The effect of acrylonitrile on gap junctional intercellular communication in rat astrocytes

Rats chronically exposed to acrylonitrile (ACN) have shown a dose-dependent increase in the incidence of astrocytomas in the brain. The mechanism(s) b y which ACN induces cancer in rodents has not been established. ACN does no t appear to be directly genotoxic in the brain and thus a nongenotoxic mode of action has been proposed. Inhibition of gap junctional intercellular co mmunication (GJIC) has been shown to be a property of many nongenotoxic car cinogens. The present study examined the effects of ACN on GJIC in a rat as trocyte transformed cell line, DI TNC1 cells (a target cell for ACN carcino genicity) and primary cultured hepatocytes (a nontarget cell for ACN carcin ogenicity). ACN inhibited GJIC in rat astrocytes in a dose-dependent manner . Inhibition of GJIC was observed following 2 h treatment with 0.10 mmol/L and 1.00 mmol/L ACN. However, in primary cultured hepatocytes, ACN exposed did not result in inhibition of GJIC even after 48 h of continued treatment . In the astrocytes, GJIC inhibition plateaued after 4 h of treatment and r emained blocked throughout the entire experimental period examined. Inhibit ion of GJIC in DI TNC1 cells was reversed by removal of ACN from the cultur e medium after 4 or 24 h of treatment. Cotreatment of astrocytes with vitam in E reduced the effect of ACN-induced inhibition of GJIC. Similarly, inhib ition of GJIC was prevented by treatment with 2-oxothiazolidine-4-carboxyli c acid (OTC), a precursor of glutathione synthesis. Decreasing cellular glu tathione by treatment with buthionine sulfoxamine alone (without ACN) did n ot affect GJIC in astrocytes. Collectively, these results demonstrate that treatment with ACN caused a selective inhibition of GJIC in rat DI TNC1 ast rocytes (the target cell type), but not in rat hepatocytes (a nontarget tis sue). Inhibition of GJIC in astrocytes was reversed by treatment with antio xidants and suggests a potential role for oxidative stress in ACN-induced c arcinogenesis.