Disruption of thyroid hormone-dependent hypothalamic set-points by environmental contaminants
Disruption of thyroid hormone-dependent hypothalamic set-points by environmental contaminants
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DOI：
10.1016/j.mce.2010.04.010
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发表时间：
2010-07-29
影响因子：
4.1
通讯作者：
Demeneix, Barbara A.
中科院分区：
文献类型：
--
作者：
Decherf, Stephanie;Seugnet, Isabelle;Demeneix, Barbara A.
下丘脑整合代谢和内分泌信号。因此，它代表了多种内分泌干扰化学物质（EDC）的潜在目标。我们研究了两种环境丰富的外源性物质——阻燃剂四溴双酚 A (TBBPA) 和防污剂三丁基锡 (TBT)——对下丘脑的影响。这些 EDC 通过不同的核受体影响内分泌信号传导，包括甲状腺激素受体 (TR) 或其伴侣视黄醇 X 受体 (RXR)。使用报告基因检测在体内研究了与代谢控制有关并受甲状腺激素、促甲状腺激素释放激素 (Trh) 和 4 型黑皮质素受体 (Mc4r) 调节的两个下丘脑基因的启动子序列。妊娠母鼠的慢性暴露或新生儿急性暴露于 TBBPA 会消除 Trh 和 Mc4r 转录的激活。哺乳期母鼠接触 TBT 会增强 Trh 的激活，而不影响 Mc4r 转录。因此，围产期接触 EDC 会影响核受体信号传导，从而调节控制代谢反应的下丘脑设定点。 (C) 2010 Elsevier Ireland Ltd. 保留所有权利。
The hypothalamus integrates metabolic and endocrine signals. As such it represents a potential target for a wide spectrum of endocrine disrupting chemicals (EDCs). We investigated hypothalamic effects of two environmentally abundant xenobiotics, the flame-retardant tetrabromo bisphenol A (TBBPA) and the anti-fouling agent tributyltin (TBT). These EDCs affect endocrine signalling through different nuclear receptors including the thyroid hormone receptor (TR) or its partner, the retinoid X receptor (RXR). Promoter sequences of two hypothalamic genes implicated in metabolic control and regulated by thyroid hormone, thyrotropin-releasing hormone (Trh) and type 4 melanocortin receptor (Mc4r), were studied in vivo using reporter assays. Chronic exposure of gestating dams or acute exposure of their newborns to TBBPA abrogated activation of both Trh and Mc4r transcription. Exposure of lactating dams to TBT amplified activation of Trh without affecting Mc4r transcription. Thus, perinatal exposure to EDCs affecting nuclear receptor signalling modulates hypothalamic set-points controlling metabolic responses. (C) 2010 Elsevier Ireland Ltd. All rights reserved.