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Mechanistic relationships between hepatic genotoxicity and carcinogenicity in male B6C3F1 mice treated with polycyclic aromatic hydrocarbon mixtures

  • Genotoxicity and Carcinogenicity
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Abstract

The genotoxicity of a complex mixture [neutral fraction (NF)] from a wood preserving waste and reconstituted mixture (RM) mimicking the NF with seven major polycyclic aromatic hydrocarbons (PAHs) and benzo(a)pyrene (BaP) was investigated by determining DNA adducts and tumor incidence in male B6C3F1 mice exposed to three different doses of the chemical mixtures. The peak values of DNA adducts were observed after 24 h, and the highest levels of PAH–DNA adducts were exhibited in mice administered NF + BaP, and the highest tumor incidence and mortality were also observed in this group. DNA adduct levels after 1, 7, or 21 days were significantly correlated with animal mortality and incidence of total tumors including liver, lung, and forestomach. However, only hepatic DNA adducts after 7 days significantly correlated with liver tumor incidence. Most proteins involved in DNA repair including ATM, pATR, Chk1, pChk1, DNA PKcs, XRCC1, FANCD2, Ku80, Mre11, and Brca2 were significantly lower in liver tumor tissue compared to non-tumor tissue. Expressions of proteins involved in apoptosis and cell cycle regulation were also significantly different in tumor versus non-tumor tissues, and it is possible that PAH-induced changes in these gene products are important for tumor development and growth.

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Acknowledgments

We thank Dr. Annika Gillespie and Rebecca Lingenfelter for their efforts during animal experiments. This research work was supported by National Institute of Health grants P30-ES09106, P42-ES04917, ES-09132, and ES-019689, HL-087174, HL-112516 (to BM), and the Center for Translational Environmental Health Research (CTEHR), P30ES023512.

Conflict of interest

The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, 77843, USA

    Tracie D. Phillips & Stephen H. Safe

  2. School of Public Health, Texas A&M University Health Science Center, College Station, TX, 77843, USA

    Molly Richardson, Lingyu He, Thomas J. McDonald, Leslie H. Cizmas, Kirby C. Donnelly & Guo-Dong Zhou

  3. Baylor College of Dentistry, Texas A&M University Health Science Center, Dallas, TX, 75246, USA

    Yi-Shing Lisa Cheng

  4. Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX, 77030, USA

    Fen Wang & Guo-Dong Zhou

  5. Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA

    Bhagavatula Moorthy

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  1. Tracie D. Phillips
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  2. Molly Richardson
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  3. Yi-Shing Lisa Cheng
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  4. Lingyu He
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  6. Leslie H. Cizmas
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  10. Bhagavatula Moorthy
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Correspondence to Guo-Dong Zhou.

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Kirby C. Donnelly: deceased.

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Phillips, T.D., Richardson, M., Cheng, YS.L. et al. Mechanistic relationships between hepatic genotoxicity and carcinogenicity in male B6C3F1 mice treated with polycyclic aromatic hydrocarbon mixtures. Arch Toxicol 89, 967–977 (2015). https://doi.org/10.1007/s00204-014-1285-8

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