Aryl hydrocarbon receptor expression in cerebellar granule neurons: Implications for development and neurotoxicity.

摘要

2,3,7,8-tetrachorodibenzo-p-dioxin (TCDD) is a ubiquitous and persistent environmental contaminant that exerts developmental toxicity by binding to the aryl hydrocarbon receptor (AhR). The AhR is a ligand activated transcription factor that belongs to the basic helix-loop-helix/Per-Arnt-Sim (bHLH/PAS) superfamily. Upon ligand binding, AhR regulates drug metabolizing enzyme, inflammatory mediator, and cell cycle regulatory gene expression. While developmental TCDD exposure has been associated with neurobehavioral abnormalities involving cognitive and locomotor systems, the precise regional and cellular targets of neurotoxicity remain unclear.; It is hypothesized that TCDD exposure disrupts endogenous AhR signaling events during brain development. Epidemiological and animal studies have shown that perinatal TCDD exposure produces neurobehavioral problems consistent with abnormal cerebellar development. Cellular and molecular evidence further suggests that inappropriate AhR activation during development could lead to cerebellar neurotoxicity. Our studies determined that AhR was expressed and transcriptionally active in cerebellar granule precursors (GNP) during critical developmental periods. Furthermore, TCDD reduced GNP proliferation and instigated premature cell death. These findings suggest that TCDD interferes with granule neuron production during cerebellar development.; A secondary hypothesis tested in these studies was that TCDD hinders GNP maturation by disrupting the requisite genetic differentiation programs. Accordingly, GNP gene profiling studies demonstrated altered expression patterns consistent with premature maturation following TCDD treatment both in vitro and in vivo. TCDD-exposed neuroblasts exhibited accelerated neurite outgrowth and differentiation marker expression. These changes were accompanied by increases in PSA-NCAM-positive GNPs and altered betaIII-tubulin expression patterns, consistent with accelerated maturation. Postnatal TCDD exposure stimulated premature TAG-1 expression coincidentally with aberrant GNP migration patterns in mouse cerebellum. Furthermore, the normal spatiotemporal programmed GNP death was altered in TCDD-treated mice. These results suggest that TCDD produces developmental neurotoxicity by precociously activating the gene expression programs associated with GNP maturation.; Our findings imply that AhR stimulation during GNP development regulates genes related to cell cycle regulation, differentiation, and migration. These observations suggest potential roles for AhR in cerebellar GNP maturation. TCDD might interfere with these actions by displacing an endogenous ligand from its normal developmental functions. Therefore, TCDD exposure could adversely impact cerebellar cell interactions and neural circuitry formation, thereby leading to functional abnormalities.