Etheno adducts formed in DNA of vinyl chloride-exposed rats are highly persistent in liver

Abstract

Preweanling rats were exposed to 600 p.p.m. (4 h/day) of the human carcinogen vinyl chloride for 5 days to determine the molecular dosimetry of DNA adducts in liver, lung and kidney. 7-(2'-Oxoethyl)guanine (7OEG) was the major DNA adduct detected, representing ∼98% of all adducts. N², 3-Ethenoguanine (εG) and 3, N⁴-etheno-2'-deoxycytidine (εdC) were present at ∼1% of the 7OEG concentration, while 1, N⁶-etheno-2'-deoxyadenosine was present in even lower concentrations. Liver had 3- to 8-fold higher amounts of the DNA adducts than lung and kidney. The persistence of all four adducts was determined at 3, 7 and 14 days post-exposure. Whereas 7OEG had a t½ of ∼62 h, all three etheno adducts were highly persistent. After accounting for dilution due to growth-related cell proliferation, εG had a t½ of ∼30 days, while EdC and εdA were not repaired. These data suggest that these cyclic adducts are poorly recognized by liver DNA repair enzymes and have the potential for accumulation upon chronic exposure. This, coupled with the known miscoding properties of the ethenobases, provides a strong rational for examining their role in vinyl chloride-induced cancer and their utility as biomarkers of exposure.