AhR-mediated gene expression in the developing mouse telencephalon.
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.
Gohlke
Julia M
JM
Environmental Systems Biology Group, Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, RTP, NC 27709, USA.
Stockton
Pat S
PS
Sieber
Stella
S
Foley
Julie
J
Portier
Christopher J
CJ
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D055028:Comparative Genomic Hybridization; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D055751:SOXC Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013687:Telencephalon / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D013723:Teratogens / Q000633:toxicity*
D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D055751:SOXC Transcription Factors; C490793:Sox11 protein, mouse; D013723:Teratogens