Comparison of the effects of di-(2-ethylhexyl)adipate on hepatic peroxisome proliferation and cell replication in the rat and mouse

Abstract

The effects of di-(2-ethylhexyl)adipate (DEHA) have been compared in female F344 rats and female B6C3F1 mice fed diets containing 0–4.0% DEHA 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 peroxisome proliferation as demonstrated by the induction of peroxisomal (cyanide-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 containing 5-bromo-2′-deoxyuridine during study weeks 0–1, 3–4 and 12–13. After 1 week DEHA treatment hepatocyte labelling index values were increased 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 index values in the rat, a sustained stimulation of replicative DNA synthesis 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 formation of liver tumours in chronic studies with DEHA in female mice, but not in female rats, than the magnitude of stimulation of hepatic peroxisome proliferation.