TCDD-MEDIATED CHANGES IN HEPATIC EPIDERMAL GROWTH-FACTOR RECEPTOR MAYBE A CRITICAL EVENT IN THE HEPATOCARCINOGENIC ACTION OF TCDD

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent liver tumor pro moter in rats, with females being more sensitive than males. The epide rmal growth factor receptor (EGFR) pathway has been implicated in alte red cell growth patterns induced by tumor promoters. We investigated h epatic EGFR levels in a two-stage initiation promotion model. The TCDD doses were chosen to encompass the dose range administered in a previ ous chronic bioassay currently used to determine the cancer potency co mmonly used for human health risk assessments. TCDD was administered b iweekly by oral gavage to female Sprague-Dawley rats for 30 weeks foll owing initiation by a single dose of diethylnitrosamine (DEN). TCDD-me diated decreased EGF receptor levels were demonstrated in intact but n ot ovariectomized animals, consistent with previous tumor data. Likewi se, previous studies have shown that TCDD induces cell proliferation i n intact rats but not ovariectomized rats. We report a significant dos e-dependent decrease in plasma membrane EGF receptor maximum binding c apacity 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 significa nt correlation between EGF receptor effects and liver TCDD concentrati on. The decrease in plasma membrane EGFR determined by equilibrium bin ding was confirmed quantitatively by EGF stimulation of EGFR autophosp horylation as well as qualitatively by immunohistochemical detection i n control and treated rats. These results demonstrate that the observe d down modulation of the EGFR by TCDD is ovarian-dependent and is a se nsitive effect induced at dose levels associated with TCDD hepatocarci nogenicity in rodent bioassays.