GENE-EXPRESSION AND CELL-PROLIFERATION IN RAT-LIVER AFTER 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN EXPOSURE

Recently 4 genes (plasminogen activator inhibitor 2, interleukin 1beta , clone 1, and clone 141) that are transcriptionally or posttranscript ionally responsive to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have been cloned from a human skin keratinocyte cell line. We determined wh ether these genes were expressed in the livers of Sprague-Dawley rats following exposure to TCDD and whether there was a relationship betwee n expression and hepatic cell proliferation. TCDD was administered by using a dose loading/maintenance regimen to achieve rapid quasi-steady -state TCDD liver concentrations of 0.03, 30, or 150 ng/g of liver. Ge ne expression was determined by Northern analysis using polyadenylated mRNA isolated from liver tissue of male and female animals exposed to TCDD for 1 or 14 days and hybridized with the human complementary DNA clone corresponding to one of the four human TCDD-responsive genes. U nder low-stringency hybridization conditions, only the expression of c lone 1 could be detected . A dose- and time-dependent expression of th is gene was observed in the liver of both male and female rats. Expres sion of clone 1 was not detected in rats subjected to either a two-thi rds partial hepatectomy or exposure to a single administration of the hepatic tumor promoters Wy-14643, carbon tetrachloride. or phenobarbit al at doses that induce hepatic cell proliferation. Liver:body weight ratios were elevated in rats exposed to the middle and high TCDD doses . Histopathological observation and analysis of serum enzyme levels in dicated no evidence of TCDD-induced liver necrosis. Cell proliferation was evaluated immunohistochemically after 7-day 5-bromo-2'-deoxyuridi ne administration. No increase in total hepatic labeling index was obs erved for any of the TCDD-exposed treatment groups compared to control s at week 1 or week 2. An increase in the periportal hepatocyte prolif eration labeling pattern was observed in TCDD-treated animals. While t hese results demonstrate that a human TCDD-responsive gene is expresse d in the liver of TCDD-treated male and female Sprague-Dawley rats, th e expression of this gene is not linked to hepatic cell proliferation or the sex-specific tumor-promoting activity of TCDD.