Interactions between the environmental pollutant 2,3,7,8- tetrachlorodibenzo-p-dioxin and coxsackievirus infection : Experimental studies in mice

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.