Sex differentiation of liver functions has been shown to be attenuated in preneoplastic rat liver nodules. The present study was performed to investigate whether nodules from male rats are to some extent withdrawn from the normal growth hormone (GH) regulation of these functions. Male and female Wistar rats were treated according to a modified resistant hepatocyte model (RH-model), with diethylnitrosamine initiation and promotion with intragastric administration of 2-acetylaminofluorene (2-AAF) combined with partial hepatectomy (PH). Eleven months post-initiation male rats were treated with either human (hGH) or bovine growth hormone (bGH) or ovine prolactin (oPRL) by continuous infusion for 1 week. The mRNA expression of a number of genes known to be sex differentiated in liver from adult control rats was compared in nodular and surrounding tissue from nodule-bearing male, female and hormone-treated male rats. The basal mRNA expression of the female-predominant cytochrome P4502C12 (CYP2C12) was increased and the male-predominant CYP2C11 was decreased in liver nodules from male rats compared with the surrounding liver. Expression of the prolactin receptor (PRL-r; female > male) and the steroid 5α-reductase (female > male) genes was decreased in male nodules, whereas no difference was observed with respect to GHreceptor (GH-r; female > male) expression in nodules versus surrounding tissue. Early nodules obtained from males treated according to the original RH-model (dietary 2-AAF, 0.02%) and isolated 2 weeks after completion of the 2-AAF/PH treatment showed significantly lower GH-r mRNA levels than the total liver tissue. In hepatocellular carcinomas from hormonally unmanipulated males 11 months post-initiation the decrease in PRL-r expression was even more pronounced than in the nodules and a significant decrease in GH-r expression was seen. In female nodules the only significant difference with respect to the sex differentiated parameters was a lower 5α-reductase expression than in the surrounding tissue. Continuous infusion of both hGH and bGH feminized the expression of all the sex differentiated genes in male tissues and eliminated the previously detected differences between nodules and surrounding tissue. oPRL also eliminated the differences between nodules and surrounding tissue in males and partly feminized the expression of both the 5αreductase and the PRL-r genes. Although the expression of several sex differentiated parameters in liver nodules is altered compared with surrounding tissue, the preneoplastic lesions respond adequately to the feminizing effect of continuous GH infusion, thereby indicating that nodular tissue is not withdrawn from the normal endocrine control of rat liver.
Bibliographical noteFunding Information:
Dr Stefan Andersson is gratefully acknowledged for providing a 5a-reductase cDNA clone. The construct for the PRL-r gene was kindly supplied by Dr John Robertson and the cDNA for the GH-r gene was originally obtained from Dr Lawrence Mathews. The present study was supported by grants from the NIH (1RO1, CA 57925-02) and the Swedish Cancer Society.