Induction of oxidative stress in rat brain by acrylonitrile (ACN)

Chronic treatment with acrylonitrile (ACN) has been shown to produce a dose -related increase in glial cell tumors (astrocytomas) in rats. The mechanis m(s) for ACN-induced carcinogenicity remains unclear. While ACN has been re ported to induce DNA damage in a number of short-term systems, evidence for a genotoxic mechanism of tumor induction is the brain is not strong. Other toxic mechanisms appear to participate n the induction of tumor or induce the astrocytomas solely. In particular, nongenotoxic mechanisms of carcinog en induction have been implicated in this ACN-induced carcinogenic effect i n the rat brain. One major pathway of ACN metabolism is through glutathione (GSH) conjugation. Extensive utilization and depletion of GSH, an importan t intracellular antioxidant, by ACN may lead to cellular oxidative stress. The present study examined the ability of ACN to induce oxidative stress in male Sprague-Dawley rats. Rats were administered ACN at concentrations of 0, 5, 10, 100, or 200 ppm in the drinking water and sampled after 14, 28, o r 90 days of continuous treatment. Oxidative DNA damage indicated by the pr esence of 8-hydroxy-2'-deoxyguanosine (OH8dG) and lipid peroxidation indica ted by the presence of malondialdehyde (MDA), a lipid peroxidation product, in rat brains and livers were examined. The levels of reactive oxygen spec ies (ROS) were also determined in different rat tissues. Both the levels of nonenzymatic antioxidants (GSH, vitamin E) and the activities of enzymatic antioxidants (catalase, superoxide dismutase, glutathione peroxidase) in r at brains and livers were measured. Increased levels of OH8dG, MDA, and ROS were found in the brains of ACN-treated rats. Decreased levels of GSH and activities of catalase and SOD were also observed in the brains of ACN-trea ted rats compared to the control group. Interestingly, there were no change s of these indicators of oxidative stress in the livers of ACN-treated rats . Rat liver is not a target for ACN-induced carcinogenesis. These data indi cate that ACN selectively induces oxidative stress in rat brain at doses th at produce carcinogenesis in chronic treatment studies. (C) 1998 Society of Toxicology.