Goldey E S, Crofton K M
Department of Biology, Wofford College, Spartanburg, South Carolina 29303, USA.
Toxicol Sci. 1998 Sep;45(1):94-105. doi: 10.1006/toxs.1998.2495.
The nervous system is dependent upon thyroid hormones for normal development, and we previously reported that developmental Aroclor 1254 (A1254) exposure caused hypothyroxinemia, hearing loss and other behavioral changes in rats. (Goldey et al., 1995a; Herr et al., 1996). The hypothesis that A1254-induced hypothyroxinemia may have contributed to the observed functional changes was tested in primiparous Long-Evans rats given daily oral doses of corn oil (control) or 8 mg/kg of Aroclor 1254 from gestation day (GD) 6 through postnatal day (PND) 21. In addition, from PND 4 to PND 21, all pups in one-half of the litters received daily, subcutaneous injections of saline or 100 micrograms/kg thyroxine (T4), to yield four groups of litters: corn oil plus saline (CO-S),. corn oil plus T4 (CO-T4), Aroclor 1254 plus saline (PCB-S), and Aroclor 1254 plus T4 (PCB-T4). We measured thyroid hormone concentrations (T4 and T3) in serum collected from 7-, 14-, and 21-day-old pups. The kinetics of the injected T4 were also monitored in the CO-T4 and PCB-T4 groups on PND 7 and 21 by measuring T4 and T3 at 1, 3, 5, 8, and 24 h after injection. Circulating T4 concentrations were dramatically depleted in the PCB-S group relative to CO-S. The kinetics study indicated that T4 therapy raised circulating T4 concentrations following in the PCB-T4 pups to near CO-S concentrations, but only for approximately 6 h postinjection, and T4 concentrations fell precipitously thereafter to near PCB-S concentrations. In accord with previous studies, PCB-S pups showed early eye opening, an effect which was exacerbated by T4 injection (in both the CO-T4 and the PCB-T4 groups). Motor activity (figure-eight maze) testing also replicated our finding of an age-dependent, transient reduction in motor activity on PND 15 that was significantly attenuated in the PCB-T4 group. Similarly, we again found reduced acoustic startle amplitudes on PND 23 and low-frequency (1 kHz) hearing loss in animals tested as adults (the latter determined by reflex modification audiometry). Importantly, the hearing loss at 1 kHz in PCB-exposed animals was significantly attenuated by T4 replacement therapy. These data suggest the hypothesis that hypothyroxinemia is involved in PCB-induced alterations in motor and auditory function, while other effects (e.g., eye opening) appear to have a different mechanism of action.
神经系统的正常发育依赖于甲状腺激素，我们之前报道过，发育期接触艾氏剂1254（A1254）会导致大鼠甲状腺素血症、听力丧失及其他行为改变。（戈尔迪等人，1995年a；赫尔等人，1996年）。我们对初产的长-伊斯特曼大鼠进行了试验，从妊娠第6天（GD）至出生后第21天（PND），每天经口给予玉米油（对照）或8毫克/千克的艾氏剂1254，以验证A1254诱导的甲状腺素血症可能导致所观察到的功能变化这一假说。此外，从PND 4至PND 21，半数窝中的所有幼崽每天接受皮下注射生理盐水或100微克/千克甲状腺素（T4），从而产生四组幼崽：玉米油加生理盐水（CO-S）、玉米油加T4（CO-T4）、艾氏剂1254加生理盐水（PCB-S）和艾氏剂1254加T4（PCB-T4）。我们测量了从7日龄、14日龄和21日龄幼崽采集的血清中的甲状腺激素浓度（T4和T3）。在PND 7和21时，通过在注射后1、3、5、8和24小时测量T4和T3，还监测了CO-T4组和PCB-T4组中注射T4的动力学。与CO-S组相比，PCB-S组的循环T4浓度显著降低。动力学研究表明，T4治疗使PCB-T4组幼崽注射后的循环T4浓度升高至接近CO-S组的浓度，但仅在注射后约6小时内如此，此后T4浓度急剧下降至接近PCB-S组的浓度。与之前的研究一致，PCB-S组幼崽睁眼较早，T4注射（CO-T4组和PCB-T4组均如此）加剧了这种效应。运动活动（8字形迷宫）测试也重现了我们之前的发现，即PND 15时运动活动出现与年龄相关的短暂降低，而PCB-T4组这种降低明显减弱。同样，我们再次发现PND 23时听觉惊吓幅度降低，以及成年期测试的动物出现低频（1千赫）听力丧失（后者通过反射修正听力测定法确定）。重要的是，T4替代疗法显著减轻了接触PCB动物的1千赫听力丧失。这些数据提示了这样一种假说，即甲状腺素血症参与了PCB诱导的运动和听觉功能改变，而其他效应（如睁眼）似乎具有不同作用机制。
