Age-Dependent Carcinogenic Susceptibility in Rat Liver Is Related to Potential of Gap Junctional Intercellular Communication

Connexin 32 (Cx32) is a major gap junction protein in the liver. The authors previously demonstrated that transgenic rats carrying a dominant negative mutant of Cx32 (Cx32 Delta Tg) have much decreased capacity for gap junctional intercellular communication (GJIC) and increased susceptibility to diethylnitrosamine (DEN)-induced hepatocarcinogenesis as compared to littermate wild-type (wt) rats. To evaluate the age-dependent susceptibility to DEN-induced hepatocarcinogenesis and alteration of GJIC function, male Cx32 Delta Tg and wt rats at 10, 30, or 85 weeks old were given a single intraperitoneal administration of DEN (40 mg/rat) and sacrificed 12 weeks later. The number and area of glutathione S-transferase placental form (GST-P)-positive preneoplastic foci were significantly increased in the liver of 10- and 30-wk-old Cx32 Delta Tg rats compared with age-matched wt. However, in the 85-wk-old rats, both Cx32 Delta Tg and wt rats had similarly large number and area of GST-P-positive foci, and the difference was not significant. Interestingly, function of hepatic GJIC was reduced and protein and mRNA expression of Cx32 were decreased with aging in wt rats. These results suggest that a decline of hepatic intercellular communication through gap junction results in increased susceptibility to DEN-induced hepatocarcinogenesis in aged rats.