INHIBITORY EFFECTS OF 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN ON RAT HEPATOCYTE PROLIFERATION INDUCED BY 2/3-PARTIAL-HEPATECTOMY

To better understand the mode of action of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced alterations in hepatic cell proliferation and the potential link to tumour-promoting activity, we investigated the effects of TCDD on the expression of certain key genes involved in liver cell growth and the effects of TCDD on induced hepatocyte cell proliferation. Gene expression analysis was conducted, by Northern blot hybridization, using RNA isolated from female Sprague-Dawley rat livers collected at various times during a 14-day dosing period with TCDD known to produce alterations in cell proliferation. No major changes were observed in the expression of the transforming growth factors TGF-alpha and TGF-beta or in oncogenes ras, src and myc. However, the expression of the transcription factors C/EBP, HNF-1 alpha and HNF-4 decreased after 14 days of TCDD treatment. To investigate how TCDD affects hepatic growth, cell proliferation analysis was conducted in rats stimulated to undergo hepatocyte proliferation following either 2/3 partial hepatectomy or lead nitrate treatment. Cell proliferation was quantified by means of immunocytochemical detection of Proliferating Cell Nuclear Antigen (PCNA). Fourteen days of pretreatment with TCDD caused an overall inhibiton of hepatocytes in the growth fraction (G(1), S, G(2) and M) from 61 +/- 3% in the control-partial hepatectomy group to 41 +/- 3% in the TCDD-partial hepatectomy group. A periportal pattern of cell proliferation was observed in the TCDD-partial hepatectomy group as compared to the panlobular pattern of cell proliferation in the control-partial hepatectomy group. TCDD pretreatment also produced an inhibition of cell proliferation induced by the liver mitogen lead nitrate. TCDD-induced inhibition of hepatocyte proliferation could play a role in TCDD tumour promotion and hepatocarcinogenesis through the creation of a environment whereby preneoplastic cells continue to expand while normal hepatocyte proliferation is inhibited.