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- Funseth, Eva, et al.
(författare)
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Effects of coxsackievirus B3 infection on the acute-phase protein metallothionein and on cytochrome P-4501A1 involved in the detoxification processes of TCDD in the mouse
- 2002
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Ingår i: Science of the Total Environment. - 0048-9697 .- 1879-1026. ; 284:1-3, s. 37-47
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Tidskriftsartikel (refereegranskat)abstract
- During acute infections, the synthesis of acute-phase proteins and other proteins participating in the host defence are stimulated in the liver and kidney. In previous studies of coxsackievirus B3 (CB3) infection in mice, we found that cadmium (Cd) accumulates in the kidney, whereas 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) accumulates in the liver. To study if CB3 infection affects the synthesis of the Cd-binding protein metallothionein (MT) and the TCDD-binding/detoxifying cytochrome P-450 (CYP-450) isozyme CYP1A1, the basal and TCDD-induced levels of serum MT and liver CYP1A1 isozyme were determined in healthy and CB3-infected A/J mice. Furthermore, because interferons affect CYP450 activity, the serum levels of the interferons alpha (IFN-alpha) and -beta (IFN-beta) were measured in CB3-infected mice and in mice treated with the interferon-inducer polyinosinic/polycytidylic acid (poly I/C). Virus or poly I/C was administered intraperitoneally (i.p.) on day 0 and 500 ng TCDD/kg bodyweight on day 1. On day 4, CB3 infection had induced MT approximately 10-fold, regardless of TCDD treatment (P < 0.01 in infected mice and P < 0.001 in infected, TCDD-treated mice). TCDD alone induced a 10-fold increase in CYP1A1 activity (P < 0.001), whereas infection alone suppressed the normal CYP1A1 activity by 75% (P < 0.001). Infection also suppressed the TCDD-induced CYP1A1 activity by approximately 30% (n.s.). Poly I/C suppressed CYP1A1 by 20-25% (n.s.) at both basal and TCDD-induced levels. Serum IFN-alpha and IFN-beta levels were undetectable in controls, in TCDD-treated and in the poly I/C-treated groups on day 4, probably because the short IFN peak is detectable only hours after injection. Conversely, on day 4 of the infection, IFN-alpha and IFN-beta were consistently raised in the TCDD-treated infected mice, whereas increased IFNs as a result of infection alone could be detected in only one individual. These results suggest that the normal host responses during acute infections down-regulate detoxifying processes in favour of acute-phase protein synthesis. This may explain the observed changed pattern of accumulation, excretion and toxicity of the environmental pollutants cadmium and TCDD during this common virus infection.
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- Funseth, Eva
(författare)
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Interactions between the environmental pollutant 2,3,7,8- tetrachlorodibenzo-p-dioxin and coxsackievirus infection : Experimental studies in mice
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis focuses on the interactions between 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and infection. A model of human coxsackievirus type B3 (CB3) infection, adapted to A/J mice, was used.The effects on some immune cell populations and host resistance to CB3 infection were studied immediately after TCDD exposure and 3 months later. NK cell activity increased in blood and spleen at both samplings, whereas T cell proliferation decreased by 60-65%. This finding was interpreted as a compensatory activation of NK cells because of T cell suppression. At 3 months, mortality was found to increase during early infection despite that TCDD limited the inflammatory lesions and virus count in themyocardium. The size of the inflammatory lesion correlated positively to myocardial virus and calcium content, but negatively to the magnesium content. Calcification is a negative prognostic sign and magnesium deficiency increases the risk for arrhythmias.Despite the beneficial effects in the myocardium, immunosuppressive effects of TCDD may have changed the virulence and pathogenesis in other organs. TCDD tissue accumulation was determined during ongoing CB3 infection. Infection increased the accumulation in the organs actively involved in the infectious process, i.e. the thymus, spleen, heart and pancreas, but also in the brain. In the thymus, the toxicity threshold concentration was surpassed during infection. TCDD administered before infection was redistributed during the infection, chiefly to the above-mentioned organs. The TCDD concentration also markedly increased in adipose tissue, a major TCDD storage depot, suggesting increased retention in the body. TCDD induced cytochrome P450 1A1 (CYP1A1) in the liver tenfold, whereas infection suppressedCYP1A1 activity by 75%. These results suggest that CB3 infection down-regulates TCDD metabolism and elimination, which helps explain the increased TCDD accumulation observed in the present study. This could also increase the risk for toxic insult of TCDD in target organs. Since infectious agents are common environmental factors that can influence the toxicity of chemical compounds, this should be considered in risk assessments of toxic substances present in the environmental setting.
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