Genetic variation in liver tumor susceptibility, plasma testosterone levels, and androgen receptor binding in six inbred strains of mice

Abstract

We compared six inbred mouse strains for their relative susceptibilities to liver and lung tumor induction. Male and female mice were treated at 12 days of age with a single i.p. injection of N-ethyl-N-nitrosourea (ENU; 0.25 mumol/g), and tumor multiplicity was analyzed at 32 weeks of age (males) or 44 weeks of age (females). Male mice of the SWR/J and C57BL/6J strains were relatively resistant to hepatocarcinogenesis, averaging 0 and 0.3 tumors per animal, respectively. Male C57BR/cdJ, P/J, and SM/J mice had intermediate susceptibilities, averaging seven to 17 tumors per animal, and male CBA/J mice were the most susceptible, averaging 45 tumors per animal. Female mice were more resistant than male mice: no liver tumors were observed for SWR/J females; C57BL/6J, SM/J, P/J, and CBA/J females averaged less than one tumor per animal and C57BR/cdJ females averaged five tumors per animal. In contrast to the results for liver tumor induction, there was no difference between the sexes in lung tumor susceptibility. Male and female SWR/J mice were the most susceptible, averaging 14 lung tumors per animal; male and female CBA/J mice were moderately susceptible, averaging six tumors per animal and the C57BR/cdJ, C57BL/6J, P/J, and SM/J strains were relatively resistant, averaging less than three tumors per animal. To determine if levels of testosterone, a potent liver tumor promoter in mice, or its receptor contribute to the strain variation in liver tumor susceptibility, we measured levels of plasma testosterone as well as binding properties of the hepatic androgen receptor for the six inbred strains. Plasma testosterone in male mice ranged from 1.8 to 7.4 ng/ml and in females ranged from 0.21 to 0.42 ng/ml, which is consistent with the greater susceptibility of male mice to liver tumor development. However, variation in testosterone levels among the different strains of mice was not correlated with liver tumor susceptibility. We also demonstrated the presence of high affinity androgen receptors in mouse hepatic cytosol. The amounts of this receptor for the six strains tested ranged from 24 to 34 fmol/mg cytosolic protein. The apparent KD of the receptor for [3H]mibolerone (a synthetic androgen) differed between the strains: SWR/J, C57BL/6J, and C57BR/cdJ mice had the highest affinity (KD = 0.22 nM), P/J and CBA/J strains had an intermediate affinity (KD = 0.36 nM), and the SM/J strain had the lowest affinity receptor (KD = 0.45 nM). The strain variation in the affinity or abundance of the androgen receptor was not related to the strain variation in liver tumor induction.