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. 2009 Sep;111(1):64-71.
doi: 10.1093/toxsci/kfp133. Epub 2009 Jun 22.

Acrylonitrile-induced oxidative stress and oxidative DNA damage in male Sprague-Dawley rats

Xinzhu Pu  1 , Lisa M Kamendulis, James E Klaunig
Affiliations

Acrylonitrile-induced oxidative stress and oxidative DNA damage in male Sprague-Dawley rats

Xinzhu Pu et al. Toxicol Sci. 2009 Sep.

Abstract

Studies have demonstrated that the induction of oxidative stress may be involved in brain tumor induction in rats by acrylonitrile. The present study examined whether acrylonitrile induces oxidative stress and DNA damage in rats and whether blood can serve as a valid surrogate for the biomonitoring of oxidative stress induced by acrylonitrile in the exposed population. Male Sprague-Dawley rats were treated with 0, 3, 30, 100, and 200 ppm acrylonitrile in drinking water for 28 days. One group of rats were also coadministered N-acetyl cysteine (NAC) (0.3% in diet) with acrylonitrile (200 ppm in drinking water) to examine whether antioxidant supplementation was protective against acrylonitrile-induced oxidative stress. Direct DNA strand breakage in white blood cells (WBC) and brain was measured using the alkaline comet assay. Oxidative DNA damage in WBC and brain was evaluated using formamidopyrimidine DNA glycosylase (fpg)-modified comet assay and with high-performance liquid chromatography-electrochemical detection. No significant increase in direct DNA strand breaks was observed in brain and WBC from acrylonitrile-treated rats. However, oxidative DNA damage (fpg comet and 8'hydroxyl-2-deoxyguanosine) in brain and WBC was increased in a dose-dependent manner. In addition, plasma levels of reactive oxygen species (ROS) increased in rats administered acrylonitrile. Dietary supplementation with NAC prevented acrylonitrile-induced oxidative DNA damage in brain and WBC. A slight, but significant, decrease in the GSH:GSSG ratio was seen in brain at acrylonitrile doses > 30 ppm. These results provide additional support that the mode of action for acrylonitrile-induced astrocytomas involves the induction of oxidative stress and damage. Significant associations were seen between oxidative DNA damage in WBC and brain, ROS formation in plasma, and the reported tumor incidences. Since oxidative DNA damage in brain correlated with oxidative damage in WBC, these results suggest that monitoring WBC DNA damage maybe a useful tool to assess acrylonitrile-induced oxidative stress in humans.

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Figures

FIG. 1.
FIG. 1.
Direct DNA damage in rat WBC following exposure to acrylonitrile (ACN) in drinking water ± NAC in diet for 28 days measured by alkaline comet assay. Values represent the means ± SD in nine animals.
FIG. 2.
FIG. 2.
Direct DNA damage in rat brain following exposure to acrylonitrile (ACN) in drinking water ± NAC in diet for 28 days measured by alkaline comet assay. Values represent the means ± SD in three animals.
FIG. 3.
FIG. 3.
Oxidative DNA damage in rat WBC following exposure to acrylonitrile (ACN) in drinking water ± NAC in diet for 28 days measured by fpg-modified alkaline comet assay. Values represent the means ± SD in nine animals. *Statistically different from control (p < 0.05, ANOVA with Dunnett’s post hoc test).
FIG. 4.
FIG. 4.
Oxidative DNA damage in rat brain following exposure to acrylonitrile (ACN) in drinking water ± NAC in diet for 28 days measured by fpg-modified alkaline comet assay. Values represent the means ± SD in three animals. *Statistically different from control (p < 0.05, ANOVA with Dunnett’s post hoc test).
FIG. 5.
FIG. 5.
OH8dG level in rat WBC following the exposure to acrylonitrile (ACN) in drinking water ± NAC for 28 days. Values represent the means ± SD in three animals. *Statistically different from respective control (p < 0.05, ANOVA with Dunnett's post hoc test).
FIG. 6.
FIG. 6.
OH8dG level in rat brain following the exposure with acrylonitrile (ACN) in drinking water ± NAC for 28 days. Values represent the means ± SD in nine animals. *Statistically different from respective control (p < 0.05, ANOVA with Dunnett's post hoc test).
FIG. 7.
FIG. 7.
Effect of acrylonitrile (ACN) on the formation of ROS in rat plasma following the exposure in drinking water for 28 days. Values represent the means ± SD in three animals. *Statistically different from respective control (p < 0.05, ANOVA with Dunnett's post hoc test).
FIG. 8.
FIG. 8.
Effect of acrylonitrile (ACN) on GSG/GSSG in rat brain cortexes following the exposure in drinking water for 28 days. Values represent the means ± SD in six observations. *Statistically different from control (p < 0.05, ANOVA with Dunnett's post hoc test).
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