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MORTALITY IN DIOXIN-EXPOSED MICE INFECTED WITH INFLUENZA: MITOCHONDRIAL TOXICITY (REYES-LIKE SYNDROME) VERSUS ENHANCED INFLAMMATION AS THE MODE OF ACTION
Citation:
Luebke, R W., C B. Copeland, L. R. Bishop, M. J. Daniels, AND M I. Gilmour. MORTALITY IN DIOXIN-EXPOSED MICE INFECTED WITH INFLUENZA: MITOCHONDRIAL TOXICITY (REYES-LIKE SYNDROME) VERSUS ENHANCED INFLAMMATION AS THE MODE OF ACTION. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 69(1):109-116, (2002).
Description:
Abstract
Increased mortality following influenza A infection was reported in B6C3F1 mice exposed to a low (0.01 g/kg) dose of dioxin. However, mortality was not associated with increased viral load and antibody titers to the virus were not decreased at doses of TCDD 10 g/kg, suggesting that viral overgrowth, secondary to immunosuppression, was not the proximate cause of death. We tested the hypothesis that mitochondrial toxicity and dysfunction, similar to Reyes syndrome (RS) in humans, is responsible for increased mortality in dioxin-exposed, infected B6C3F1 female mice, based on similarities in the biochemical and immunological events that occur in RS and in TCDD-exposed animals. Dose-related effects of TCDD alone, infection with influenza A alone and combined TCDD exposure/influenza infection were evaluated. Mice were given a single i.p. injection of 0, 0.001, 0.01, 0.1 or 1.0 g TCDD/kg, 7 d before infection by intranasal instillation of an estimated LD10-20 of influenza A Hong Kong/8/68 (H3N2) and were terminated 1, 7 and 10 d after infection. Serum, bronchoalveolar lavage fluid (BALF) and lung tissue were collected for various measurements, including clinical chemistries, cell counts, cytokine analysis and viral titers. TCDD exposure did not increase mortality, virus titers were similar at all doses of TCDD and there was no dioxin-related effect on serum NH3 or glucose concentrations, two prominent indicators of the altered mitochondrial oxidative metabolism typically observed in RS. A study was therefore conducted at higher doses of TCDD. A single injection of 0, 0.025, 0.5 or 10 g TCDD/kg preceded infection by 7 days; sub-groups of noninfected control and highest dose group (10 g TCDD/kg) mice were also evaluated for biochemical and immunological endpoints on the equivalent of infection day 4 to provide baseline data. Five days after infection the same endpoints described above were evaluated. The 10 g TCDD/kg dose increased mortality, but once again did not increase virus titer; as in previous experiments, serum biochemistry endpoints did not support mitochondrial dysfunction. Rather, constituents in BALF implicate increased pulmonary inflammation as the mode of TCDD action. These results suggest that RS is an unlikely explanation for increased influenza mortality in TCDD-exposed mice.
Key words: dioxin, immunotoxicity, host resistance, Reye's Syndrome, influenza infection, pulmonary inflammation.