Gauger Kelly J, Kato Yoshihisa, Haraguchi Koichi, Lehmler Hans-Joachim, Robertson Larry W, Bansal Ruby, Zoeller R Thomas
Biology Department, Molecular and Cellular Biology Program, Morrill Science Center, University of Massachusetts, Amherst, MA 01003, USA.
Environ Health Perspect. 2004 Apr;112(5):516-23. doi: 10.1289/ehp.6672.
Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants routinely found in human and animal tissues. Developmental exposure to PCBs is associated with neuropsychologic deficits, which may be related to effects on thyroid hormone (TH) signaling in the developing brain. However, PCBs may interfere with TH signaling solely by reducing circulating levels of TH, or they may exert direct effects on TH receptors (TRs). Therefore, we tested whether maternal exposure to a commercial PCB mixture, Aroclor 1254 (A1254), exerts effects in the fetal brain by one or both of these mechanisms. Dams were dosed daily with 0, 1, or 4 mg/kg A1254 from gestational day 6 (GD6) until they were sacrificed on GD16. A1254 significantly reduced circulating levels of triiodothyronine (T3) and thyroxine (T4) in pregnant rats but increased the expression of several TH-responsive genes in the fetal cortex, including neuroendocrine-specific protein A (NSP-A), RC3/neurogranin, and Oct-1. These findings are consistent with a direct action of PCBs on TRs. However, we did not identify parent PCB congeners or metabolites that bound to rat TRs isolated from hepatic nuclei. These findings indicate that PCBs can interfere with TH signaling in the fetal brain by direct actions on the fetus rather than by producing maternal hypothyroidism.
多氯联苯（PCBs）是常见的环境污染物，经常在人和动物组织中被发现。发育期接触多氯联苯与神经心理缺陷有关，这可能与发育中的大脑中甲状腺激素（TH）信号传导受到影响有关。然而，多氯联苯可能仅通过降低循环中的甲状腺激素水平来干扰甲状腺激素信号传导，或者它们可能对甲状腺激素受体（TRs）产生直接影响。因此，我们测试了母体接触商业多氯联苯混合物Aroclor 1254（A1254）是否通过这些机制中的一种或两种对胎儿大脑产生影响。从妊娠第6天（GD6）开始，每天给孕鼠腹腔注射0、1或4mg/kg的A1254，直至在GD16处死。A1254显著降低了孕鼠循环中的三碘甲状腺原氨酸（T3）和甲状腺素（T4）水平，但增加了胎儿皮质中几种甲状腺激素反应性基因的表达，包括神经内分泌特异性蛋白A（NSP-A）、RC3/神经颗粒蛋白和Oct-1。这些发现与多氯联苯对甲状腺激素受体的直接作用一致。然而，我们没有鉴定出与从肝细胞核中分离出的大鼠甲状腺激素受体结合的母体多氯联苯同系物或代谢物。这些发现表明多氯联苯可通过对胎儿的直接作用而非导致母体甲状腺功能减退来干扰胎儿大脑中的甲状腺激素信号传导。
