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Gene Expression and Cell Proliferation in Rat Liver after 2,3,7,8-Tetrachlorodibenzo-p-dioxin Exposure¹

Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709

Recently 4 genes (plasminogen activator inhibitor 2, interleukin 1ß, clone 1, and clone 141) that are transcriptionally or posttranscriptionally responsive to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have been cloned from a human skin keratinocyte cell line. We determined whether these genes were expressed in the livers of Sprague-Dawley rats following exposure to TCDD and whether there was a relationship between 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. Gene 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. Under low-stringency hybridization conditions, only the expression of clone 1 could be detected. A dose- and time-dependent expression of this gene was observed in the liver of both male and female rats. Expression of clone 1 was not detected in rats subjected to either a two-thirds partial hepatectomy or exposure to a single administration of the hepatic tumor promoters Wy-14643, carbon tetrachloride, or phenobarbital 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 indicated no evidence of TCDD-induced liver necrosis. Cell proliferation was evaluated immunohistochemically after 7-day 5-bromo-2'-deoxyuridine administration. No increase in total hepatic labeling index was observed for any of the TCDD-exposed treatment groups compared to controls at week 1 or week 2. An increase in the periportal hepatocyte proliferation labeling pattern was observed in TCDD-treated animals. While these results demonstrate that a human TCDD-responsive gene is expressed in the liver of TCDD-treated male and female Sprague-Dawley rats, the expression of this gene is not linked to hepatic cell proliferation or the sex-specific tumor-promoting activity of TCDD.

¹ Partially funded by a grant from the American Paper Institute.

² To whom requests for reprints should be addressed, at Chemical Industry Institute of Toxicology, P. O. Box 12137, Research Triangle Park, NC 27709.

Received 10/ 7/92. Accepted 3/12/93.

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