Characteristics of 2,3,7,8-tetrachlorodibenzo-p-dioxin induced endotoxin hypersensitivity: association with hepatotoxicity.
Hepatic clearance is a major route of endotoxin detoxification. In the present study, the potential relationship between TCDD-induced endotoxin hypersensitivity and hepatotoxicity was examined. Acute doses of 50, 100, or 200 micrograms TCDD/kg body weight induced an endotoxin hypersensitive state in B6C3F1 mice as demonstrated by increased mortality 24-48 h following i.v. injection of endotoxin. This hypersensitive state occurred when endotoxin was administered 7 days following TCDD exposure, but not 1 day post-TCDD exposure. TCDD did not affect endogenous serum endotoxin levels. However, clearance of injected endotoxin was significantly inhibited following exposure to TCDD. Six hours post endotoxin treatment serum triglycerides were significantly increased in TCDD/endotoxin-treated mice compared to either treatment alone. Methylprednisolone and uridine were both examined in this model due to their roles in inflammation and RNA synthesis, respectively. Both compounds significantly reversed the mortality associated with the combined exposure. [3H]Uridine incorporation into liver was decreased following TCDD treatment alone, further suggesting impaired RNA synthesis. Studies performed on congenic mice indicate that the observed effects segregate with the Ah locus. The ability of methylprednisolone and uridine to reverse the mortality associated with TCDD/endotoxin treatment is consistent with an inflammatory response and impaired hepatic detoxification mechanisms. Thus, changes in hepatic handling of endotoxin, caused by progressive TCDD-induced liver dysfunction, may be responsible for the endotoxin hypersensitivity.
Rosenthal
G J
GJ
National Institute of Environmental Health Sciences, Systemic Toxicology Branch, Research Triangle Park, NC 27709.
Lebetkin
E
E
Thigpen
J E
JE
Wilson
R
R
Tucker
A N
AN
Luster
M I
MI
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001806:Blood Urea Nitrogen; D056486:Chemical and Drug Induced Liver Injury; D004147:Dioxins / Q000633:toxicity*; D004347:Drug Interactions; D004731:Endotoxins / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D008055:Lipids / Q000097:blood; D008107:Liver Diseases / Q000378:metabolism; D008775:Methylprednisolone / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D012313:RNA / Q000096:biosynthesis; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000235:genetics
D001786:Blood Glucose; D004147:Dioxins; D004731:Endotoxins; D008055:Lipids; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; D012313:RNA; D000410:Alanine Transaminase; D008775:Methylprednisolone