Acrylonitrile (
ACN) produces
tumors in rats, particularly
gliomas of the brain, but tests for genotoxicity have yielded mixed results and no
ACN-
DNA adducts have been identified in the brain. To examine the possibility that
ACN-related
brain tumors were not a consequence of binding of
ACN to brain
DNA, experiments were conducted to investigate possible epigenetic mechanisms. Male Sprague-Dawley rats were exposed to 0, 3, 30, and 300 ppm
ACN in
drinking water for 21 days, a range that includes doses associated with brain
tumorigenesis. In the 30 and 300 ppm
ACN groups, 8-oxodeoxyguanosine (8-oxodG) levels were two fold greater than in the controls. Measures of
glutathione levels,
glutathione peroxidase and
catalase were not significantly changed, but
cyst(e)ine was somewhat increased. No changes were found in brain
cytochrome oxidase activity, which indicates a lack of metabolic
hypoxia. Also, no effects on
thiobarbituric acid reactive substances were found, indicating a lack of lipid peroxidation. In an additional experiment, male Sprague-Dawley rats were exposed to 0 or 100 ppm
ACN in
drinking water for 94 days; interim sacrifices were conducted at 3, 10, and 31 days. Levels of brain nuclear
DNA 8-oxodG were significantly increased in
ACN-exposed rats compared with controls. Another group of animals were given weekly i.v.
injections of 5 mg/kg methylnitrosurea and no increases in
8-oxodG were found. These studies suggest the possibility that
ACN-induced
tumors may be produced by a mode of action involving
8-oxodG. The formation of
8-oxodG is not understood, but does not appear to involve lipid peroxidation or disruption of
antioxidant defenses.