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

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.

Detection of tris-(2, 3-dibromopropyl) isocyanurate as a neuronal toxicant in environmental samples using neuronal toxicity-directed analysis

“…Thus, further studies are warranted to provide more systematic understanding on the potential adverse effects of TBC. Although other endpoints such as neuronal differentiation, migration and intracellular response may be more sensitive and specific than viability [4,9,16,19,26,27], for contaminated or industrialized regions, the survival of developing CGNs is a well accepted endpoint reflecting the potent neuronal toxicity. Based on the results, the primary cultured CGNs were concluded to be sufficiently specific for neuronal toxicity directed analysis in our study.…”

Excessive activation of AhR signaling disrupts neuronal migration in the hippocampal CA1 region in the developing mouse

“…In particular, AhR-null mice showed impaired neurogenesis in the developing cerebellum and adult hippocampus (Dever et al, 2016;Latchney et al, 2013). It should be noted that impairments of neurogenesis were observed by not only TCDD exposure (Collins et al, 2008), but also by AhR-null disruption (Dever et al, 2016, Latchney et al, 2013. Further studies are needed to elucidate the mechanism of AhR-mediated regulation of neurogenesis during mammalian brain development.…”

“…The second possibility is that CA-AhR perturbs neurogenesis, a process that precedes neuronal migration, and thus causes abnormal neuronal migration. Indeed, postnatal TCDD exposure reduces the number of newborn granule neurons in the developing mouse cerebellum (Collins et al, 2008), suggesting that neurogenesis is impaired by the TCDDdependent enhancement of AhR signaling. Thus, it is reasonable to speculate that the mechanism of the CA-AhRmediated impairment of neurogenesis is similar to the one induced by TCDD exposure.…”

The Aryl Hydrocarbon Receptor Contributes to the Proliferation of Human Medulloblastoma Cells

“…AhR by dioxin interfered with GNP proliferation and differentiation, suggesting that the AhR has some involvement in the maturation of these progenitors (Williamson et al, 2005;Collins et al, 2008). Of interest, MB tumors are thought to arise from GNPs that lose growth control (Wechsler-Reya and Scott, 2001).…”

“…Our laboratory has published results suggesting that the AhR is highly expressed and transcriptionally active during the peak proliferative phase of GNP neurogenesis. Moreover, abnormal activation of the AhR by TCDD dysregulated GNP proliferation and maturation, suggesting that the AhR has a role in the proliferation of GNPs (Williamson et al, 2005;Collins et al, 2008).…”