Aryl hydrocarbon receptor-dependent induction of apoptosis by 2,3,7,8-tetrachIorodiberizo-p-dioxin in cerebellar granule cells from mouse

摘要

2,3,7,8-Tetraehlorodibenzo-p-dioxin (TCDD) is a prototypical environmental contaminant with neurotoxic properties that alters neurodevelopment and behavior. TCDO is a ligand of the aryl hydrocarbon receptor (AhR), which is a key signaling molecule to fully understand the toxic and carcinogenic properties of dioxin. Much effort is underway to unravel the molecular mechanisms and the signaling pathways involved in TCDD-indueed neurotoxicity, and to define its molecular targets in neurons. We have used cerebellar granule cells (CGC) from wild-type (AhR+/+) and AhR-null {AhR-/-) mice to characterize the cell death that takes place in neurons after TCDD toxidty. TCDD induced cell death in CGC cultures from wi!d-type mice with an EC_50 of 127 +- 21 nM. On the contrary, when CGC neurons from AhR-null mice were treated with TCDD no significant cell death was observed. The role of AhR in TCDD-induced death was further assessed by using the antagonists resveratrol and alpha-naphtoflavone, which readily protected against TCDD toxicity in AhR+/+ CGC cultures, AhR+/+ CGC cultures treated with TCDD showed nuclear fragmentation, DNA laddering, and increased caspase 3 activity, similarly to what was found by the use of staurosporine, a well-established inducer of apoptosis, Finally, the AhR pathway was active in CGC because TCDD could induce the expression of the target gene cytochrome P45O 1A2 in AhR+/+ CGC cultures. All together these results support the hypothesis that TCDD toxicity in CGC neurons involves the AhR and that it takes place mainly through an apoptotic process. AhR could be then considered a novel target in neurotoxicity and neurodegeneration whose down-modulation could block certain xenobiotic-related adverse effects in CNS.