Toxicological Sciences 60, 327-337 (2001)
Copyright © 2001 by the Society of Toxicology
REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY |
Increased Tumor Necrosis Factor-
Production by Peripheral Blood Leukocytes from TCDD-Exposed Rhesus Monkeys
* Department of Physiology, Dartmouth Medical School, Lebanon, New Hampshire 03756;
Harlow Center for Biological Psychology; University of Wisconsin, Madison, Wisconsin 53715;
Department of Obstetrics and Gynecology, University of Tennessee, Memphis, Tennessee 38103; and
§ National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709
Previous work has shown that exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is associated with a dose-dependent increase in the incidence and severity of endometriosis in the rhesus monkey. Studies also suggest that immune mechanisms participate in TCDD-mediated toxicity and the pathogenesis of endometriosis. Thirteen years after TCDD treatment was terminated, we characterized the phenotypic distribution of peripheral blood mononuclear cells (PBMC) from TCDD-exposed and -unexposed rhesus monkeys and determined the ability of these cells to produce cytokines and exert cytolytic activity against NK and T-cell-sensitive cell lines. We also determined whether elevated serum levels of TCDD, dioxin-like PHAH congeners, and triglycerides correlated with changes in PBMC phenotype or function. For all animals, TCDD exposure correlated with increased PBMC tumor necrosis factor-alpha (TNF-
) secretion in response to stimulation by T-cell mitogen and decreased cytolytic activity against NK-sensitive target cells. Furthermore, increased production of this cytokine by PHA-stimulated leukocytes was associated with elevated serum triglyceride levels. Leukocyte TNF- secretion in response to viral antigen and PBMC production of interferon gamma (IFN
), IL-6, and IL-10 following exposure to mitogen or antigen were unaffected by previous TCDD treatment. Although TCDD exposure was not associated with changes in PBMC surface antigen expression, elevated serum concentrations of TCDD, 1,2,3,6,7,8-hexachlorodibenzofuran and 3,3',4,4',5-pentachlorobiphenyl correlated with increased numbers of CD3+/CD25- and CD3-/CD25+ leukocytes and enhanced secretion of TNF- by mitogen-stimulated PBMC. These findings indicate that TCDD-exposed rhesus monkeys with endometriosis exhibit long-term alterations in systemic immunity associated with elevated serum levels of specific PHAH congeners.
Key Words: endometriosis; rhesus; environmental toxicants; dioxin; TCDD; PCBs (polychlorinated biphenyls); dioxin-like chemicals.
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