Gore A C, Wu T J, Oung T, Lee J B, Woller M J
Kastor Neurobiology of Aging Laboratories, Fishberg Research Center for Neurobiology, and Brookdale Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, NY 10029, USA.
J Neuroendocrinol. 2002 Oct;14(10):814-23. doi: 10.1046/j.1365-2826.2002.00845.x.
Polychlorinated biphenyls (PCBs) cause abnormal development and physiology of the reproductive system. We hypothesized that these effects may be mediated, at least in part, by neuroendocrine cells in the hypothalamus that integrate inputs to and outputs from the central nervous system and reproductive systems. The effects of two PCB mixtures, Aroclor 1221 and Aroclor 1254, were tested on the hypothalamic GT1-7 cells, which synthesize and secrete the key hypothalamic hormone, gonadotropin-releasing hormone (GnRH). GT1-7 cells were treated for 24 h in dose-response experiments and GnRH gene expression and release were quantified. Aroclor 1221 was stimulatory to GnRH gene expression, particularly at post-transcriptional levels (GnRH cytoplasmic mRNA), and increased GnRH peptide levels, suggesting a post-translational regulation of GnRH biosynthesis. It also caused a qualitative increase in GT1-7 neurite outgrowth and cell confluency. Aroclor 1254 had very different effects from Aroclor 1221. It inhibited GnRH nuclear mRNA levels at high dosages, and stimulated GnRH mRNA at low doses, suggesting a post-transcriptional mechanism of regulation. Aroclor 1254 did not alter GnRH peptide levels. Qualitatively, Aroclor 1254 caused a retraction of GT1-7 cell processes and neurotoxicity at high dosages. In order to gauge the involvement of the oestrogen receptor in these responses, the oestrogen receptor antagonist, ICI 182,780 (ICI) was coadministered in other studies with the PCBs. While effects of Aroclor 1221 on GnRH gene expression were not blocked by ICI, its effects on GnRH peptide levels were blocked by ICI, indicating that some but not all of the effects of Aroclor 1221 are mediated by the classical oestrogen receptor alpha and/or beta. The inhibitory effects of Aroclor 1254 on GnRH gene expression were not prevented by ICI, although ICI itself had stimulatory effects on GnRH gene expression that were blocked by cotreatment with Aroclor 1254. These results demonstrate a novel mechanism for effects of the two PCBs directly on GnRH gene expression, and indicate a hypothalamic level for endocrine disruption by these environmental toxicants.
多氯联苯（PCBs）会导致生殖系统发育异常和生理功能紊乱。我们推测，这些影响可能至少部分是由下丘脑的神经内分泌细胞介导的，这些细胞整合了中枢神经系统和生殖系统的输入与输出。我们测试了两种多氯联苯混合物，即氯丹1221和氯丹1254，对下丘脑GT1 - 7细胞的影响，该细胞能合成并分泌关键的下丘脑激素促性腺激素释放激素（GnRH）。在剂量反应实验中，将GT1 - 7细胞处理24小时，然后对GnRH基因表达和释放进行定量分析。氯丹1221对GnRH基因表达有刺激作用，尤其是在转录后水平（GnRH细胞质mRNA），并增加了GnRH肽水平，这表明GnRH生物合成存在翻译后调控。它还使GT1 - 7神经突生长和细胞汇合度在质量上有所增加。氯丹1254的作用与氯丹1221非常不同。高剂量时它抑制GnRH核mRNA水平，低剂量时则刺激GnRH mRNA，提示存在转录后调控机制。氯丹1254没有改变GnRH肽水平。从质量上看，氯丹1254在高剂量时会导致GT1 - 7细胞突起回缩和神经毒性。为了评估雌激素受体在这些反应中的作用，在其他研究中，将雌激素受体拮抗剂ICI 182,780（ICI）与多氯联苯共同给药。虽然ICI没有阻断氯丹1221对GnRH基因表达的影响，但其对GnRH肽水平的影响被ICI阻断，这表明氯丹1221的部分而非全部作用是由经典的雌激素受体α和/或β介导的。氯丹1254对GnRH基因表达的抑制作用没有被ICI阻止，尽管ICI本身对GnRH基因表达有刺激作用，但这种作用被与氯丹1254共同处理所阻断。这些结果证明了两种多氯联苯直接影响GnRH基因表达的新机制，并表明这些环境毒物在内分泌干扰方面存在下丘脑水平的作用。
