Characterization of phenotypic alterations induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin on thymocytes in vivo and its effect on apoptosis.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly toxic environmental pollutant and is well known for inducing thymic atrophy in mice, although the exact mechanism of its action remains unclear. Recent studies from our laboratory demonstrated that TCDD induces apoptosis in thymocytes and that Fas- mice (lpr/lpr) were more resistant to TCDD-induced immunotoxicity when compared to the Fas+ wild-type mice. Inasmuch as induction of apoptosis is associated with alterations in adhesion molecule expression, in the current study we analyzed the expression of a variety of surface molecules on thymocytes treated with TCDD in vivo. Interestingly, in thymocytes from mice treated with a single dose of 50 micrograms/kg body wt of TCDD, there was a significant increase in the density of expression of CD3, alpha beta TCR, CD44, and IL-2R, and a decrease in the expression of J11d, CD4, and CD8 molecules when compared to the control thymocytes. These alterations were first visible 3 days after TCDD treatment and increased on Days 5 and 10 posttreatment. Furthermore, most of the alterations in the density of expression of various markers were dose dependent with minimal but significant changes at 0.1 microgram and maximum alterations at 50 micrograms/kg body wt of TCDD. At most lower concentrations (0.1-5 micrograms/kg), TCDD caused alterations in the density of cell surface markers but not in the percentage of cells expressing a specific molecule. It is striking that the phenotypic alterations were similar to those seen in normal thymocytes undergoing spontaneous apoptosis in vitro as previously reported. Together, the current study suggests that TCDD treatment induces phenotypic changes in thymocytes that are similar to those seen in normal thymocytes undergoing apoptosis. Also, because detection of apoptosis in vivo is difficult, phenotypic alterations in the density of thymocyte surface molecules may serve as a useful biomarker for toxicity involving apoptosis.
Kamath
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Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg 24061, USA.
Nagarkatti
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PS
Nagarkatti
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M
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D015415:Biomarkers; D005260:Female; D005434:Flow Cytometry; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects*; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects; D013997:Time Factors
D000954:Antigens, Surface; D015415:Biomarkers; D000072317:Polychlorinated Dibenzodioxins