Peroxisome proliferation due to di (2-ethylhexyl) adipate, 2-ethylhexanol and 2-ethylhexanoic acid.
The dose-response relationships for peroxisome proliferation due to Di (2-ethylhexyl) adipate (DEHA), 2-ethylhexanol (EH), 2-ethylhexanoic acid (EHA) have been investigated in rats and mice. Linear dose-response relationships were observed for induction of cyanide-insensitive palmitoyl CoA oxidation (PCO), used as a enzyme marker of peroxisome proliferation, by DEHA, EH and EHA in both species. Relative liver weights were also increased in a dose related manner. On a molar basis, DEHA was twice as potent as EH or EHA which were equipotent and PCO was stimulated to a greater extent in male mice than in rats or female mice. At doses above 8 mmol/kg/day, EH was toxic to rats (both sexes) and similarly EHA at 13.5 mmol/kg/day lead to the death of female rats. In a attempt to explain the species difference in carcinogenicity of DEHA previously reported, we also used Fischer 344 rats and B6C3F1 mice. DEHA administration (2.5 g/kg/day) to Fischer 344 rats and B6C3F1 mice lead to toxicity in female rats. Relative liver weights were increased in a dose related fashion by DEHA administration to both rats and mice, PCO but not catalase was markedly increased (up to 15 fold in male rats). Light microscopy examination indicated some glycogen loss, a dose related hypertrophy and increased eosinophilia in both rats and mice. Electron microscopy confirmed peroxisome proliferation accompanied by a marked reduction of lipid in the centrilobular hepatocytes. These data suggest EHA to be the proximate peroxisome proliferator derived from DEHA.(ABSTRACT TRUNCATED AT 250 WORDS)
Keith
Y
Y
Département de Biochimie et Toxicologie Alimentaires, ENS.BANA, Dijon, France.
Cornu
M C
MC
Canning
P M
PM
Foster
J
J
Lhuguenot
J C
JC
Elcombe
C R
CR
D000272:Adipates / Q000633:toxicity*; D000818:Animals; D002208:Caproates / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity; D005260:Female; D000441:Hexanols / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008830:Microbodies / Q000187:drug effects*; D008854:Microscopy, Electron; D009929:Organ Size / Q000187:drug effects; D010084:Oxidation-Reduction; D051381:Rats; D011916:Rats, Inbred F344
D000272:Adipates; D002208:Caproates; D002273:Carcinogens; D000441:Hexanols; C040668:2-ethylhexanoic acid; C013966:dioctyl adipate; C034017:2-ethylhexanol