The effect of connexin32 null mutation on hepatocarcinogenesis in different mouse strains

Connexin32 (Cx32) is the major gap junctional protein in mouse liver. We ha ve shown recently that the formation of liver tumours in Cx32-deficient mic e is strongly increased in comparison with control wild-type mice, demonstr ating that the deficiency in gap junctional communication has an enhancing effect on hepatocarcinogenesis. We have now compared the effect of Cx32 def iciency on liver carcinogenesis in two strains of mice with differing susce ptibility to hepatocarcinogenesis. Heterozygous Cx32(+/-) females were cros sed with male Cx32 wild-type C57BL/6J (low susceptibility) or C3H/Je (high susceptibility) mice. Since the Cx32 gene is located on the X-chromosome, t he resulting Fl males segregated to the genotypes Cx32(Y/+) and Cx32(Y/-). Genotyping was performed by PCR-analysis using tail-tip DNA, Weanling male mice were i.p. injected with a single dose of N-nitrosodiethylamine and wer e killed 16, 21 or 26 weeks later. The number, volume fraction and size dis tribution of precancerous liver lesions characterized by a deficiency in th e marker enzyme glucose-6-phosphatase were quantitated. The results demonst rate that Cx32 deficiency only slightly affects the number of enzyme-altere d lesions, but strongly enhances their growth, both in the resistant and th e susceptible mouse strain, suggesting that decreased intercellular communi cation results in tumour promoting activity irrespective of the genetic bac kground of the mouse strain used. Since Cx32-deficient C3H/He hybrids were similar to 5-10 times more sensitive than C3H/He hybrids with an intact Cx3 2 gene, this mouse strain may prove very useful for toxicological screening purposes.