Hepatic peroxisome (microbody) proliferation in rats fed plasticizers and related compounds

Abstract

Male rats were fed the plasticizers di-(2-ethylhexyl) phthalate (DEHP), di-(2-ethylhexyl) adipate (DEHA), di-(2-ethylhexyl) sebacate (DEHS), adipic acid, and diethyl phthalate at a dietary concentration of 2% for 3 weeks. Hepatic peroxisome proliferation in association with an increase in liver size, increase of hepatic activities of the peroxisome-associated enzymes catalase and carnitine acetyltransferase, and hypolipidemia were observed in animals treated with DEHP, DEHA, and DEHS but not in animals fed adipic acid and diethyl phthalate. To relate structure to biological activity, additional groups of rats were fed 2-ethylhexyl alcohol (a metabolite of DEHP), hexyl alcohol. 2-ethylhexanoic acid, hexanoic acid, 2-ethylhexyl aldehyde, hexylaldehyde, and 2-ethylhexyl amine at a 2% dose level. The changes induced by 2-ethylhexyl alcohol and 2-ethylhexanoic acid were comparable to those induced by DEHP, DEHA, and DEHS, suggesting that 2-ethylhexyl alcohol is the active part of the molecule responsible for peroxisome proliferation. 2-Ethylhexyl aldehyde induced a moderate increase in peroxisome population. No effect on hepatic peroxisomes or their associated enzymes was induced by the straight-chained analogs hexyl alcohol, hexanoic acid, and hexyl aldehyde. The hepatic effects of plasticizers capable of inducing peroxisome proliferation are similar to those resulting from treatment with clofibrate and other hypolipidemic drugs.