Possible mechanisms of thyroid hormone disruption in mice by BDE 47, a major polybrominated diphenyl ether congener
Possible mechanisms of thyroid hormone disruption in mice by BDE 47, a major polybrominated diphenyl ether congener
复制标题
DOI：
10.1016/j.taap.2007.09.015
复制
发表时间：
2008-02-01
影响因子：
3.8
通讯作者：
Bimbaum, Linda S.
中科院分区：
文献类型：
--
作者：
Richardson, Vicki M.;Staskal, Daniele F.;Bimbaum, Linda S.
多溴联苯醚（PBDEs）是一类多卤代芳香族化合物，在商业上用作消费品中的阻燃剂。这些化合物已被证明在急性暴露后会降低啮齿动物体内甲状腺激素的浓度。本研究检测了2,2',4,4'-四溴联苯醚（BDE 47）降低循环甲状腺激素浓度的能力，并将其与BDE 47对参与甲状腺激素内稳态的基因的影响相结合。将9周龄的雌性C57BL/6小鼠经口给予3、10或100 mg/kg/天的BDE 47，持续4天。在最后一次给药24小时后（第5天）对动物实施安乐死，并收集肝脏、肾脏和血清进行分析。BDE 47在100 mg/kg/天的剂量下使血清总甲状腺素（T - 4）浓度显著降低43%。肝脏T - 4 - 葡糖醛酸化活性没有增加，但在100 mg/kg/天的BDE 47剂量下，肝脏Ugt1a1、Ugt1a7和Ugt2b5 mRNA表达显著增加，同时T - 4浓度显著降低。细胞色素P450 2B（PROD）活性的诱导在最低剂量（3 mg/kg/天）时发生。Cyp2b10 mRNA表达在10和100 mg/kg/天的剂量下也显著增加。这些关键发现表明BDE激活了核受体CAR。Mdr1a mRNA表达的降低也在给予的最低剂量（3 mg/kg/天的BDE 47）时发生。BDE 47暴露还降低了肝脏转甲状腺素蛋白和单羧酸转运蛋白8（Mct8）mRNA的表达，这表明虽然尿苷二磷酸葡萄糖醛酸转移酶（UGTs）的诱导可能是T - 4降低的部分原因，但其他机制也参与其中。在肾脏中未观察到影响。我们得出结论，肝脏UGTs和转运蛋白的变化可能与BDE 47暴露后循环T - 4的降低有关。由爱思唯尔公司出版。
Polybrominated diphenyl ethers (PBDEs) are a class of polyhalogenated aromatic compounds commercially used as fire retardants in consumer products. These compounds have been shown to decrease thyroid hormone concentrations in rodents after acute exposures. This study examines the ability of 2,2',4,4'-tetrabromodiphenyl ether (BDE 47) to decrease circulating thyroid hormone concentrations and pairs this with BDE 47-induced effects on genes involved in thyroid hormone homeostasis. Female C57BL/6 mice (9 weeks old) were orally administered 3, 10, or 100 mg/kg/day of BDE 47 for 4 days. Animals were euthanized 24 h after the final dose (day 5) and liver, kidney, and serum were collected for analysis. BDE 47 caused a significant 43% decrease at 100 mg/kg/day in serum total thyroxine (T-4) concentrations. There was no increase in hepatic T-4-glucuronidation activity, but significant increases in hepatic Ugt1a1, Ugt1a7, and Ugt2b5 mRNA expression accompany significant decreases in T-4 concentrations at 100 mg/kg/day of BDE 47. Induction of PROD activity occurred at the lowest dose (3 mg/kg/day). Cyp2b10 mRNA expression also increased significantly at 10 and 100 mg/kg/day. These key findings show that BDE activates the nuclear receptor, CAR. Decreases in Mdr1a mRNA expression also occurred at the lowest dose administered (3 mg/kg/day BDE 47). BDE 47 exposure also decreased hepatic transthyretin and monocarboxylate transporter 8 (Mct8) mRNA expression, suggesting that while induction of UGTs may be partly responsible for T-4 decreases, other mechanisms are also involved. No effects were seen in the kidney. We conclude that changes in hepatic UGTs and transporters may be involved in decreases in circulating T-4 following BDE 47 exposure. Published by Elsevier Inc.