Kuriyama Sergio, Fidalgo-Neto Antonio, Mathar Wolfgang, Palavinskas Richard, Friedrich Karen, Chahoud Ibrahim
Institute of Clinical Pharmacology and Toxicology, Benjamin Franklin Medical Center, Freie Universität Berlin, 14195 Berlin, Germany.
Toxicology. 2003 Apr 15;186(1-2):11-20. doi: 10.1016/s0300-483x(02)00602-9.
Toxic equivalency factor (TEF) has been proposed to estimate the risk of polychlorinated biphenyl (PCB) congeners. However, ortho chlorine substitution in the two phenyl rings gives each PCB its own pattern of toxicity which is different from the mechanism of action of 2,3,7,8-tetrachlorodibenzo-p-dioxin. The present study evaluated the effect of prenatal and postnatal exposure to a low dose of the mono-ortho pentachlorobiphenyl PCB 118 on thyroid hormone concentrations and EROD activity in rats. Moreover, the tissue distribution of PCB 118 following one oral dose was evaluated. Sprague-Dawley rats were treated by gavage on GD 6 with 375 microg of PCB 118/kg b.w. Decreases in thyroxine and TSH levels were observed in dams at the end of lactation. Perinatal exposure to a low dose of PCB 118 permanently disrupted the hypothalamo-pituitary-thyroid (HPT) axis leading to a significant increase in thyroxine levels in offspring, as a 'thyroid resistance syndrome'. It is noteworthy that no changes in hepatic EROD activity were detected in dams at the end of lactation, even in the presence of high amounts of PCB in liver. Based on hepatic EROD activity (as a biomarker for aryl hydrocarbon receptor (AhR) induction), the mechanism of thyroid homeostasis disruption seems to be AhR-independent. Additionally, the 'thyroid resistance syndrome' observed in our study indicates the need for further detailed investigations on the HPT axis. We conclude that not only TEF, but also AhR-independent responses should be taken into account for risk assessment of mono-ortho PCB congeners.
已提出毒性当量因子（TEF）来估计多氯联苯（PCB）同系物的风险。然而，两个苯环上的邻位氯取代赋予了每种多氯联苯独特的毒性模式，这与2,3,7,8 - 四氯二苯并 - p - 二恶英的作用机制不同。本研究评估了产前和产后低剂量单邻位五氯联苯PCB 118暴露对大鼠甲状腺激素浓度和EROD活性的影响。此外，还评估了单次口服剂量后PCB 118的组织分布。在妊娠第6天，通过灌胃给Sprague - Dawley大鼠施用375微克/千克体重的PCB 118。在哺乳期结束时，观察到母鼠甲状腺素和促甲状腺激素水平下降。围产期低剂量PCB 118暴露永久性地破坏了下丘脑 - 垂体 - 甲状腺（HPT）轴，导致后代甲状腺素水平显著升高，即“甲状腺抵抗综合征”。值得注意的是，即使肝脏中存在大量的PCB，在哺乳期结束时母鼠肝脏的EROD活性也未检测到变化。基于肝脏EROD活性（作为芳烃受体（AhR）诱导的生物标志物），甲状腺稳态破坏的机制似乎与AhR无关。此外，我们研究中观察到的“甲状腺抵抗综合征”表明需要对HPT轴进行进一步详细研究。我们得出结论，对于单邻位PCB同系物的风险评估，不仅应考虑TEF，还应考虑与AhR无关的反应。
