title: Inhibition of acute TCDD toxicity by treatment with anti-tumor necrosis factor antibody or dexamethasone.
abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) acute toxicity is characterized in part by a wasting syndrome with depletion of adipose tissue. Tumor necrosis factor (TNF) induces a similar response during chronic infection. The similarities of these toxic effects led to a hypothesis that TNF plays a role in TCDD acute toxicity. To test this hypothesis pharmacologic doses of an antibody specific for murine TNF and the potent anti-inflammatory agent Dexamethasone (DEX) were used to inhibit TCDD toxicity in mice. TNF antibody treatment resulted in a 54% reduction in TCDD-mediated mortality while DEX treatment, a glucocorticoid agonist that inhibits transcription of TNF, reduced mortality by 92%. Cyp 1A1 induction, the most commonly measured TCDD-mediated response, was not blocked by DEX, demonstrating separation of this biochemical effect from acute toxic responses to TCDD. These data suggest that TCDD-mediated changes in the TNF pathway may be an important mechanism for acute TCDD toxicity.
authors.affiliation: Syntex Research, Palo Alto, California 94303.
authors.forename: M J
authors.initials: MJ
authors.lastname: Taylor
authors.forename: G W
authors.initials: GW
authors.lastname: Lucier
authors.forename: J F
authors.initials: JF
authors.lastname: Mahler
authors.forename: M
authors.initials: M
authors.lastname: Thompson
authors.forename: A C
authors.initials: AC
authors.lastname: Lockhart
authors.forename: G C
authors.initials: GC
authors.lastname: Clark
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D000918:Antibody Specificity; D001835:Body Weight / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D003907:Dexamethasone / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000072317:Polychlorinated Dibenzodioxins / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000502:physiology*
chemical_list: D000906:Antibodies; D000072317:Polychlorinated Dibenzodioxins; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System