Gauger Kelly J, Giera Stefanie, Sharlin David S, Bansal Ruby, Iannacone Eric, Zoeller R Thomas
Molecular and Cellular Biology Program, University of Massachusetts Amherst, Massachusetts 01003, USA.
Environ Health Perspect. 2007 Nov;115(11):1623-30. doi: 10.1289/ehp.10328.
Polychlorinated biphenyls (PCBs) may interfere with thyroid hormone (TH) signaling by reducing TH levels in blood, by exerting direct effects on TH receptors (TRs), or both.
Our objective was to identify individual PCBs that directly affect TH signaling by acting on the TR.
We administered a mixture of six PCB congeners based on their ortho substitution pattern, including PCBs 77 and 126 (non-ortho), PCBs 105 and 118 (mono-ortho), and PCBs 138 and 153 (di-ortho), to pregnant Sprague-Dawley rats from gestational days (G) 6 to 16. This mixture, or various combinations of the components, was also evaluated in a transient transfection system using GH3 cells.
The mixture reduced serum TH levels in pregnant rats on G16 but simultaneously up-regulated the expression of malic enzyme in liver. It also functioned as a TR agonist in vitro; however, none of the individual PCB congeners comprising this mixture were active in this system. Using the aryl hydrocarbon receptor (AhR) antagonist alpha-naphthoflavone, and the cytochrome P450 (CYP)1A1 antagonist ellipticine, we show that the effect of the mixture on the thyroid hormone response element required AhR and CYP1A1.
We propose that PCB 126 induces CYP1A1 through the AhR in GH3 cells, and that CYP1A1 activates PCB 105 and/or 118 to a form a compound that acts as a TR agonist. These data suggest that some tissues may be especially vulnerable to PCBs interfering directly with TH signaling due to their capacity to express CYP1A1 in response to coplanar PCBs (or other dioxin-like molecules) if sufficient mono-ortho PCBs are present.
多氯联苯（PCBs）可能通过降低血液中甲状腺激素（TH）水平、对甲状腺激素受体（TRs）产生直接影响或两者兼而有之，来干扰甲状腺激素信号传导。
我们的目的是确定通过作用于TR直接影响甲状腺激素信号传导的单个多氯联苯。
我们根据邻位取代模式，给妊娠第6至16天的Sprague-Dawley孕鼠施用六种多氯联苯同系物的混合物，包括多氯联苯77和126（非邻位）、多氯联苯105和118（单邻位）以及多氯联苯138和153（双邻位）。还在使用GH3细胞的瞬时转染系统中评估了该混合物或其各种成分组合。
该混合物降低了妊娠第16天孕鼠的血清TH水平，但同时上调了肝脏中苹果酸酶的表达。它在体外也起TR激动剂的作用；然而，构成该混合物的单个多氯联苯同系物在该系统中均无活性。使用芳烃受体（AhR）拮抗剂α-萘黄酮和细胞色素P450（CYP）1A1拮抗剂玫瑰树碱，我们表明该混合物对甲状腺激素反应元件的影响需要AhR和CYP1A1。
我们提出多氯联苯126通过GH3细胞中的AhR诱导CYP1A1，并且CYP1A1将多氯联苯105和/或118激活为一种充当TR激动剂的化合物。这些数据表明，如果存在足够的单邻位多氯联苯，一些组织可能因其响应共平面多氯联苯（或其他二噁英类分子）而表达CYP1A1的能力，特别容易受到多氯联苯直接干扰甲状腺激素信号传导的影响。
