Effects of in vivo-administered 2,3,7,8-tetrachlorodibenzo-p-dioxin on receptor binding of epidermal growth factor in the hepatic plasma membrane of rat, guinea pig, mouse, and hamster.

Abstract

The effect of in vivo-administered 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on epidermal growth factor (EGF) receptor activity of the rat hepatic plasma membrane was studied. TCDD causes a significant reduction in EGF binding at an early stage of toxicity (day 2) and at very low doses (1 pug/kg, single i.p., rat). This reduction appears to be due to a decline in the number of receptors. There is a good correlation between levels of decline in EGF binding and loss of body weight among TCDD-treated rats. The reduction in EGF binding occurs at a relatively low dose in the guinea pig (a very sensitive species) and at high doses in the hamster (a tolerant species). Among three mice strains, TCDD (115 ptg/kg, single i.p.) caused 98% reduction in EGF binding in the sensitive strains (C57BL/6J and CBA/J) but only a 50% reduction in the tolerant strain (AKR/J). To relate the above biochemical changes to in vivo effects, TCDD was postnatally administered (through mother's milk) to mouse neonates. The most prominent toxic manifestations were early eye opening and incisor eruption, loss in body weight gain, and retardation of hair growth. All of these symptoms have been ascribed to EGF effects. TCDD was also found to stimulate phosphorylation of the EGF receptor in the rat hepatic plasma membrane. This phosphorylation effect was observed at day 1 and persisted until the end of the test (day 10). It has long been recognized that agents causing reduction in number of EGF receptors (e.g., phorbol esters) elicit in vivo cellular responses that are similar to those caused by exposure to excess doses of growth factors. Accordingly, a hypothesis has been proposed to ascribe some of the EGF-like effects of TCDD, such as fatty infiltration of the liver and hyperplastic proliferation of gastric epithelia and epidermal cells to its action on the EGF receptor. 2,3,7, is an extremely toxic compound. The oral LD50 values in the male guinea pig and the rat are cited as 0.6 ,g/kg and 22 pug/kg, respectively (1). The action pattern of TCDD is unusual in that animals treated with a single dose steadily lose weight for several weeks, until death occurs, usually in 2-8 weeks. There are marked species differences in sensitivity (2): e.g., as compared to the above species, the Golden Syrian hamster is very tolerant to TCDD; its LD50 value is cited as >5000 pug/kg. Furthermore, the toxic manifestations also qualitatively vary from species to species. The basic biochemical cause for such toxic actions of TCDD is unknown (3).We have recently found that many plasma membrane proteins and functions of the hepatocytes from TCDD-treated rats are quantitatively different from those of untreated rats (4-6).As a follow-up of such a study, the current investigation was undertaken with the following objectives: (i) find several biochemical parameters on the plasma membrane that are severely affected by TCDD, (ii) study whether any of the changes occur at low enough doses and at very early stages in susceptible species, and only at high doses in tol...

Aryl hydrocarbon receptor, cell cycle regulation, toxicity, and tumorigenesis

“…TCDD specifically activates tyrosine kinases associated with the EGFR [Madhukar et al, 1984[Madhukar et al, , 1988 and induces the association of adaptor proteins such as SHC, GRB2, and SOS with EGFR [Park et al, 1998]. While TCDD is not an EGFR ligand [Sewall et al, 1995], it seems that cross-talk between AHR and EGFR signaling is critical for TCDD-induced developmental toxicity [Partanen et al, 1998] and hepatocarcinogenicity [Sewall et al, 1993].…”

Placental markers of human exposure to polychlorinated biphenyls and polychlorinated dibenzofurans.

“…However, it is known that halogenated aromatics modify the EGF receptor. TCDD decreases EGF binding in rat liver (29,30) and in a cultured human keratinocyte cell line (31). It has been hypothesized that this effect is mediated through TCDD interactions with the Ah receptor (31 thiocyanate levels.…”

Molecular Mechanism of Inhibition of Estrogen-Induced Cathepsin D Gene Expression by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) in MCF-7 Cells

“…Phosphoenolpyruvate carboxy kinase, glucose-6-phosphatase, and tryptophan 2,3-dioxygenase activities and mRNA levels are decreased in rats treated with an acutely toxic dose (125 g/kg of body weight) of TCDD (72). Rat uterine c-fos and epidermal growth factor receptor mRNA levels are also decreased (2,3), and decreased epidermal growth factor receptor mRNA levels or binding activity has been observed in several animal species and mammalian cells (33,36,43). TCDD inhibits several estrogen (E2)-induced responses in the rodent uterus (21,66) and mammary gland including the development and formation of mammary tumors in female Sprague-Dawley rats and B6D2 mice (22,32,38).…”