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
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
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DOI：
10.1002/jat.2839
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发表时间：
2014-02
影响因子：
3.3
通讯作者：
Takashi Tanida;K. Tasaka;Eiichi Akahoshi;M. Ishihara-Sugano;M. Saito;Shigehisa Kawata;Megumi Danjo;Junko Tokumoto;Y. Mantani;D. Nagahara;Y. Tabuchi;T. Yokoyama;H. Kitagawa;M. Kawata;N. Hoshi
中科院分区：
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作者：
Takashi Tanida;K. Tasaka;Eiichi Akahoshi;M. Ishihara-Sugano;M. Saito;Shigehisa Kawata;Megumi Danjo;Junko Tokumoto;Y. Mantani;D. Nagahara;Y. Tabuchi;T. Yokoyama;H. Kitagawa;M. Kawata;N. Hoshi
已知胎儿暴露于二恶英和相关化合物会破坏中脑多巴胺能系统的正常发育，该系统调节行为，认知和情感。这些化学品的毒性主要由芳烃受体（AhR）信号传导介导。之前，我们在体外鉴定了AhR的一种新的结合基序，即AhR-反应元件III（AHRE-III）。该基序位于编码酪氨酸羟化酶（TH）的基因上游，酪氨酸羟化酶是多巴胺生物合成的限速酶。为了提供体内证据，我们研究了2，3，7，8-四氯二苯并对二恶英（TCDD）是否可以调节中脑多巴胺能神经元中AHRE-III的转录活性。我们生产了插入AHRE-III增强子、TH基因启动子和c-myc-taged荧光素酶基因的转基因小鼠。对转基因母鼠单次口服TCDD（0-2000 ng kg-1体重）可显著增强其3天和8周龄后代A9、A10和A8区域的TH免疫反应（ir）强度。与对照组相比，200 ng kg-1 TCDD处理的母鼠的后代在8周时表现出A9区TH-和双（TH和c-myc）-ir神经元数量的显著增加。这些结果表明，胎儿暴露于TCDD上调TH的表达，并增加TH-ir神经元在中脑。此外，结果表明，TCDD通过A9区的AhR-AHRE-III-介导的途径直接反式激活TH启动子。胎儿暴露于TCDD通过AhR-AHRE-III信号通路引起TH稳定上调，并导致中脑TH-ir神经元过度生长，这意味着可能参与神经发育障碍的病因学，如注意力缺陷/多动障碍（ADHD）。版权所有© 2013约翰威利父子有限公司.
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.