Toxicity of 2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD) to the Human Thymus After Implantation in SCID Mice

Abstract

There are conflicting data with regard to the sensitivity of the human immune system to the toxic action of the highly toxic environmental pollutant 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD). SCID mice engrafted with human fetal thymus and liver tissue fragments (SCID-hu mice), which sustain normal human T cell differentiation in the thymus graft, were used to directly assess the sensitivity of the human thymus for TCDD. Wistar rats and SCID-hu mice were exposed to 1, 5, or 25 μg TCDD/kg body weight. Histopathologic effects were evaluated for rat thymus and transplanted human thymus on Day 4 after exposure. The relative size of the cortex showed a dose-dependent decrease in both the normal rat thymus and grafted human thymus (significant at 25 μg/kg). SCID-ra mice (SCID mice with a fetal rat thymus and liver graft) were used as an intermediate model between the normal rat and SCID-hu mice, and were exposed to the same dose levels of TCDD. However, 90% of the SCID-ra mice developed a cutaneous graft-versus-host reaction, associated with lymphodepletion of the rat thymus grafts, and hence a limited number of SCID-ra mice were available for evaluation of TCDD effects. The data obtained in SCID-ra mice were in line with those in normal rat and grafted human thymus. In gas chromatography/mass spectrometry analysis, TCDD tissue concentrations in the normal rat thymus and grafted human thymus were similar. We conclude that the human thymus serves as a target for TCDD, and that the human thymus and the Wistar rat thymus display a comparable sensitivity to the toxic action of TCDD.