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Differential Induction of N²,3-Ethenoguanine in Rat Brain and Liver after Exposure to Vinyl Chloride¹

Curriculum in Toxicology [E. J. M., J. A. S.] and Department of Environmental Sciences and Engineering [H. K., A. R., J. A. S.], University of North Carolina, Chapel Hill, North Carolina 27599-7431

Although vinyl chloride (VC) clearly induces hepatic angiosarcoma in humans and rodents, a causal association with brain tumors has not been definitively established with the available epidemiological and experimental evidence. Because VC acts by genotoxic mechanisms, DNA adduct formation is thought to be a sensitive biomarker of early events in carcinogenesis. Adult male Sprague Dawley rats were exposed to 0 or 1100 ppm VC for 1 or 4 weeks (6 h/day, 5 days/week) by inhalation. Male weanlings were similarly exposed for 5 days. Another group of male adults was exposed to 1100 ppm [¹³C₂]VC in a nose-only inhalation apparatus for 5 days (6 h/day). A sensitive gas chromatography high-resolution mass spectrometry assay was used to measure the major promutagenic DNA adduct, N²,3-ethenoguanine (N²,3-G), in rat brain and hepatocyte (HEP) DNA. The respective concentrations of N²,3-G in control rat brain DNA at 1 and 4 weeks were 5.0 ± 0.9 and 5.6 ± 1.1 N²,3-G/10⁸ unmodified guanine. There was no change in N²,3-G in adult rat brain after exposure to 1100 ppm VC for 1 or 4 weeks. In HEPs from the same animals, these adduct concentrations increased from 5.5 ± 1.4 to 55 ± 2.0 N²,3-G/10⁸ unmodified guanine after a 1-week exposure and from 3.0 ± 0.3 to 110 ± 20 N²,3-G/10⁸ unmodified guanine after a 4-week exposure. When weanlings were exposed to 1100 ppm VC for 5 days, there was a statistically significant (P = 0.04) increase in N²,3-G in brain from 1.5 ± 0.2 to 4.4 ± 1.1 N²,3-G/10⁸ unmodified guanine. Weanlings exposed to 1100 ppm VC had an even greater increase in N²,3-G in HEPs from 1.6 ± 0.1 to 97 ± 5.0 N²,3-G/10⁸ unmodified guanine. [¹³C₂]N²,3-G was not detected in brain DNA from adult rats exposed to 1100 ppm [¹³C₂]VC for 5 days but was present in HEP DNA at 55 ± 4.0 [¹³C₂]N²,3-G/10⁸ unmodified guanine. The concentrations of the endogenous adduct in both organs were unchanged after this exposure. 7-(Oxoethyl)guanine (OEG), the major DNA adduct formed by VC, was reduced to 7-(2-hydroxyethyl)guanine and measured by liquid chromatography-electrospray ionization-tandom mass spectrometry in brain and HEP DNA from rats exposed to 1100 ppm VC for 1 week. Whereas 4.0 ± 0.8 OEG/10⁶ unmodified guanine were present in HEP DNA from VC-exposed rats, no adducts were detectable in brain DNA (detection limit, 0.3 OEG/10⁶ unmodified guanine). These findings indicate that the genotoxic metabolite of VC is not formed in or transported to adult rat brain. Thus, it is unlikely that N²,3-G or other VC-induced promutagenic DNA adducts play a significant role in initiating carcinogenesis in adult rat brain after exposure to VC. The data for weanling rats are less clear. Whereas a small increase in N²,3-G in the brains of weanlings was found after exposure to 1100 ppm VC, the resulting adduct concentration was similar to that measured in unexposed adults. Future exposures of weanling rats to the stable isotopically labeled compound will be necessary to conclusively determine whether this increase was due to VC.

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