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

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.