Effects of vinylidene chloride on DNA synthesis and DNA repair in the rat and mouse: A comparative study with dimethylnitrosamine

Abstract

Exposure to vinylidene chloride (VDC) vapor has been reported to induce tumors in mice, but rats are apparently insensitive to this effect of VDC. This species difference has been correlated with the greater capacity of mice to activate VDC to a reactive electrophile which can react with macromolecules. To increase our understanding of the molecular events associated with this species difference, we have investigated the potential of VDC to cause DNA alkylation, DNA repair, and DNA replication in the liver and kidneys of rats and mice. For comparative purposes, the potent carcinogen dimethylnitrosamine (DMN) was also studied. Male Sprague-Dawley rats and CD-1 mice were exposed to 10 and 50 ppm VDC for 6 hr. DNA alkylation after 50 ppm [ 14C]VDC was minimal in liver and kidney of both rats and mice (one or two orders of magnitude less than reported for DMN in rats). Similarly, DNA repair in the kidney of mice exposed to 50 ppm VDC was only 38% higher than control values, while DNA repair in the liver of mice injected with 20 mg/kg DMN was elevated 637%. However, tissue damage and increased DNA replication (25-fold) were seen in the kidneys of mice exposed to 50 and 10 ppm VDC. Comparable effects were not seen in the liver of mice exposed to VDC (50 or 10 ppm) or in the liver or kidneys of rats exposed to 10 ppm VDC. Thus an important distinction between DMN and VDC has been demonstrated. Tumorigenic doses of DMN produced relatively little tissue damage, but were associated with a high degree of DNA alkylation and DNA repair synthesis. In contrast, exposure to tumorigenic doses of VDC resulted in massive tissue damage but induced minimal DNA alkylation or DNA repair synthesis. This suggests that the tumors observed in mice exposed to VDC arise primarily through effects of the chemical on nongenetic components of the cells. Consequently protection of humans from levels of VDC sufficient to cause tissue damage should also serve to preclude any carcinogenic activity of VDC.