Modulation of 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity in F344 rats by di(2-ethylhexyl)phthalate.
The effects of cotreatment with a hyperlipidemic chemical, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and a hypolipidemic agent, di(2-ethylhexyl)-phthalate (DEHP), on lipid metabolism and toxicologic responses were studied in F344 rats. Treatment with TCDD alone (160 micrograms/kg) caused an increase in serum triglycerides and cholesterol while treatment with DEHP alone (2 g/kg/day) caused a decrease in triglycerides and cholesterol versus untreated controls. When administered before or after TCDD, DEHP caused a decrease in TCDD-induced hyperlipidemia. This change was attributed to enhanced hepatic peroxisomal beta-oxidation and decreased hepatic lipid synthesis resulting from treatment with DEHP. TCDD treatment produced a fatty liver, as determined by gravimetric analysis of extracted lipid and microscopic examination of liver sections which revealed extensive cytoplasmic vacuolization that stained positive with Oil Red 0, but did not induce peroxisomal beta-oxidation. Thus, an increase in hepatic or serum lipid levels is not sufficient for induction of peroxisome proliferation. Neither TCDD nor DEHP treatment affected mitochondrial beta-oxidation. Pretreatment of rats with DEHP, followed by daily exposure to this hypolipidemic agent after treatment with TCDD, had a partial protective effect against TCDD-induced fatty liver, body weight loss and mortality. Microscopic examination of liver sections confirmed the suppression of TCDD-induced fatty liver by pretreatment with DEHP. When DEHP treatment was initiated after the TCDD dose, there was less protection against the above parameters of TCDD toxicity. This study demonstrates that TCDD-induced fatty liver, hyperlipidemia and mortality can be antagonized by treatment with a hypolipidemic agent such as DEHP.
Tomaszewski
K E
KE
National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
Montgomery
C A
CA
Melnick
R L
RL
D042962:Acyl-CoA Oxidase; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D004051:Diethylhexyl Phthalate / Q000494:pharmacology* / Q000633:toxicity; D004147:Dioxins / Q000494:pharmacology*; D004347:Drug Interactions; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000139:chemically induced / Q000473:pathology; D007700:Kinetics; D007928:Lethal Dose 50; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008830:Microbodies / Q000201:enzymology; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism; D010795:Phthalic Acids / Q000494:pharmacology*; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344; D014280:Triglycerides / Q000097:blood; D014617:Vacuoles / Q000473:pathology
D004147:Dioxins; D005227:Fatty Acids; D010795:Phthalic Acids; D000072317:Polychlorinated Dibenzodioxins; D014280:Triglycerides; D002784:Cholesterol; D004051:Diethylhexyl Phthalate; D010088:Oxidoreductases; D042962:Acyl-CoA Oxidase