Benzo\[a\]pyrene-enhanced mutagenesis by asbestos in the lung of lambda-lacI transgenic rats

Our plain-English summary of Benzo[a]pyrene-enhanced mutagenesis by asbestos in the lung of lambda-lacI transgenic rats, by P. Loli, J. Topinka, P. Georgiadis, et al (Mutation Research, 2004).

The study

• Authors: P. Loli, J. Topinka, P. Georgiadis, M. Dusinská, M. Hurbánková, Z. Kováciková, K. Volkovová, T. Wolff, D. Oesterle, S.A. Kyrtopoulos
• Journal: Mutation Research
• Published: 2004;553(1-2):79-90
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

To study the suspected mechanism of the interaction between tobacco smoking and asbestos exposure in the modulation of cancer risk, the mutagenic potential of asbestos in combination with the tobacco smoke carcinogen benzo[a]pyrene (B[a]P) was examined in vivo in the rat lung. B[a]P was administered intratracheally in one set of experiments, or by two daily intraperitoneal injections in another set of experiments, to lambdalacI transgenic rats, together with 1, 2 or 4 x 2 mg amosite in one experiment. In the first experiment, the combined action of amosite and B[a]P caused a synergistic (superadditive) increase of mutation frequency in the lung, as compared to groups treated only with asbestos or B[a]P. In the second experiment, i.p. treatment with B[a]P did not significantly alter the mutation frequency induced by amosite, neither after 4 nor after 16 weeks of exposure. The B[a]P-DNA adduct levels were unaffected by amosite co-treatment in both experiments. We assume that the synergistic increase of mutation frequency after intratracheal treatment was due to the mitogenic activities of B[a]P and of amosite. In conclusion, our findings indicate that a weak and delayed mutagenic effect of amosite in rat lung observed in another study was strongly enhanced by the concomitant action of B[a]P. The striking enhancement effect of B[a]P may provide a basis for understanding the suspected synergism of smoking on asbestos carcinogenesis.

In plain English

This was an animal experiment in which the tobacco-smoke carcinogen benzo[a]pyrene (B[a]P) was given to Big Blue lambda-lacI transgenic rats together with amosite asbestos, to see whether B[a]P altered asbestos-induced mutation in the lung. Amosite was instilled into the trachea as single doses of 1 or 2 mg, or as four weekly 2 mg doses; B[a]P was given either by two daily intraperitoneal injections of 40 mg/kg body weight or instilled intratracheally at 10 mg per animal. Injected intraperitoneally, B[a]P did not significantly alter the mutation frequency induced by amosite, at either 4 or 16 weeks. When both agents were instilled intratracheally, B[a]P alone gave a mutation frequency of 61.3 per million PFU, while 2 mg amosite plus B[a]P gave about 150 (P = 0.004); amosite alone for 4 weeks was not significantly mutagenic, and the combined effect exceeded the additive effect more than three-fold, with synergistic factors of 1.6, 3.4 and 3.0 listed in Table 5. B[a]P-DNA adduct levels were unaffected by amosite co-treatment in both experiments. Cell proliferation, judged qualitatively in wild-type F344 rats, was highest 2 days after combined treatment.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: In vivo animal experiment in transgenic (lambda-lacI, Big Blue) rats, with a supporting cell-proliferation experiment in wild-type F344 rats
• Who was studied: Big Blue lambda-lacI transgenic rats (groups of five in the intraperitoneal B[a]P experiment, groups of three in the intratracheal experiment) plus groups of three wild-type male F344 rats, 9 weeks old, used for cell proliferation
• Exposure: Amosite fibres instilled intratracheally (1 mg, 2 mg, or four weekly doses of 2 mg) combined with benzo[a]pyrene, given either as two consecutive daily intraperitoneal injections of 40 mg/kg b.w. or intratracheally at 10 mg per animal
• Main results:
  • Intratracheal co-instillation: B[a]P alone gave a mutation frequency of 61.3 per 10^6 PFU, while 2 mg amosite plus B[a]P gave about 150 per 10^6 PFU (P = 0.004)
  • Amosite alone, given once or repeatedly over 4 weeks, produced no significant mutagenic effect; B[a]P alone doubled mutation frequency (P = 0.024)
  • After intratracheal co-exposure the net induced mutation frequency was more than three-fold the additive effect; Table 5 lists synergistic factors of 1.6 (1 mg amosite), 3.4 (2 mg) and 3.0 (4 x 2 mg)
  • With B[a]P given intraperitoneally, the mutation frequency induced by amosite was not significantly changed at 4 or at 16 weeks
  • B[a]P-DNA adduct levels in lung were not changed by amosite co-treatment in either the intraperitoneal or the intratracheal experiment
  • Cell proliferation (BrdU-labelled nuclei, judged qualitatively) was greatest 2 days after combined amosite and B[a]P treatment
  • Malondialdehyde in lung tissue differed significantly from control only after combined exposure to the highest amosite dose plus intraperitoneal B[a]P for 4 weeks
• The authors' conclusion: The authors concluded that a weak and delayed mutagenic effect of amosite in rat lung, observed in another study, was strongly enhanced by concomitant B[a]P, and they proposed that each agent may act as a co-mutagen of the other by causing enhanced cell proliferation
• Limitations the authors state:
  • The authors stated the B[a]P dose used was much higher than amounts taken up by tobacco smokers and that intratracheal instillation is not fully comparable to human inhalation exposure
  • BrdU-labelled cells were distributed heterogeneously, so cell proliferation could only be judged qualitatively
  • Single very high mutation frequencies regarded as jackpot mutations were excluded from statistical evaluation

Topics

The National Library of Medicine indexes this study under subjects our site covers: Amosite.

Medical terms in this study, explained in our Lexicon: Asbestos Exposure, Amosite, Carcinogenesis.

Related studies

• Benzo[a]pyrene-enhanced mutagenesis by man-made mineral fibres in the lung of lamda-lacI transgenic rats — J. Topinka, P. Loli, et al. (2006)
• Mutagenesis by asbestos in the lung of lambda-lacI transgenic rats — J. Topinka, P. Loli, et al. (2004)
• On the mechanism of cogenotoxic action between ingested amphibole asbestos fibres and benzo[a]pyrene: I. Urinary and serum mutagenicity studies with rats — C. Varga, G. Horváth, et al. (1998)
• Effects of 6-month daily supplementation with oral beta-carotene in combination or not with benzo[a]pyrene on cell-cycle markers in the lung of ferrets — A. Fuster, C. Picó, et al. (2008)
• P53 mutations in tumours induced by intraperitoneal injection of crocidolite asbestos and benzo[a]pyrene in rats — K. Unfried, N. Kociok, et al. (1997)
• Differential diagnosis of malignant tumours in the abdominal cavity of rats after intraperitoneal injection of crocidolite or benzo[a]pyrene — J. Friemann, M. Varnai, et al. (1996)

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