The little mutation suppresses DEN-induced hepatocarcinogenesis in mice and abrogates genetic and hormonal modulation of susceptibility

Abstract

In mice, the sex difference in susceptibility to hepatocarcinogenesis results from the tumor promoting activity of testosterone and from the inhibition of tumor promotion by ovarian hormones. We investigated the role of growth hormone in the sex-dependent regulation of susceptibility, because sex hormones are known to regulate the temporal pattern of growth hormone secretion and subsequent sex differences in liver gene expression. We found that in both males and females, wild-type mice developed significantly more tumors than growth hormone-deficient, C57BL/6J-lit/lit (B6-lit/lit) mutant mice following perinatal treatment with the carcinogen N,N-diethylnitrosamine (DEN). B6 wild-type males developed 36-59-fold more liver tumors per animal than age matched B6-lit/lit males and wild-type females developed 11-fold more tumors than B6-lit/lit females. We bred the little mutation onto the more susceptible C57BR/cdJ (BR) and C3H/HeJ (C3H) strains to assess the effect of growth hormone deficiency on hepatocarcinogenesis on additional genetic backgrounds. Growth hormone deficiency suppressed liver tumor development to <1% in males of each strain and in BR strain females. In B6 and C3H females, growth hormone deficiency caused 2-4-fold reductions in the volume fraction of the liver occupied by preneoplastic lesions. Furthermore, in contrast to wild-type strains, neither gonadectomy nor strain background significantly affected susceptibility in lit/lit mice, as mean liver tumor multiplicities ranged from 0 to 0.24 +/- 0.44 and the volume fraction of preneoplastic lesions ranged from 0.21 +/- 0.22 to 0.61 +/- 1.9%. These results demonstrate that both strain and sex hormonal effects on susceptibility to liver carcinogenesis are dependent on wild-type levels of growth hormone.

The Pathology of Aging 129S6/SvEvTac Mice

“…3,48,72 Male predisposition is seen not only in the context of spontaneous hepatic tumorigenesis but also in diverse experimental settings, including the induction of liver tumors by a wide variety of carcinogens or infectious agents. 4,47 Endocrine ablation studies have demonstrated that sexual differences in susceptibility results from the opposing effects of male and female sex hormones, with testosterone enhancing and ovarian hormones and prolactin inhibiting hepatocellular tumor development. 4,21 Blepharitis/blepharoconjunctivitis represented by far the most prevalent nonneoplastic age-related disorder affecting both male and female 129S6/SvEvTac mice, but it has been only occasionally reported in laboratory mice.…”

“…4,47 Endocrine ablation studies have demonstrated that sexual differences in susceptibility results from the opposing effects of male and female sex hormones, with testosterone enhancing and ovarian hormones and prolactin inhibiting hepatocellular tumor development. 4,21 Blepharitis/blepharoconjunctivitis represented by far the most prevalent nonneoplastic age-related disorder affecting both male and female 129S6/SvEvTac mice, but it has been only occasionally reported in laboratory mice. 60 Ulcerative blepharoconjunctivitis is an age-related disorder that appears to be more common in BALB/c, C57BL/6, and 129P3/J than other inbred lines of mice.…”

Impact of reduced insulin‐like growth factor‐1/insulin signaling on aging in mammals: novel findings

“…These mechanisms include resistance to oxidative and cytotoxic stress Murakami et al, 2003;Bokov et al, 2007), increased activity of antioxidant enzymes (BrownBorg et al, 2001;Romanick et al, 2004), reduced body temperature (Hunter et al, 1999;Hauck et al, 2001) and reduced susceptibility to cancer (Yang et al, 1996;Bugni et al, 2001;Deitel et al, 2002;Ikeno et al, 2003). Recent elegant studies by AmadorNoguez et al (2004AmadorNoguez et al ( , 2007 have added to the list of likely mechanisms of extended longevity in GH-deficient mice.…”

Genetic differences in the IGF-I gene among inbred strains of mice with different serum IGF-I levels

“…The previous report demonstrated that GH-deficient little mice with the background of C3H showed comparable susceptibility to hepatocarcinogenesis compared with those with a B6 background; these results contrast with those in wild-type, GH-sufficient, C3H mice, which were significantly more susceptible compared with B6 (Bugni et al 2001). These results support reduced hepatic GH action in B6 mice.…”