Oxidative DNA damage is one of the key events thought to be involved in mutation and
cancer. The present study examined the accumulation of M1dG, 3-(2'-deoxy-beta-D-erythro-pentofuranosyl)-pyrimido[1,2-a]-purin-10(3H)-one,
DNA adducts after single dose or 1-year exposure to polyhalogenated
aromatic hydrocarbons (PHAH) in order to evaluate the potential role of oxidative DNA damage in PHAH toxicity and carcinogenicity. The effect of PHAH exposure on the number of M1dG adducts was explored initially in female mice exposed to a single dose of either
2,3,7,8-tetrachlorodibenzo-p-dioxin (
TCDD) or a PHAH mixture. This study demonstrated that a single exposure to PHAH had no significant effect on the number of M1dG adducts compared to the
corn oil control group. The role of M1dG adducts in
polychlorinated biphenyl (PCB)-induced toxicity and carcinogenicity was further investigated in rats exposed for a year to
PCB 153,
PCB 126, or a mixture of the two.
PCB 153, at doses up to 3000 microg/kg/day, had no significant effect on the number of M1dG adducts in liver and brain tissues from the exposed rats compared to controls. However, 1000 ng/kg/day of
PCB 126 resulted in M1dG adduct accumulation in the liver. More importantly, coadministration of equal proportions of
PCB 153 and
PCB 126 resulted in dose-dependent increases in M1dG adduct accumulation in the liver from 300 to 1000 ng/kg/day of
PCB 126 with 300-1000 microg/kg/day of
PCB 153. Interestingly, the coadministration of different amounts of
PCB 153 with fixed amounts of
PCB 126 demonstrated more M1dG adduct accumulation with higher doses of
PCB 153. These results are consistent with the results from
cancer bioassays that demonstrated a synergistic effect between
PCB 126 and
PCB 153 on toxicity and
tumor development. In summary, the results from the present study support the hypothesis that oxidative DNA damage plays a key role in toxicity and carcinogenicity following long-term PCB exposure.