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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
Author(s) -
Tanida Takashi,
Tasaka Ken,
Akahoshi Eiichi,
IshiharaSugano Mitsuko,
Saito Michiko,
Kawata Shigehisa,
Danjo Megumi,
Tokumoto Junko,
Mantani Youhei,
Nagahara Daichi,
Tabuchi Yoshiaki,
Yokoyama Toshifumi,
Kitagawa Hiroshi,
Kawata Mitsuhiro,
Hoshi Nobuhiko
Publication year - 2014
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.2839
Subject(s) - aryl hydrocarbon receptor , tyrosine hydroxylase , offspring , endocrinology , medicine , dopaminergic , downregulation and upregulation , aryl hydrocarbon receptor nuclear translocator , midbrain , transactivation , biology , transgene , dopamine , chemistry , gene expression , transcription factor , gene , central nervous system , biochemistry , pregnancy , genetics
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). Copyright © 2013 John Wiley & Sons, Ltd.