Thymus, TCDD

Atrophy of the thymus is a consistent finding in mammals poisoned by 2,3,7,8-TCDD, and suppression of thymus-dependent cellular immunity, particularly in young animals, may contribute to their death. Although the mechanisms of 2,3,7,8-TCDD toxicity are unclear, research areas include the role of thyroid hormones (Rozman et al. 1984) interference with plasma membrane functions (Matsumura 1983) alterations in ligand receptors (Vickers et al. 1985) the causes of hypophagia (reduced desire for food) and subsequent attempts to alter or reverse the pattern of weight loss (Courtney et al. 1978 Seefeld et al. 1984 Seefeld and Peterson 1984) and excretion kinetics of biotransformed metabolites (Koshakji et al. 1984). 

Apart from general toxic action, dioxins, in particular 2,3,7,8-TCDD, cause thymus involution and immunodeficiency, however, less pronounced than in die event of HIV infection. Experiments with mice have shown that cell-mediated immunity was suppressed even at doses of 0,04 mcg/kg. 

Faith, R.E. and Moore, J.A., Impairment of thymus-dependent immune functions by exposure of the developing immune system to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), J. Toxicol. Environ. Health, 3, 451, 1977... 

In summary, although numerous AhR-dependent changes in the bone marrow and thymus have been found in TCDD-treated mice, it appears that these effects are self-limiting in adult mice, as T and B cell numbers are not reduced in secondary lymphoid tissue except after exposure to high doses of TCDD or in the context of an adaptive immune response. More subtle effects, such as changes in the antigenic specificity of peripheral T and B lymphocyte populations, have not been documented. 

A particularly potent immunosuppressive chemical is TCDD, dioxin. This inhibits the differentiation of T cells by damaging the epithelial cells in the cortex of the thymus. These cells are involved in the maturation of T cells. A receptor is involved with this toxic effect, the AHR receptor, to which TCDD binds very strongly. The receptor is expressed in the thymus. Mice, which to do not express this receptor, do not show this particular toxic effect of TCDD even at 10 times higher doses. 

TCDD. Decreased thymus weight after 2,3,7,8-TCDD exposure was observed in rats dosed by gavage with 0.71 g/kg/day for 6 weeks (Vos et al. 1973), in the F3 generation of rats receiving... 

TCDD to young adult male Leeds strain rats (Badesha et al. 1995). A 30-day exposure to approximately 0. 1 g/kg/day (or a total dose of approximately 3 g/kg) resulted in an exposure duration-dependent reduction of in vitro lipopolysaccharide-induced production of interleukin-1 in cultures of their splenic macrophages. A 180-day exposure to approximately 0.017 g/kg/day suppressed the production of interleukin-2 by either concanavalin A or phorbol ester/calcium ionophore stimulation, and reduced the lectin-induced proliferation of splenic T cells. The authors concluded that exposure to a low dietary dose of 2,3,7,8-TCDD suppresses the functions of several T-cell subsets. The highest NOAEL value for immunological effects (decreased thymus weight) was 0.0007 g/kg/day... 

The only information regarding immunological effects in animals after dermal exposure to CDDs was obtained from an intermediate-duration study in HRS/J mice (Hebert et al. 1990). Mice dermally exposed to 0.01 g 2,3,7,8-TCDD 2 days per week for 20 weeks had decreased thymus/body weight ratio. No effects were observed at 0.005 g. 

Utilize an in vivo bone marrow-thymus reconstitution model and mouse strains with arrested T-cell development to define the cellular and molecular targets of 2,3,7,8-TCDD that lead to thymic atrophy, and determine how these events relate to its overall action on the immune system. Dr. Gasiewicz is also determining what controls the functional activity of the Ah receptor, what target genes are affected in sensitive tissues, and how the modulated expression of these genes leads to the toxic responses observed after exposure to... 

De Heer C, Schuurman H-J, Liem AKD, et al. 1995. Toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to the human thymus after implantation in SCID mice. Toxicol Appl Pharmacol 134 296-304. 

Dencker L, Hassoun E, D Argy R, et al. 1985. Fetal thymus organ culture as an in vitro model for the toxicity of 2,3,7,8-TCDD and its congeners. Mol Pharmacol 27 133-140. 

Madsen C, Larsen JC. 1989. Relative toxicity of chlorinated dibenzo-para-dioxins, and dibenzofiirans measured by thymus weight and liver-enzyme induction in perinatally dosed rats 2,3,7,8-TCDD, 2,3,4,7,8-PCDF, 1,2,3,7,8-PCDD. Chemosphere 18 955-966. 

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