2,3,7,8-Tetrachlorodibenzo-p-dioxin induces apoptosis of articular chondrocytes in culture.
Positive associations of halogenated aromatic hydrocarbons and arthritis have been reported in human populations. Although 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most potent congener of its class, is associated with musculoskeletal dysfunctions in humans and animals, its role on arthritis remains unknown. Apoptosis of chondrocytes has become a focus of interest in the pathogenesis of arthritis. We investigated the potential of TCDD as an inducer of chondrocyte apoptosis and evaluated its mechanism of action. Rabbit chondrocytes in culture were exposed to TCDD. Responses of dioxin-responsive genes and enzyme activity were analyzed by RT-PCR and EROD assay, respectively. Generation of reactive oxygen species (ROS) and nitric oxide (NO) were also determined. A panel of different approaches including caspase-3 assay, ELISA, flow cytometry, and TUNEL staining was utilized to detect apoptotic effects. Dioxin induced mRNAs of dioxin-responsive genes and EROD activity in an AhR-dependent manner. Dose-dependent increases in ROS and NO production were observed. All apoptosis detection techniques used in this study revealed an increase of apoptotic effects in a dose-dependent manner. The increase of apoptosis was blocked by inhibitors of ROS or NO, suggesting that apoptotic effects may be mediated via ROS- and NO-dependent pathways. This is a first report to demonstrate the potential of TCDD to induce apoptosis in chondrocytes, which could be an initial process in cartilage degradation. This finding may shed a new light in studying the possible role of environmental pollutants in the etiology of arthritis.
Department of Pharmacology, Catholic University of Daegu, Republic of Korea. yangjh@cu.ac.kr
Jae-Ho
JH
Yang
Hyun-Gyo
HG
Lee
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002358:Cartilage, Articular / Q000166:cytology*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1; D004785:Environmental Pollutants / Q000633:toxicity; D009569:Nitric Oxide / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018570:Risk Assessment
D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D019363:Cytochrome P-450 CYP1A1