TCDD-mediated changes in hepatic epidermal growth factor receptor may be a critical event in the hepatocarcinogenic action of TCDD

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent liver tumor promoter in rats, with females being more sensitive than males. The epidermal growth factor receptor (EGFR) pathway has been implicated in altered cell growth patterns induced by tumor promoters. We investigated hepatic EGFR levels in a two-stage initiation promotion model. The TCDD doses were chosen to encompass the dose range administered in a previous chronic bioassay currently used to determine the cancer potency commonly used for human health risk assessments. TCDD was administered biweekly by oral gavage to female Sprague-Dawley rats for 30 weeks following initiation by a single dose of diethylnitrosamine (DEN). TCDD-mediated decreased EGF receptor levels were demonstrated in intact but not ovariectomized animals, consistent with previous tumor data. Likewise, previous studies have shown that TCDD induces cell proliferation in intact rats but not ovariectomized rats. We report a significant dose-dependent decrease in plasma membrane EGF receptor maximum binding capacity in both initiated and non-initiated intact rats at TCDD doses equivalent to 3.5, 10.7, 35.7 and 125 ng/kg/day. There was a significant correlation between EGF receptor effects and liver TCDD concentration. The decrease in plasma membrane EGFR determined by equilibrium binding was confirmed quantitatively by EGF stimulation of EGFR autophosphorylation as well as qualitatively by immunohistochemical detection in control and treated rats. These results demonstrate that the observed down modulation of the EGFR by TCDD is ovarian-dependent and is a sensitive effect induced at dose levels associated with TCDD hepatocarcinogenicity in rodent bioassays.