title: Fetal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin transactivates aryl hydrocarbon receptor-responsive element III in the tyrosine hydroxylase immunoreactive neurons of the mouse midbrain.
abstract: Fetal exposure to dioxins and related compounds is known to disrupt normal development of the midbrain dopaminergic system, which regulates behavior, cognition and emotion. The toxicity of these chemicals is mediated mainly by aryl hydrocarbon receptor (AhR) signaling. Previously, we identified a novel binding motif of AhR, the AhR-responsive element III (AHRE-III), in vitro. This motif is located upstream from the gene encoding tyrosine hydroxylase (TH), the rate-limiting enzyme of dopamine biosynthesis. To provide in vivo evidence, we investigated whether 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) could regulate AHRE-III transcriptional activity in midbrain dopaminergic neurons. We produced transgenic mice with inserted constructs of the AHRE-III enhancers, TH gene promoter and the c-myc-tagged luciferase gene. Single oral administrations of TCDD (0-2000 ng kg⁻¹ body weight) to the transgenic dams markedly enhanced TH-immunoreactive (ir) intensity in the A9, A10 and A8 areas of their offspring at 3 days and 8 weeks of age. The offspring of dams treated with 200 ng kg⁻¹ TCDD exhibited significant increases in the numbers of TH- and double (TH and c-myc)-ir neurons in area A9 compared with controls at 8 weeks. These results show that fetal exposure to TCDD upregulates TH expression and increases TH-ir neurons in the midbrain. Moreover, the results suggest that TCDD directly transactivates the TH promoter via the AhR-AHRE-III-mediated pathway in area A9. Fetal exposure to TCDD caused stable upregulation of TH via the AhR-AHRE-III signaling pathway and overgrowth of TH-ir neurons in the midbrain, implying possible involvement in the etiology of neurodevelopmental disorders such as attention-deficit/hyperactivity disorder (ADHD).
authors.affiliation: Department of Anatomy and Neurobiology, Kyoto Prefectural University of Medicine, Kawaramachi Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan; Department of Animal Science, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai cho, Nada, Kobe, 657-8501, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tanida
authors.forename: Ken
authors.initials: K
authors.lastname: Tasaka
authors.forename: Eiichi
authors.initials: E
authors.lastname: Akahoshi
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Ishihara-Sugano
authors.forename: Michiko
authors.initials: M
authors.lastname: Saito
authors.forename: Shigehisa
authors.initials: S
authors.lastname: Kawata
authors.forename: Megumi
authors.initials: M
authors.lastname: Danjo
authors.forename: Junko
authors.initials: J
authors.lastname: Tokumoto
authors.forename: Youhei
authors.initials: Y
authors.lastname: Mantani
authors.forename: Daichi
authors.initials: D
authors.lastname: Nagahara
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Tabuchi
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Yokoyama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitagawa
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kawata
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Hoshi
mesh_terms: D000818:Animals; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000187:drug effects* / Q000378:metabolism; D008636:Mesencephalon / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009929:Organ Size; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011401:Promoter Regions, Genetic; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism*
chemical_list: D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D014446:Tyrosine 3-Monooxygenase
keywords: 2,3,7,8-tetrachlorodibenzo-p-dioxin; aryl hydrocarbon receptor; aryl hydrocarbon receptor responsive element III; immunohistochemistry; tyrosine hydroxylase