| 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is known to induce many toxic effects in vivo and in vitro. However, its fundamental cause to produce such toxicity has not yet been totally elucidated. One of the main problems is that there are many toxic phenomena that cannot be solely explained by the classical genomic model of the action of TCDD which is based on its ability to activate aryl hydrocarbon receptor (AhR) and induce detoxification enzymes and proteins, particularly cytochrome P450s (CYPs). This current work has produced the evidence supporting the existence of a nongenomic pathway of TCDD-activated AhR, using MCF10A, an immortalized human mammary epithelial cell line, and MMDD1, a mouse kidney macula densa cell line, as cell models. This newly identified pathway was named as nongenomic pathway because the initial signaling takes place in the cytosol, and aryl hydrocarbon receptor nuclear translocator (ARNT), the AhR's dimerization partner necessary for the classical genomic model is not required in this nongenomic pathway. This nongenomic pathway is initiated by an increase in intracellular calcium concentration and activation of cytosolic phospholipase A2 (cPLA2), followed by the activation of protein kinases, which are further responsible for the activation of transcription factors and induction of gene expression such as cyclooxygenase-2 (Cox-2). The induction of Cox-2 has also been observed in the kidney samples from Ahr nls is mice which carry a mutated Ahr gene and encode AhR protein incapable to enter into the nucleus. This finding suggests that the induction of Cox-2 by TCDD in vivo, at least in mouse kidney, does not require the translocation of AhR into the nucleus and is also through the nongenomic pathway of AhR. In view of the importance of Cox-2 in the etiology of hydronephrosis, the current finding that such an action of TCDD to induce Cox-2 is clearly mediated by the nongenomic pathway provides key evidence needed to establish the toxicological significance of this nongenomic pathway of ligand-activated AhR in mediating the toxic actions of TCDD. |
