Jana N R, Sarkar S, Ishizuka M, Yonemoto J, Tohyama C, Sone H
Regional Environment Division, Environmental Health Sciences Division, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki, 305 0053, Japan.
Biochem Biophys Res Commun. 1999 Mar 24;256(3):462-8. doi: 10.1006/bbrc.1999.0367.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds modulate various endocrine functions by enhancing ligand metabolism, altering hormone synthesis, down regulating receptor levels, and interfering with gene transcription. In the present study, we investigated the effects of TCDD on testosterone signal transduction pathways and vice versa in the androgen receptor (AR) positive LNCaP prostate cancer cell line. TCDD induced CYP1A1 mRNA and related enzyme activity in these cells, with dose and time-dependence. Both normal and testosterone-stimulated cell growth was inhibited by TCDD. The expression levels of the aryl hydrocarbon receptor (AhR), the aryl hydrocarbon receptor nuclear translocator (ARNT), and AR were not affected by exposure to TCDD at a dose of 10 nM for a 24 hr time period. Testosterone treatment dose-dependently inhibited the TCDD-induced CYP1A1 mRNA accumulation and related enzyme activity. Reciprocally, TCDD also dose-dependently inhibited testosterone-dependent transcriptional activity and testosterone-regulated prostate specific antigen (PSA) expression. Taken together, these results demonstrate antiandrogenic functions of TCDD and a specific ligand-induced bilateral transcriptional interference between TCDD and testosterone mediated signal transduction pathways.
2,3,7,8-四氯二苯并-对-二噁英（TCDD）及相关化合物通过增强配体代谢、改变激素合成、下调受体水平以及干扰基因转录来调节多种内分泌功能。在本研究中，我们研究了TCDD对雄激素受体（AR）阳性的LNCaP前列腺癌细胞系中睾酮信号转导途径的影响，反之亦然。TCDD在这些细胞中诱导CYP1A1 mRNA及相关酶活性，呈剂量和时间依赖性。正常细胞生长和睾酮刺激的细胞生长均被TCDD抑制。在10 nM剂量下暴露24小时，芳烃受体（AhR）、芳烃受体核转运蛋白（ARNT）和AR的表达水平不受TCDD影响。睾酮处理呈剂量依赖性地抑制TCDD诱导的CYP1A1 mRNA积累及相关酶活性。相反，TCDD也呈剂量依赖性地抑制睾酮依赖性转录活性和睾酮调节的前列腺特异性抗原（PSA）表达。综上所述，这些结果证明了TCDD的抗雄激素功能以及TCDD与睾酮介导的信号转导途径之间特定的配体诱导的双向转录干扰。
