Effect of PCB 126 on hepatic metabolism of thyroxine and perturbations in the hypothalamic-pituitary-thyroid axis in the rat
Effect of PCB 126 on hepatic metabolism of thyroxine and perturbations in the hypothalamic-pituitary-thyroid axis in the rat
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DOI：
10.1093/toxsci/kfj069
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发表时间：
2006-03-01
影响因子：
3.8
通讯作者：
Almekinder, TL
中科院分区：
文献类型：
--
作者：
Fisher, JW;Campbell, J;Almekinder, TL
本研究的目的是检查成年雄性大鼠给予强效共面（非邻位）PCB，3，3 '，4，4'，5-五氯联苯（PCB 126）后下丘脑-垂体-甲状腺（HPT）轴的时间和剂量依赖性紊乱。对成年雄性Sprague-Dawley大鼠单次经口推注剂量为0、7.5、75或275 μ g PCB 126/ kg bw（溶于玉米油）。在22天内定期处死大鼠。7.5 μ g/kg剂量诱导肝乙氧基试卤灵-O-脱乙基EROD活性，但未观察到肝尿苷二磷酸葡萄糖醛酸转移酶（UDPGTs）活性或血清TSH、T-4或fT（4）浓度的变化。两个最高剂量导致体重增加适度下降，诱导肝脏EROD和UDPGT活性，血清TSH浓度升高，血清T-4和fT（4）浓度降低。每日形成的甲状腺素葡糖苷酸的量（pM/mg蛋白质）随着肝脏中PCB 126的浓度曲线下面积（AUCC）（μ g/kg/天）线性增加，然后在PCB 126剂量为275 μ g/kg时减慢。HPT轴的扰动与PCB 126剂量呈非线性关系。正如预期的那样，观察到血清T-4的AUCC（μ g/dl/天）与血清TSH的AUCC（ng/dl/天）之间呈反比关系;然而，该关系是高度非线性的。这些数据支持PCB 126的作用模式，包括通过芳香烃受体AhR诱导肝脏UDPGTs。然而，HPT轴的剂量-反应特征是非线性和复杂的，需要复杂的工具，如PBPK模型，来表征剂量反应。
The objective of this research was to examine the time- and dose-dependent disturbances in the hypothalamic-pituitary-thyroid ( HPT) axis of adult male rats administered a potent coplanar ( non-ortho) PCB, 3,3', 4,4', 5-pentachlorobiphenyl ( PCB 126). Adult male Sprague-Dawley rats were administered a single oral bolus dose of 0, 7.5, 75, or 275 mu g PCB 126/ kg bw dissolved in corn oil. The rats were sacrificed periodically over 22 days. The 7.5-mu g/kg dose induced hepatic ethoxyresorufin-O-deethylation EROD activity, but no changes were observed in hepatic uridine diphosphate glucuronyl transferases ( UDPGTs) activity or serum TSH, T-4, or fT(4) concentrations. The two highest doses caused a modest decline in weight gain, induced hepatic EROD and UDPGT activities, increased serum TSH concentrations, and decreased serum T-4 and fT(4) concentrations. The amount of thyroxine glucuronide formed daily ( pM/mg protein) increased linearly with the area-under-the-concentration-curve ( AUCC) for PCB 126 in liver ( mu g/kg/day) and then slowed at the 275-mu g/kg PCB 126 dose. Perturbations in the HPT axis were nonlinear with respect to PCB 126 dosing. As expected, an inverse relationship between the AUCC for serum T-4 ( mu g/dl/day) and the AUCC for serum TSH ( ng/dl/day) was observed; however, the relationship was highly nonlinear. These data support a mode of action for PCB 126 involving induction of hepatic UDPGTs by the aryl hydrocarbon receptor AhR. However, the dose-response characteristics of the HPT axis are nonlinear and complex, requiring sophisticated tools, such as PBPK models, to characterize dose response.