Carcinogenesis, Vol 19, 1427-1435, Copyright © 1998 by Oxford University Press
NJ Walker, BD Miller, MC Kohn, GW Lucier and AM Tritscher
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent tumor promoter in
two-stage initiation-promotion models and induces cell proliferation and
development of enzyme-altered hepatic foci. It is believed that increased
cell proliferation is a necessary step in carcinogenesis. Therefore, the
analysis of the effect of TCDD on cell proliferation in rat liver may aid
in the understanding of the mechanism of hepatocarcinogenesis induced by
TCDD. The aim of this study was to investigate the time course and
reversibility of cell proliferation in non-initiated and
diethylnitrosamine-initiated female rats exposed biweekly to a daily
averaged dose of 125 ng TCDD/kg/day for up to 60 weeks. In addition we
evaluated the suitability of different dose metrics for the evaluation of
TCDD-induced changes in cell proliferation and CYP1A1 enzyme induction.
Cell proliferation was measured as the incorporation of
5-bromo-2'-deoxyuridine (BrdU) into hepatocytes undergoing replicative DNA
synthesis. Mean BrdU labeling indices in TCDD-treated animals were not
increased over controls after 14 weeks exposure, but were increased 8- and
2-fold after 30 and 60 weeks' treatment respectively, despite similar liver
levels of TCDD at all these times (23-30 p.p.b.). In comparison, CYP1A1
activity, as measured by ethoxyresorufin deethylase activity, was
significantly induced at all times points analyzed. Sixteen weeks following
cessation of TCDD treatment, labeling indices were still significantly
elevated over controls, but after 30 weeks of withdrawal, labeling indices
were no different from controls, indicating that TCDD-induced changes in
cell proliferation were reversible. Dosimetric analysis indicated that rat
liver tissue burden was suitable for prediction of CYP1A1 expression but
not cell proliferation and that the area under the curve was unsuitable for
prediction of both TCDD-induced changes in CYP1A1 expression and cell
proliferation.
ARTICLES
Differences in kinetics of induction and reversibility of TCDD-induced changes in cell proliferation and CYP1A1 expression in female Sprague- Dawley rat liver
Laboratory of Computational Biology and Risk Analysis, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA. walker3@niehs.nih.gov
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