Expression of Cytokines and Immunoglobulins in Toxicant-Exposed Human Lymphocytes

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Although there is significant evidence that 2,3,7,8-tetrachlorodibenzodioxin (TCDD) alters lymphocyte function in mice, there have been very few studies which examine the effects of TCDD on human lymphocytes. While there have been a number of inadvertent exposures to TCDD, via industrial accidents or environmental contamination, there have been no consistent immunological defects observed in exposed individuals. Studies in German chemical workers have demonstrated alterations in lymphocytes subpopulations and functional parameters 20 years after exposure to TCDD. As part of a continued effort to assess the health effects of environmental exposures to TCDD it is imperative that we examine endpoints which have the potential to be sensitive predictors of human exposure and to correlate these biomarkers with blood TCDD levels, determine influence of potential confounding variables on biomarker expression, and evaluate inter- and intra-individual variation. Identification of additional biomarkers may aid in identifying individuals or populations at greater risk of developing disease or neoplasia after exposure to dioxins and related compounds. Samples of peripheral blood lymphocytes were obtained from several cohorts of control or TCDD-exposed individuals. These samples were mitogen-stimulated in culture, alone or in the presence of TCDD, and the cells and culture supernatants harvested after 72 hr. To date we have examined supernatants from a group of workers who were employed at a chemical plant in Hamburg-Moorfleet, Germany operated by Boehringer-Ingelheim from 1951-1984 that produced organochlorine herbicides and pesticides (including 2,4,5-trichlorophenoxyacetic acid) and opioids. TCDD contamination at this plant was confirmed in 1984 and significant increases in mortality have been observed in a cohort of workers employed at this plant for at least 3 months from 1952-1984. Peripheral blood for lymphocyte isolation and serum dioxin analysis was obtained from a cohort of 110 individuals in 1992, in collaboration with clinicians at the University of Mainz (Detlev Jung and Johannes Konietzko) and a biostatistician at the German cancer Research center. In vitro treatment with TCDD resulted in a significant decreases in the mitogen-stimulated production of the T Helper 1 type (TH1) cytokines Interleukin 2 (IL2) and Interferon gamma (IFNgamma) in ymphocyte cultures from this cohort. We believe the alterations TH1 cytokines are a result of the in vitro exposure as there is limited correlation with standard biomarkers of TCDD exposure such as total TCDD plasma levels or total plasma TEQ. In contrast, there appears to be a dose-related correlation between individual TCDD body burden and decreased secretion of the T Helper 2 type cytokine Interleukin 4. Significant correlations were also seen between in vitro TCDD-inducible ethoxyresorufin-O-deethylase activity and secretion of tumor necrosis factor alpha. While it appears that there may be some significant effects on immunoglobulin (Ig) secretion, particularly for IgA and IgG2, interindividual variability is quite high, and sophisticated statistical analyses will be required to tease out exposure-specific effects. In collaboration with Dr. Joseph Haseman, the dataset is undergoing multivariate analysis to examine correlations between immunologic effects and in vivo and in vitro biomarkers of exposure, and to determine the effects of confounding variables such as gender, smoking status, etc.