese hamster embryo cells. Cancer Res. 1989 Nov 1;49(21):6032–6038. [PubMed] [Google Scholar]
  15. Cosma G. N., Jamasbi R., Marchok A. C. Growth inhibition and DNA damage induced by benzo[a]pyrene and formaldehyde in primary cultures of rat tracheal epithelial cells. Mutat Res. 1988 Sep;201(1):161–168. doi: 10.1016/0027-5107(88)90122-4. [DOI] [PubMed] [Google Scholar]
  16. Craft T. R., Bermudez E., Skopek T. R. Formaldehyde mutagenesis and formation of DNA-protein crosslinks in human lymphoblasts in vitro. Mutat Res. 1987 Jan;176(1):147–155. doi: 10.1016/0027-5107(87)90262-4. [DOI] [PubMed] [Google Scholar]
  17. D'Amico D., Carbone D., Mitsudomi T., Nau M., Fedorko J., Russell E., Johnson B., Buchhagen D., Bodner S., Phelps R. High frequency of somatically acquired p53 mutations in small-cell lung cancer cell lines and tumors. Oncogene. 1992 Feb;7(2):339–346. [PubMed] [Google Scholar]
  18. Fearon E. R., Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990 Jun 1;61(5):759–767. doi: 10.1016/0092-8674(90)90186-i. [DOI] [PubMed] [Google Scholar]
  19. Grafstrom R. C., Fornace A., Jr, Harris C. C. Repair of DNA damage caused by formaldehyde in human cells. Cancer Res. 1984 Oct;44(10):4323–4327. [PubMed] [Google Scholar]
  20. Grafström R. C., Hsu I. C., Harris C. C. Mutagenicity of formaldehyde in Chinese hamster lung fibroblasts: synergy with ionizing radiation and N-nitroso-N-methylurea. Chem Biol Interact. 1993 Jan;86(1):41–49. doi: 10.1016/0009-2797(93)90110-k. [DOI] [PubMed] [Google Scholar]
  21. Graves R. J., Trueman P., Jones S., Green T. DNA sequence analysis of methylene chloride-induced HPRT mutations in Chinese hamster ovary cells: comparison with the mutation spectrum obtained for 1,2-dibromoethane and formaldehyde. Mutagenesis. 1996 May;11(3):229–233. doi: 10.1093/mutage/11.3.229. [DOI] [PubMed] [Google Scholar]
  22. Guicherit R., Schulting F. L. The occurrence of organic chemicals in the atmosphere of The Netherlands. Sci Total Environ. 1985 Jun;43(3):193–219. doi: 10.1016/0048-9697(85)90129-9. [DOI] [PubMed] [Google Scholar]
  23. Hanaoka T., Yamano Y., Katsuno N., Kagawa J., Ishizu S. Elevated serum levels of pantropic p53 proteins in chromium workers. Scand J Work Environ Health. 1997 Feb;23(1):37–40. doi: 10.5271/sjweh.176. [DOI] [PubMed] [Google Scholar]
  24. Harrington J. M., Shannon H. S. Mortality study of pathologists and medical laboratory technicians. Br Med J. 1975 Nov 8;4(5992):329–332. doi: 10.1136/bmj.4.5992.329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Harris C. C. p53 tumor suppressor gene: from the basic research laboratory to the clinic--an abridged historical perspective. Carcinogenesis. 1996 Jun;17(6):1187–1198. doi: 10.1093/carcin/17.6.1187. [DOI] [PubMed] [Google Scholar]
  26. Heck H. D., Casanova M., Starr T. B. Formaldehyde toxicity--new understanding. Crit Rev Toxicol. 1990;20(6):397–426. doi: 10.3109/10408449009029329. [DOI] [PubMed] [Google Scholar]
  27. Hemminki K., Partanen R., Koskinen H., Smith S., Carney W., Brandt-Rauf P. W. The molecular epidemiology of oncoproteins. Serum p53 protein in patients with asbestosis. Chest. 1996 Mar;109(3 Suppl):22S–26S. doi: 10.1378/chest.109.3_supplement.22s. [DOI] [PubMed] [Google Scholar]
  28. Hollstein M. C., Peri L., Mandard A. M., Welsh J. A., Montesano R., Metcalf R. A., Bak M., Harris C. C. Genetic analysis of human esophageal tumors from two high incidence geographic areas: frequent p53 base substitutions and absence of ras mutations. Cancer Res. 1991 Aug 1;51(15):4102–4106. [PubMed] [Google Scholar]
  29. Hollstein M., Shomer B., Greenblatt M., Soussi T., Hovig E., Montesano R., Harris C. C. Somatic point mutations in the p53 gene of human tumors and cell lines: updated compilation. Nucleic Acids Res. 1996 Jan 1;24(1):141–146. doi: 10.1093/nar/24.1.141. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Hubal E. A., Schlosser P. M., Conolly R. B., Kimbell J. S. Comparison of inhaled formaldehyde dosimetry predictions with DNA-protein cross-link measurements in the rat nasal passages. Toxicol Appl Pharmacol. 1997 Mar;143(1):47–55. doi: 10.1006/taap.1996.8076. [DOI] [PubMed] [Google Scholar]
  31. Iggo R., Gatter K., Bartek J., Lane D., Harris A. L. Increased expression of mutant forms of p53 oncogene in primary lung cancer. Lancet. 1990 Mar 24;335(8691):675–679. doi: 10.1016/0140-6736(90)90801-b. [DOI] [PubMed] [Google Scholar]
  32. Johansson E. B., Tjälve H. The distribution of [14C]dimethylnitrosamine in mice. Autoradiographic studies in mice with inhibited and noninhibited dimethylnitrosamine metabolism and a comparison with the distribution of [14C]formaldehyde. Toxicol Appl Pharmacol. 1978 Aug;45(2):565–575. doi: 10.1016/0041-008x(78)90118-7. [DOI] [PubMed] [Google Scholar]
  33. Kerns W. D., Pavkov K. L., Donofrio D. J., Gralla E. J., Swenberg J. A. Carcinogenicity of formaldehyde in rats and mice after long-term inhalation exposure. Cancer Res. 1983 Sep;43(9):4382–4392. [PubMed] [Google Scholar]
  34. Lane D. P. p53 and human cancers. Br Med Bull. 1994 Jul;50(3):582–599. doi: 10.1093/oxfordjournals.bmb.a072911. [DOI] [PubMed] [Google Scholar]
  35. Luo J. C., Neugut A. I., Garbowski G., Forde K. A., Treat M., Smith S., Carney W. P., Brandt-Rauf P. W. Levels of p53 antigen in the plasma of patients with adenomas and carcinomas of the colon. Cancer Lett. 1995 May 8;91(2):235–240. doi: 10.1016/0304-3835(95)03744-h. [DOI] [PubMed] [Google Scholar]
  36. Luo J. C., Zehab R., Anttila S., Ridanpaa M., Husgafvel-Pursiainen K., Vainio H., Carney W., De Vivo I., Milling C., Brandt-Rauf P. W. Detection of serum p53 protein in lung cancer patients. J Occup Med. 1994 Feb;36(2):155–160. doi: 10.1097/00043764-199402000-00010. [DOI] [PubMed] [Google Scholar]
  37. Ma T. H., Harris M. M. Review of the genotoxicity of formaldehyde. Mutat Res. 1988 Jul;196(1):37–59. doi: 10.1016/0165-1110(88)90027-9. [DOI] [PubMed] [Google Scholar]
  38. Magana-Schwencke N., Ekert B. Biochemical analysis of damage induced in yeast by formaldehyde. II. Induction of cross-links between DNA and protein. Mutat Res. 1978 Jul;51(1):11–19. doi: 10.1016/0027-5107(78)90003-9. [DOI] [PubMed] [Google Scholar]
  39. Magaña-Schwencke N., Ekert B., Moustacchi E. Biochemical analysis of damage induced in yeast by formaldehyde. I. Induction of single-strand breaks in DNA and their repair. Mutat Res. 1978 May;50(2):181–193. doi: 10.1016/0027-5107(78)90023-4. [DOI] [PubMed] [Google Scholar]
  40. McLaughlin J. K. Formaldehyde and cancer: a critical review. Int Arch Occup Environ Health. 1994;66(5):295–301. doi: 10.1007/BF00378361. [DOI] [PubMed] [Google Scholar]
  41. Merk O., Speit G. Significance of formaldehyde-induced DNA-protein crosslinks for mutagenesis. Environ Mol Mutagen. 1998;32(3):260–268. doi: 10.1002/(sici)1098-2280(1998)32:3<260::aid-em9>3.0.co;2-m. [DOI] [PubMed] [Google Scholar]
  42. Migliore L., Ventura L., Barale R., Loprieno N., Castellino S., Pulci R. Micronuclei and nuclear anomalies induced in the gastro-intestinal epithelium of rats treated with formaldehyde. Mutagenesis. 1989 Sep;4(5):327–334. doi: 10.1093/mutage/4.5.327. [DOI] [PubMed] [Google Scholar]
  43. Miller C. W., Simon K., Aslo A., Kok K., Yokota J., Buys C. H., Terada M., Koeffler H. P. p53 mutations in human lung tumors. Cancer Res. 1992 Apr 1;52(7):1695–1698. [PubMed] [Google Scholar]
  44. Morgan K. T., Jiang X. Z., Starr T. B., Kerns W. D. More precise localization of nasal tumors associated with chronic exposure of F-344 rats to formaldehyde gas. Toxicol Appl Pharmacol. 1986 Feb;82(2):264–271. doi: 10.1016/0041-008x(86)90201-2. [DOI] [PubMed] [Google Scholar]
  45. Nishioka H. Lethal and mutagenic action of formaldehyde in Hcr + and Hcr - strains of Escherichia coli. Mutat Res. 1973 Feb;17(2):261–265. doi: 10.1016/0027-5107(73)90175-9. [DOI] [PubMed] [Google Scholar]
  46. Partanen R., Koskinen H., Oksa P., Hemminki K., Carney W., Smith S., Brandt-Rauf P. Serum oncoproteins in asbestosis patients. Clin Chem. 1995 Dec;41(12 Pt 2):1844–1847. [PubMed] [Google Scholar]
  47. Quievryn G., Zhitkovich A. Loss of DNA-protein crosslinks from formaldehyde-exposed cells occurs through spontaneous hydrolysis and an active repair process linked to proteosome function. Carcinogenesis. 2000 Aug;21(8):1573–1580. [PubMed] [Google Scholar]
  48. Quinlan D. C., Davidson A. G., Summers C. L., Warden H. E., Doshi H. M. Accumulation of p53 protein correlates with a poor prognosis in human lung cancer. Cancer Res. 1992 Sep 1;52(17):4828–4831. [PubMed] [Google Scholar]
  49. Recio L. Oncogene and tumor suppressor gene alterations in nasal tumors. Mutat Res. 1997 Oct 31;380(1-2):27–31. doi: 10.1016/s0027-5107(97)00124-3. [DOI] [PubMed] [Google Scholar]
  50. Recio L., Sisk S., Pluta L., Bermudez E., Gross E. A., Chen Z., Morgan K., Walker C. p53 mutations in formaldehyde-induced nasal squamous cell carcinomas in rats. Cancer Res. 1992 Nov 1;52(21):6113–6116. [PubMed] [Google Scholar]
  51. Ross W. E., Shipley N. Relationship between DNA damage and survival in formaldehyde-treated mouse cells. Mutat Res. 1980 Nov;79(3):277–283. doi: 10.1016/0165-1218(80)90075-0. [DOI] [PubMed] [Google Scholar]
  52. Sen P., Costa M. Induction of chromosomal damage in Chinese hamster ovary cells by soluble and particulate nickel compounds: preferential fragmentation of the heterochromatic long arm of the X-chromosome by carcinogenic crystalline NiS particles. Cancer Res. 1985 May;45(5):2320–2325. [PubMed] [Google Scholar]
  53. Shaham J., Bomstein Y., Meltzer A., Kaufman Z., Palma E., Ribak J. DNA--protein crosslinks, a biomarker of exposure to formaldehyde--in vitro and in vivo studies. Carcinogenesis. 1996 Jan;17(1):121–125. doi: 10.1093/carcin/17.1.121. [DOI] [PubMed] [Google Scholar]
  54. Shaham J, Bomstein Y, Melzer A, Ribak J. DNA-Protein Crosslinks and Sister Chromatid Exchanges as Biomarkers of Exposure to Formaldehyde. Int J Occup Environ Health. 1997 Apr;3(2):95–104. doi: 10.1179/107735297800407695. [DOI] [PubMed] [Google Scholar]
  55. Smith S. J., Luo J. C., Brandt-Rauf P., Marion M. J. Mutant p53 protein as a biomarker of chemical carcinogenesis in humans. J Occup Environ Med. 1996 Aug;38(8):743–743. doi: 10.1097/00043764-199608000-00001. [DOI] [PubMed] [Google Scholar]
  56. Soffritti M., Maltoni C., Maffei F., Biagi R. Formaldehyde: an experimental multipotential carcinogen. Toxicol Ind Health. 1989 Oct;5(5):699–730. doi: 10.1177/074823378900500510. [DOI] [PubMed] [Google Scholar]
  57. Sozzi G., Miozzo M., Pastorino U., Pilotti S., Donghi R., Giarola M., De Gregorio L., Manenti G., Radice P., Minoletti F. Genetic evidence for an independent origin of multiple preneoplastic and neoplastic lung lesions. Cancer Res. 1995 Jan 1;55(1):135–140. [PubMed] [Google Scholar]
  58. Spandidos D. A., Anderson M. L. Oncogenes and onco-suppressor genes: their involvement in cancer. J Pathol. 1989 Jan;157(1):1–10. doi: 10.1002/path.1711570102. [DOI] [PubMed] [Google Scholar]
  59. Spengler J. D., Sexton K. Indoor air pollution: a public health perspective. Science. 1983 Jul 1;221(4605):9–17. doi: 10.1126/science.6857273. [DOI] [PubMed] [Google Scholar]
  60. Stanley L. A. Molecular aspects of chemical carcinogenesis: the roles of oncogenes and tumour suppressor genes. Toxicology. 1995 Feb 27;96(3):173–194. doi: 10.1016/0300-483x(94)02991-3. [DOI] [PubMed] [Google Scholar]
  61. Stein W. D. Analysis of cancer incidence data on the basis of multistage and clonal growth models. Adv Cancer Res. 1991;56:161–213. doi: 10.1016/s0065-230x(08)60481-9. [DOI] [PubMed] [Google Scholar]
  62. Sugiyama M., Patierno S. R., Cantoni O., Costa M. Characterization of DNA lesions induced by CaCrO4 in synchronous and asynchronous cultured mammalian cells. Mol Pharmacol. 1986 Jun;29(6):606–613. [PubMed] [Google Scholar]
  63. Tsapakos M. J., Hampton T. H., Wetterhahn K. E. Chromium(VI)-induced DNA lesions and chromium distribution in rat kidney, liver, and lung. Cancer Res. 1983 Dec;43(12 Pt 1):5662–5667. [PubMed] [Google Scholar]
  64. Tuthill R. W. Woodstoves, formaldehyde, and respiratory disease. Am J Epidemiol. 1984 Dec;120(6):952–955. doi: 10.1093/oxfordjournals.aje.a113966. [DOI] [PubMed] [Google Scholar]
  65. Vogelstein B., Fearon E. R., Hamilton S. R., Kern S. E., Preisinger A. C., Leppert M., Nakamura Y., White R., Smits A. M., Bos J. L. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988 Sep 1;319(9):525–532. doi: 10.1056/NEJM198809013190901. [DOI] [PubMed] [Google Scholar]
  66. Vähäkangas K. H., Samet J. M., Metcalf R. A., Welsh J. A., Bennett W. P., Lane D. P., Harris C. C. Mutations of p53 and ras genes in radon-associated lung cancer from uranium miners. Lancet. 1992 Mar 7;339(8793):576–580. doi: 10.1016/0140-6736(92)90866-2. [DOI] [PubMed] [Google Scholar]
  67. Wilkins R. J., Macleod H. D. Formaldehyde induced DNA-protein crosslinks in Escherichia Coli. Mutat Res. 1976 Jul;36(1):11–16. doi: 10.1016/0027-5107(76)90016-6. [DOI] [PubMed] [Google Scholar]
  68. Woutersen R. A., Appelman L. M., Wilmer J. W., Falke H. E., Feron V. J. Subchronic (13-week) inhalation toxicity study of formaldehyde in rats. J Appl Toxicol. 1987 Feb;7(1):43–49. doi: 10.1002/jat.2550070108. [DOI] [PubMed] [Google Scholar]
  69. Yuspa S. H. The pathogenesis of squamous cell cancer: lessons learned from studies of skin carcinogenesis--thirty-third G. H. A. Clowes Memorial Award Lecture. Cancer Res. 1994 Mar 1;54(5):1178–1189. [PubMed] [Google Scholar]

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