Sex-dependent promoting effect of polychlorinated biphenyls on enzyme-altered islands induced by diethylnitrosamine in rat liver

Abstract

The promoting effect of Clophen A 50, a commercial mixture of polychlorinated biphenyis (PCBs) on preneoplastic islands, initiated by diethylnitrosamine (DEN), was studied in male and female Sprague-Dawley rats. The islands were identified histochemically by loss of adenosine-5'-triphosphatase (ATPase) and/or emergence of gamma-glutamyltranspeptidase (GGTase). Treatment with 12 × 8 mg DEN/kg body wt./day initiated a similar number and total area of islands in males and females. Additional weekly application of Clophen A 50 (50 or 100 mg/kg body week, for 7 weeks) enhanced the number of ATPase-deficient islands 3-fold in males and 9-fold in females. The total area was increased 4-fold in males and 15-fold in females. Number and area of GGTasepositive islands were similarly enhanced. The emergence of a small number of islands after application of Clophen A 50 alone may indicate a weak carcinogenic potency. PCB treatment caused an increase in liver weight, which amounted to ∼55% in males and 20% in females compared to controls. This increase is partly due to cell hypertrophy, as indicated by determination of cell size. The mitogenic activity of Clophen A 50 was evaluated by measurement of the mitotic index of unaltered hepatocytes at 24, 48 h, and 7 days after application of a single dose (100/mg/kg body wt.) of Clophen A 50. The mitotic index in control animals of both sexes was ∼0.3%, and was enhanced ∼8-fold in males, 24 h after PCB treatment. In females only a slight, non-significant increase was observed. The results indicate that the sex-dependent promoting effect of Clophen A 50 is independent from its mitogenic action.