2,3,7,8-Tetracholorodibenzo-p-Dioxin Exposure Disrupts Granule Neuron Precursor Maturation in the Developing Mouse Cerebellum

ArticleinToxicological Sciences 103(1):125-36 · June 2008with7 Reads
DOI: 10.1093/toxsci/kfn017 · Source: PubMed
Abstract
The widespread environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been linked to developmental neurotoxicity associated with abnormal cerebellar maturation in both humans and rodents. TCDD mediates toxicity via binding to the aryl hydrocarbon receptor (AhR), a transcription factor that regulates the expression of xenobiotic metabolizing enzymes and growth regulatory molecules. Our previous studies demonstrated that cerebellar granule neuron precursor cells (GNPs) express transcriptionally active AhR during critical developmental periods. TCDD exposure also impaired GNP proliferation and survival in vitro. Therefore, this study tested the hypothesis that TCDD exposure disrupts cerebellar development by interfering with GNP differentiation. In vivo experiments indicated that TCDD exposure on postnatal day (PND) 6 resulted in increased expression of a mitotic marker and increased thickness of the external granule layer (EGL) on PND10. Expression of the early differentiation marker TAG-1 was also more pronounced in postmitotic, premigratory granule neurons of the EGL, and increased apoptosis of GNPs was observed. On PND21, expression of the late GNP differentiation marker GABA(A alpha 6) receptor (GABAR(A alpha 6)) and total estimated cell numbers were both reduced following exposure on PND6. Studies in unexposed adult AhR(-/-) mice revealed lower GABAR(A alpha 6) levels and DNA content. In vitro studies showed elevated expression of the early differentiation marker p27/Kip1 and the GABAR(A alpha 6) in GNPs following TCDD exposure, and the expression patterns of proteins related to granule cell neurite outgrowth, beta III-tubulin and polysialic acid neural cell adhesion molecule, were consistent with enhanced neuroblast differentiation. Together, our data suggest that TCDD disrupts a normal physiological role of AhR, resulting in compromised GNP maturation and neuroblast survival, which impacts final cell number in the cerebellum.
    • "It involves in xenobiotic-induced carcinogenesis, immunosuppression , and tumor development (Poland and Knutson, 1982; Andersson et al., 2002). Also, it is revealed that the AhR plays numerous roles in development at cellular levels (Tohkin et al., 2000; Akahoshi et al., 2006; Collins et al., 2008; Quintana et al., 2008; Stevens et al., 2009; Apetoh et al., 2010; Latchney et al., Table 5(A) ProtScale-calculated Kyte-Doolittle hydropathy scores; (B) PSKAcePred-predicted lysine acetylation sites of AhR-variants. "
    [Show abstract] [Hide abstract] ABSTRACT: Aryl hydrocarbon receptor (AhR) acts as an enhancer binding ligand-activated intracellular receptor. Chromatin remodeling components and general transcription factors such as TATA-binding protein (TBP) are evoked on AhR-target genes by interaction with its flexible transactivation domain (TAD). AhR-G1661A single nucleotide polymorphism (SNP: rs2066853) causes an arginine to lysine substitution in the acidic sub-domain of TAD at position 554 (R554K). Although, numerous studies associate the SNP with some abnormalities such as cancer, other reliable investigations refuse the associations. Consequently, the interpretation of the phenotypic results of G1661A-transition has been controversial. In this study, an in silico analysis were performed to investigate the possible effects of the transition on AhR-mRNA, protein structure, interaction properties and modifications. The analysis revealed that the R554K substitution affects secondary structure and solvent accessibility of adjacent residues. Also, it causes to decreasing of the AhR stability; altering the hydropathy features of the local sequence and changing the pattern of the residues at the binding site of the TAD-acidic sub-domain. Generating of new sites for ubiquitination and acetylation for AhR-K554 variant respectively at positions 544 and 560 was predicted. Our findings intensify the idea that the AhR-G1661A transition may affects AhR-TAD interactions, especially with the TBP, which influence AhR-target genes expression. However, the previously reported flexibility of the modular TAD could act as an intervening factor, moderate the SNP effects and causes distinct outcomes in different individuals and tissues.
    Full-text · Article · Jan 2016
    • "Early exposure of zebrafish embryos to environmentally relevant concentrations of dioxin resulted in reduced brain volume and decreased expression of neurodevelopmental genes in larvae (Hill et al., 2003). In rodents, gestational exposure to dioxin causes AHR-dependent abnormal development in a number of areas in the brain, including the cerebellum, hippocampus, the midbrain and the early region of the forebrain that matures to control advanced brain functions (Collins et al., 2008, Latchney et al., 2013, Tanida et al., 2014, Williamson et al., 2005). These abnormalities often involve changes in neuronal development and establishment of neuron cell fate (Gohlke et al., 2009, Hays et al., 2002, Latchney et al., 2013, Nguyen et al., 2013b). "
    [Show abstract] [Hide abstract] ABSTRACT: Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants. The most toxic PCBs are the non-ortho-substituted ("dioxin-like") congeners that act through the aryl hydrocarbon receptor (AHR) pathway. In humans, perinatal exposure to dioxin-like PCBs is associated with neurodevelopmental toxicity in children. Yet, the full potential for later-life neurobehavioral effects that result from early-life low level exposure to dioxin-like PCBs is not well understood. The objective of this study was to determine the effects of developmental exposure to low levels of dioxin-like PCBs on early- and later-life behavioral phenotypes using zebrafish as a model system. We exposed zebrafish embryos to either vehicle (DMSO) or low concentrations of PCB126 (0.3, 0.6, 1.2nM) for 20hours (4-24hours post fertilization), and then reared them to adulthood in clean water. Locomotor activity was tested at two larval stages (7 and 14 days post fertilization). Adult fish were tested for anxiety-related behavior using the novel tank and shoaling assays. Adult behavioral assays were repeated several times on the same group of fish and effects on intra- and inter-trial habituation were determined. While there was no effect of PCB126 on larval locomotor activity in response to changes in light conditions, developmental exposure to PCB126 resulted in impaired short- and long-term habituation to a novel environment in adult zebrafish. Cyp1a induction was measured as an indicator for AHR activation. Despite high induction at early stages, cyp1a expression was not induced in the brains of developmentally exposed adult fish that showed altered behavior, suggesting that AHR was not activated at this stage. Our results demonstrate the effectiveness of the zebrafish model in detecting subtle and delayed behavioral effects resulting from developmental exposure to an environmental contaminant.
    Article · Nov 2015
    • "Early exposure of zebrafish embryos to environmentally relevant concentrations of dioxin resulted in reduced brain volume and decreased expression of neurodevelopmental genes in larvae (Hill et al., 2003 ). In rodents, gestational exposure to dioxin causes AHRdependent abnormal development in a number of areas in the brain, including the cerebellum, hippocampus, the midbrain and the early region of the forebrain that matures to control advanced brain functions (Collins et al., 2008; Latchney et al., 2013; Tanida et al., 2014; Williamson et al., 2005). These abnormalities often involve changes in neuronal development and establishment of neuron cell fate (Gohlke et al., 2009; Hays et al., 2002; Latchney et al., 2013; Nguyen et al., 2013b). "
    Full-text · Article · May 2015
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