2,3,7,8-Tetrachlorodibenzo-p-dioxin causes increases in expression of c-erb-A and levels of protein-tyrosine kinases in selected tissues of responsive mouse strains.

Abstract

ABSTRACT2,3,7,8,-Tetrachlorodibenzo-p-dioxin (TCDD) administered in vivo causes drastic reduction in the weight of the mouse thymus at low doses (e.g., 30 pg/kg single i.p. i jection), the reduction becoming statistically significant after 2 days. To understand the cause for such thymic involution TCDD-evoked changes in various biochemical parameters in this tissue were examined. The most noticeable change was observed in the increased activity of specific protein-tyrosine kinases and protein kinase C and an increased level of p21-associated binding of [3H]GTP. Since no significant change was observed with cAMP-stimulated protein kinases and cAMP levels, the above changes appear to be a selective effect on these special classes of proteins. As a result of a time sequence study it has become apparent that the rise in proteintyrosine kinase activities becomes significant within 24 hr, whereas the rise in protein kinase C does not become sicant until 48 hr. Among protein-tyrosine kinases, pp60c-and probably pps6lskT were found to be significantly elevated by TCDD treatment. In view of similarities between TCDD and thyroid hormones in causing thymic involution, the levels of c-erb-A expression were assessed in the liver by using avian 32P-labeled v-erb-A probe and RNA transfer blot hybridization technique. The results clearly indicate that TCDD has the property to elevate levels of mRNA bearing homology to v-erb-A. Such changes in c-erb-A expression and proteintyrosine kinase occurred only in TCDD-susceptible (responsive) strains but not in tolerant (nonresponsive) strains of mice at the dose tested. Based on such observations a hypothesis has been proposed that TCDD owes its potency to its ability to stimulate the expression of one of a family of DNAs bearing homology to v-erb-A and that one of the major consequences of such an action is stimulation of various tyrosine kinases.2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a very toxic, teratogenic, and carcinogenic chemical (1-4). In addition to these deleterious effects, TCDD is known to cause atrophy of thymus (5, 6) in most experimental animals. Since this lesion occurs at sublethal doses of TCDD at an early stage of poisoning, it has been used by several scientists (e.g., refs. 2, 7, 8) as a sensitive indicator of TCDD poisoning.As for the possible cause for such a thymic lesion, Neal et al. (9) have shown that an increase in serum glucocorticoid levels is unlikely. Poland and Glover (7) have found that involution of thymus occurs at low doses of TCDD (30 ,ug/ kg) in sensitive (responsive) strains of mice but only at high doses in tolerant (nonresponsive) strains of mice. These workers used such differential responses among mouse strains as a biochemical indicator for the involvement of specific cytosolic TCDD binding proteins (i.e., TCDD receptor) in the final expression of thymic involution.Our research group has been studying the effects of TCDD on the hepatic plasma membrane receptors. To date, the plasma membrane-bound epidermal growth factor (EGF) r...

Developmental Effects of Dioxins

“…Increases in tyrosine phosphorylation appear to be a rapid and sensitive response to dioxin exposure, both in vivo (19)(20)(21)(22) and in vitro (19,23,24). The possibility of two roles for the Ah receptor, both as a transcriptional enhancer and as a regulator of second messengers such as tyrosine phosphorylation, appears to be similar to what has been described for the steroid hormones (25,26).…”

2,3,7,8-Tetrachlorodibenzo-p-dioxin-Induced Activation of a Protein Tyrosine Kinase, pp60src, in Murine Hepatic Cytosol Using a Cell-Free System

“…The activation of PKs has been clearly shown to be dependent on TCDD binding to the AHR, a cytosolic, ligandactivated transcription factor of the basic helix-loop-helix type (14,15). Evidence of AHR dependence for TCDD-induced PK activation includes dose-response relationships, structure-activity relationships, the use of responsive and nonresponsive strains of animals, and the use of AHR blockers (7)(8)(9)(10)(11)(12)(13)(14)(15).…”

Dioxin-dependent activation of murine Cyp1a-1 gene transcription requires protein kinase C-dependent phosphorylation.

“…Polycyclic hydrocarbons such as benzo[a]pyrene, which are proven ligands for the Ah receptor, can cause mutation and tumor initiation following metabolic potentiation (60). It has been shown that TCDD stimulates kinase activities in vivo, particularly those of protein kinase C and various tyrosine kinases (5,6). An understanding of the events leading to the simultaneous activation of the protein kinase C second messenger pathway (and perhaps others) and of mammalian CYPJAl transcription may provide valuable insight into the molecular basis of Ah receptor-mediated toxicity, tumor initiation and promotion, and perturbation of growth and differentiation.…”