The effects of in vitro exposure to the neurotoxins sarin (GB) and soman (GD) on unscheduled DNA synthesis by rat hepatocytes

Abstract

Large amounts of the nerve agents, sarin (GB) and soman (GD), are part of the military chemical arsenal and small amounts are on hand in numerous U.S. research laboratories. Thus, there is a potential for accidental occupational exposure to these compounds. As part of a study of mutagenic, reproductive and subchronic effects of these agents, we measured unscheduled DNA repair synthesis in isolated rat hepatocytes after exposure to GBI (stabilized with tributylamine), GBII (stabilized with diisopropylcarbodiimide) or GD. This was done to determine whether these agents or their metabolites directly damage DNA or their related proteins. Each agent was assayed at least once over concentrations ranging from 3.0 × 10 −4 to 2.4 × 10 −3 M for GBI and GBII and 2.3 × 10 −4 to 1.8 × 10 −3 for GD and at least 3 times at 2.4 × 10 −3M for GBI and GBII and 1.8 × 10 −3 M for GD, added as 20% of the culture medium. In all assays, no increase in the level of DNA synthesis was observed. On the contrary, significant decreases in repair synthesis were seen in hepatocytes exposed to GBI or GBII. The decreases in DNA synthesis seen in response to GD were less marked and not significant. These observations were not related to cell death, since 8 of 10 assays performed showed no significant decrease in the amount of DNA present in cultures exposed to the nerve agents compared to the negative controls. Our results suggest that the agents GBI, GBII and GD may either inhibit the repair of DNA or protect DNA from damage.