The influence of implantation of ectopic pituitary grafts (PGs) under the kidney capsule in male rats on the sex differences in response to promotion with a choline-deficient (CD) diet was studied in the livers of diethylnitrosamine (DEN)-initiated Wistar rats. Growth of enzyme-altered foci, liver regeneration in response to partial hepatectomy (PH) and hepatic c-myc expression were studied. The area per enzyme-altered focus was significantly larger in initiated males fed a CD diet for 10 weeks when compared with the corresponding females. The sex difference was more pronounced 1 week after a PH performed following 10 weeks on the diet. In males carrying PCs the area per focus was reduced to the same size as in females. Liver weight gain after PH was reduced in males, but not in females, by the CD diet, and the level in PG-bearing males was intermediary, significantly different from that of males without grafts. A significantly lower labeling index in surrounding, but not in focal, hepatocytes was observed in initiated, CD-treated males than in the corresponding females 1 week after PH. In initiated as well as in uninitiated males on a CD diet the expression of the c-myc gene was 3- to 4-fold higher when compared with males fed a choline-supplemented diet at the time of PH. The mRNA level in females fed a CD diet was ̃2.5-fold lower than in males, but still significantly above the level in females without the dietary treatment. A significant decrease in male c-myc expression was observed as a result of implantation of ectopic pituitaries. In conclusion, sex-differentiated promotion of DEN-initiated lesions with a CD diet is regulated by a pituitary influence on rat liver, in analogy with results preciously obtained in the resistant hepatocyte model and with dietary deoxycholic acid promotion. This might suggest that pituitary factors are major determinants of sex-differentiated promotion in rat liver.
Bibliographical noteFunding Information:
Dr A.Mode is gratefully acknowledged for providing the cytochrome P450|5^ clone. This work has been supported by the NIEHS, NIH (1RO1 CA57 925-O1), the Swedish Cancer Society, the Research Funds of the Swedish Academy of Science and the Lars Hierta and Ake Wiberg Memory Funds.