AhR-mediated gene expression in the developing mouse telencephalon

Abstract

We hypothesize that TCDD induced developmental neurotoxicity is modulated through an AhR dependent interaction with key regulatory neuronal differentiation pathways during telencephalon development. To test this hypothesis we examined global gene expression in both dorsal and ventral telencephalon tissues in E13.5 AhR -/- and wildtype mice exposed to TCDD or vehicle. Consistent with previous biochemical, pathological and behavioral studies, our results suggest TCDD initiated changes in gene expression in the developing telencephalon are primarily AhR dependent, as no statistically significant gene expression changes are evident after TCDD exposure in AhR -/- mice. Based on a gene regulatory network for neuronal specification in the developing telencephalon, the present analysis suggests differentiation of GABAergic neurons in the ventral telencephalon is compromised in TCDD exposed and AhR-/- mice. In addition, our analysis suggests Sox11 may be directly regulated by AhR based on gene expression and comparative genomics analyses. In conclusion, this analysis supports the hypothesis that AhR has a specific role in the normal development of the telencephalon and provides a mechanistic framework for neurodevelopmental toxicity of chemicals that perturb AhR signaling.

Oculomotor Deficits in Aryl Hydrocarbon Receptor Null Mouse

“…For example, TCDD leads to an increase of apoptosis in granule neuron precursor cells [26] and in cortical neurons [6]. Moreover, using telencephalon tissues in E13.5 mice, Gohlke and colleagues suggested a disruption of the differentiation of GABAergic neurons in the ventral telencephalon in TCDD-treated WT mice and in non-treated AhR−/− mice [27].…”

“…It was suggested that the AhR could play an endogenous role in the neural biology [27]. Indeed, Lin et al, which used primary cortical neurons of rats, showed that a knockdown of AhR by siRNA experiments protects neurons against NMDA-mediated excitotoxicity [28].…”

Delayed effects of developmental exposure to low levels of the aryl hydrocarbon receptor agonist 3,3′,4,4′,5-pentachlorobiphenyl (PCB126) on adult zebrafish behavior

“…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). These effects do not occur in AHR-null mice, consistent with a role for AHR in mediating dioxin-induced alteration of neuronal differentiation (Gohlke et al, 2009, Latchney et al, 2013).…”

“…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). These effects do not occur in AHR-null mice, consistent with a role for AHR in mediating dioxin-induced alteration of neuronal differentiation (Gohlke et al, 2009, Latchney et al, 2013). The AHR has also been implicated in the mechanism of neurodevelopmental toxicity caused by other AHR ligands, such as benzo[α]pyrene (Bouayed et al, 2009, Chen et al, 2012, Chepelev et al, 2015, Vignet et al, 2014).…”

Host-microbiome interactions: the aryl hydrocarbon receptor and the central nervous system

“…In zebrafish, TCDD exposure was reported to reduce the total number of neurons by 30% [61]. In mice, dioxin toxicity studies have demonstrated a similar role for AHR in the embryonic differentiation of GABAergic neurons in the telencephalon [62] and the neurogenesis of cerebellar granule cells [63]. Importantly, due to the extraordinarily high binding affinity of dioxin for the AHR, emphatic conclusions regarding the physiological role of the AHR in normal development cannot be drawn from dioxin studies alone.…”