Mutation frequency in the lacI gene of liver DNA from lambda/lacI transgenic mice following the interaction of PCBs with iron causing hepatic cancer and porphyria.

Abstract

The synergistic interaction of iron overload, AHR: genotype and exposure to a mixture of polychlorinated biphenyls (PCBs) (Aroclor 1254) in mice leads to hepatic porphyria, oxidative DNA damage and cancer. In humans, hepatocellular cancer is associated with iron overload and hepatic porphyria. Neither the mechanism of hepatic carcinogenesis induced by PCBs in rodents nor hepatocellular cancer induced by iron and porphyria in humans are understood. To test the hypothesis that chronic interaction of iron and PCBs may induce mutagenesis in liver DNA, lambda /lacI transgenic C57BL/6 mice were given iron dextran (600 mg iron/kg) and then administered Aroclor 1254 in the diet (0.01%) for 7 weeks. Hepatic iron, CYP1A activity and CYP1A1/1A2 protein were elevated >20-fold as a result of iron or Aroclor treatments, respectively, but porphyria with associated histological changes only developed in the combined iron/Aroclor treatment group. lambda/lacI shuttle vectors were isolated from liver genomic DNA and the mutational frequency (MF) in the lacI gene determined. Both iron and Aroclor treatments alone caused significant small increases in MF (1.5- and 1.4-fold, respectively), however, the MF following the combined iron and Aroclor treatment (1. 6-fold) was not greater than the additive effects. In contrast, the MF was significantly elevated (4.7-fold) in liver DNA of mice 2 weeks following five daily doses of N-nitrosodimethylamine (4 mg/kg). These studies demonstrate that neither PCBs nor iron overload caused marked point mutations even in a combination regime that leads to oxidative damage and cancer. There was also no strong evidence either that porphyrins or chronic CYP1A1 expression induced by the PCBs after this period caused marked point mutagens or simple deletions. Hence, to understand the PCBs-iron synergism more complex scenarios than point mutations or simple deletions must be invoked.