Biochemical and immunological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and their relationship in rats

摘要

2,3,7,8-Tetrachlorodibenzo-p-dioxin, also called dioxin or TCDD, has been a major topic of environmental toxicology for many years. To study interstrain differences in its acute toxicity and related biochemical effects, the male Long-Evans (L-E) strain was chosen because of its lower sensitivity to TCDD than the more commonly used Sprague-Dawley (S-D) strain. Results obtained in male L-E rats showed that, as in S-D rats, feed intake and gluconeogenesis were suppressed by TCDD. Furthermore, the impairment of these two important sources of blood glucose resulted in hypoglycemia and death. Hepatic gluconeogenesis was reduced as a result of decreased activity of hepatic phosphoenolpyruvate carboxykinase (PEPCK). This effect occurred in a similar dose range in the L-E rat as in the S-D rat. Feed intake was decreased due to elevated serum tryptophan levels, which in turn were related to reduced liver tryptophan 2,3-dioxygenase (TdO) activity. However, these dose-responses occurred in a higher dose range in L-E rats than in S-D rats, which is the likely explanation for the lower susceptibility of the L-E rat to TCDD.;To broaden the scope of this dissertation, TCDD's immunotoxicity and its relationship to acute toxicity and associated biochemical effects were investigated. The male S-D rat in which the appropriate biochemical and toxicological data have been generated previously, was used for subsequent immunological studies. Examination of humoral immunity with the enzyme linked immunosorbent assay (ELISA) showed that TCDD exposure resulted in an early and enhanced IgG response to immunization with sheep red blood cells (SRBC). Investigation of cellular immunity using a delayed-type hypersensitivity (DTH) assay demonstrated that low doses of TCDD enhanced the DTH reaction, whereas high doses suppressed it. The potential of TCDD to induce or exacerbate autoimmune-like reactions was studied by the popliteal lymph node (PLN) assay.;A possible involvement of cytokines (IL-1 and TNF) in the biochemical and immunological effects of TCDD was investigated because of the many similarities in their actions to those observed with TCDD. Like TCDD, low levels of TNF and IL-1 stimulate immune function, whereas excess and/or sustained production of TNF and IL-1, as occurs in endotoxemia, suppress appetite and gluconeogenesis (mainly by inhibiting PEPCK), leading to debilitation of host defense functions. A time-course study in male S-D rats with a single high dose of TCDD revealed a transient increase of TNF$alpha$ and IL-1$beta$ message in liver. This demonstrated, for the first time, that TCDD by itself can affect levels of these cytokines in vivo. In rats immunized with an antigen, low doses of TCDD resulted in moderately increased levels of IL-1$beta$ message which is compatible with stimulation of the immune system as demonstrated earlier by in vivo assays. High doses of TCDD, on the other hand, led to greatly elevated abundance of both TNF$alpha$ and IL-1$beta$ mRNA, which appear to mediate both immune suppression and acute toxicity as well as associated biochemical effects of TCDD in rats. (Abstract shortened by UMI.).