Sammendrag
Recently studies from our laboratory have demonstrated the complexicity between the estrogen receptor (ER) and aryl hydrocarbon receptor (AhR) interactions (for example: Mortensen, A. S. and Arukwe, A., Toxicol Appl Pharmacol, 227, 313-24 (2008); Mortensen, A. S. and Arukwe, A., Comp Hepatol, 6, 2 (2007); Mortensen, A. S. and Arukwe, A., Chem Res Toxicol, 20, 474-88 (2007). In general, these interactions include a bidirectional cross-talk between ER and AhR and direct estrogenic effects of dioxin-like PCB126 in salmon hepatocyte culture. The estrogenic effects of PCB126 were demonstrated on transcript levels of relevant genes (ERa, Vtg and zona radiata protein) and on ERa protein levels and the effect was inhibited by ER-antagonist (ICI: showing direct ER involvement). However, the role of AhR is still not clarified in a mechanistic concept. To test mechanistic role of AhR on the PCB126-mediated estrogenicity, we have used chemical that inhibit protein synthesis (cycloheximide) and inhibitor of AhR (3',4'-dimethoxyflavone: 3',4'-DMF). For example, cycloheximide is produced by the bacterium Streptomyces griseus and has been shown to inhibit protein biosynthesis in eukaryotic organisms. Cycloheximide exerts its effect by interfering with peptidyl transferase activity of the 60S ribosome, thus blocking translational elongation. In general, our data suggest the involvement of activated AhR on PCB126-mediated estrogenicity and that this involvement is modulated by protein and receptor inhibitors, respectively. Overall, our findings demonstrate a complex mode of ER-AhR interactions that were dependent on time of exposure and concentration of individual chemicals and inhibitors. The complex interactions between these two different classes of ligand-activated receptors provide novel mechanistic insights on signaling pathways.
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