COMPARISON OF THE EFFECTS OF DI-(2-ETHYLHEXYL)ADIPATE ON HEPATIC PEROXISOME PROLIFERATION AND CELL REPLICATION IN THE RAT AND MOUSE

The effects of di-(2-ethylhexyl)adipate (DEHA) have been compared in f emale F344 rats and female B6C3F1 mice fed diets containing 0-4.0% DEH A and 0-2.5% DEHA, respectively, for periods of 1, 4 and 13 weeks. In both the rat and mouse treatment with DEHA at all time points produced a dose-dependent increase in relative liver weight and hepatic peroxi some proliferation as demonstrated by the induction of peroxisomal (cy anide-insensitive palmitoyl-CoA oxidation) and microsomal (lauric acid 12-hydroxylase) fatty acid oxidising enzyme activities. The magnitude of induction of peroxisome proliferation was similar in both species. Replicative DNA synthesis was studied by implanting osmotic pumps con taining 5-bromo-2'-deoxyuridine during study weeks 0-1, 3-4 and 12-13. After 1 week DEHA treatment hepatocyte labelling index values were in creased in rats given 2.5 and 4.0% DEHA and mice given 0.6-2.5% DEHA. While DEHA treatment for 4 and 13 weeks did not increase labelling ind ex values in the rat, a sustained stimulation of replicative DNA synth esis was observed in mice given 1.2 and 2.5% DEHA. The results of this study demonstrate a species difference in the hepatic effects of DEHA , in that at some dose levels DEHA can produce a sustained stimulation of replicative DNA synthesis in mouse but not in rat liver. Sustained cell replication provides a better correlation with the observed form ation of liver tumours in chronic studies with DEHA in female mice, bu t not in female rats, than the magnitude of stimulation of hepatic per oxisome proliferation. (C) 1997 Elsevier Science Ireland Ltd.