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ToxSci Advance Access published online on June 10, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp128
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Inhibition of UV-C light-induced apoptosis in liver cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). -Inhibition of apoptosis by TCDD-

M. Chopra*, A. M. Dharmarajan{dagger}, G. Meiss{ddagger} and D. Schrenk*

* Institute of Food Chemistry and Toxicology, University of Kaiserslautern, 67663 Kaiserslautern, Germany {dagger} Anatomy and Human Biology, University of Western Australia, Crawley, WA 6009, Australia {ddagger} Institute of Biochemistry, Justus-Liebig-University Gießen, 35392 Gießen, Germany

Schrenk, Dieter, Prof. Dr. Dr., Food Chemistry and Toxicology, University of Kaiserslautern, Erwin Schrödinger Straße 52, 67659 Kaiserslautern, Germany, Telephone +49 631 205 3043, Fax +49 631 205 4398, schrenk{at}rhrk.uni-kl.de

Received April 14, 2009; revision received May 27, 2009; accepted May 27, 2009


  Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly toxic pollutant ubiquitously present in the environment. Most of the toxic effects of TCDD are believed to be mediated by high-affinity binding to the aryl hydrocarbon receptor (AhR) and subsequent effects on gene transcription. TCDD causes cancer in multiple tissues in different animal species and is classified as a class 1 human carcinogen. In initiation-promotion studies TCDD was shown to be a potent liver tumor-promotor. Among other theories it has been hypothesized that TCDD acts as a tumor-promotor by preventing initiated cells from undergoing apoptosis. We examined the effects of TCDD on UV-C light-induced apoptosis in primary rat hepatocytes and Huh-7 human hepatoma cells. TCDD inhibits UV-C light induced apoptosis in both cell types. This effect is seen with chromatin condensation and fragmentation and appears to be mediated by the AhR in rat hepatocytes. Apoptosis induced by UV-C light in these cells is caspase-dependent and is accompanied by alterations in apoptosis-related gene expression such as up-regulation of pro-apoptotic bcl-2 family genes like bak and bax, and a marked down-regulation of the expression of the anti-apoptotic bcl-2. TCDD treatment of irradiated hepatocytes induces the expression of some apoptosis-related genes (birc3, dad1, pycard, tnf). Up-stream apoptotic events, namely caspase-activation and caspase-substrate cleavage are not inhibited by TCDD treatment. We hypothesize that TCDD inhibits late-stage apoptotic events that lead to internucleosomal DNA fragmentation, maintaining chromosomal integrity probably in order to sustain metabolic capacity and hepatic elimination of substrates despite of an initiation of apoptosis.

Key Words: TCDD; apoptosis; DNA fragmentation; Arylhydrocarbon receptor.

Martin Chopra: chopra{at}rhrk.uni-kl.de,Arunasalam M Dharmarajan: dharma{at}anhb.uwa.edu.au, Gregor Meiss: Gregor.Meiss{at}chemie.bio.uni-giessen.de, Dieter Schrenk: schrenk{at}rhrk.uni-kl.de


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