The effect of connexin32 null mutation on hepatocarcinogenesis in different mouse strains.
Connexin32 (Cx32) is the major gap junctional protein in mouse liver. We have shown recently that the formation of liver tumours in Cx32-deficient mice is strongly increased in comparison with control wild-type mice, demonstrating that the deficiency in gap junctional communication has an enhancing effect on hepatocarcinogenesis. We have now compared the effect of Cx32 deficiency on liver carcinogenesis in two strains of mice with differing susceptibility to hepatocarcinogenesis. Heterozygous Cx32(+/-) females were crossed with male Cx32 wild-type C57BL/6J (low susceptibility) or C3H/He (high susceptibility) mice. Since the Cx32 gene is located on the X-chromosome, the resulting F1 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 were killed 16, 21 or 26 weeks later. The number, volume fraction and size distribution of precancerous liver lesions characterized by a deficiency in the marker enzyme glucose-6-phosphatase were quantitated. The results demonstrate that Cx32 deficiency only slightly affects the number of enzyme-altered lesions, but strongly enhances their growth, both in the resistant and the susceptible mouse strain, suggesting that decreased intercellular communication results in tumour promoting activity irrespective of the genetic background of the mouse strain used. Since Cx32-deficient C3H/He hybrids were approximately 5-10 times more sensitive than C3H/He hybrids with an intact Cx32 gene, this mouse strain may prove very useful for toxicological screening purposes.
Moennikes
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O
Institut für Toxikologie, Wilhelmstrabetae 56, 72074 Tübingen and Institut für Genetik, Bonn, Germany.
Buchmann
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A
Ott
T
T
Willecke1
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K
Schwarz
M
M
D000818:Animals; D015197:Carcinogenicity Tests; D017630:Connexins / Q000235:genetics* / Q000502:physiology*; D003433:Crosses, Genetic; D004052:Diethylnitrosamine; D005838:Genotype; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D006579:Heterozygote; D008113:Liver Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D011230:Precancerous Conditions / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology*; D013997:Time Factors; D014960:X Chromosome / Q000235:genetics; D000097002:Gap Junction beta-1 Protein
D017630:Connexins; D004052:Diethylnitrosamine; D005952:Glucose-6-Phosphatase; D000097002:Gap Junction beta-1 Protein