Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea.
Toxicology. 2011 Oct 9;288(1-3):18-26. doi: 10.1016/j.tox.2011.06.013. Epub 2011 Jun 24.
Endocrine disruptors (EDs) affect the function of animal reproductive systems. Recently, 2,2',4,4'-tetrahydroxybenzophenone (BP2), which is a component of UV protection products, was found to be an ED that interferes with the thyroid hormone (TH) axis. However, BP2 activity in the testis has not been well addressed. In this study, we have examined the effects of BP2 on steroidogenesis in testicular Leydig cells in connection with thyroid hormone signaling, which is known to play an important role in testicular development and function. Our study showed that BP2 affected the expression of steroidogenic enzyme genes in testicular Leydig cells, which is differentially regulated by thyroid hormone/thyroid hormone receptor (TR) signaling. In MA-10 Leydig cell line, TR/T3 signaling increased the expression of P450c17 and P450scc, while it decreased the expression of StAR and 3β-HSD. Interestingly, BP2 affected the expression of steroidogenic enzyme genes in a manner opposite to that of T3 signaling. BP2 downregulated the TRα/T3-activation of P450c17 and P450scc expression while enhancing the TRα/T3-repression of StAR and 3β-HSD expression. Transient transfection analyses with promoter-reporter constructs revealed that BP2 altered the expression of steroidogenic enzyme genes by affecting the cAMP and Nur77-activated promoter activity of P450c17, StAR, and 3β-HSD. Animal experiments with mice revealed that BP2 decreased the production of testosterone in the testis by affecting the expression of some steroidogenic enzyme genes in vivo. Together, these findings elucidate a molecular mechanism of BP2 action underlying testicular steroidogenesis and also suggest that BP2 acts, in part, as a thyroid antagonist that affects steroidogenesis in the testis.
内分泌干扰物 (EDs) 会影响动物生殖系统的功能。最近，发现紫外线防护产品的一种成分 2,2',4,4'-四羟基二苯甲酮 (BP2) 是一种干扰甲状腺激素 (TH) 轴的 ED。然而，BP2 在睾丸中的活性尚未得到很好的解决。在这项研究中，我们研究了 BP2 对睾丸间质细胞类固醇生成的影响，因为甲状腺激素信号转导已知在睾丸发育和功能中起着重要作用。我们的研究表明，BP2 影响了睾丸间质细胞中类固醇生成酶基因的表达，这些基因受甲状腺激素/甲状腺激素受体 (TR) 信号的差异调节。在 MA-10 间质细胞系中，TR/T3 信号增加了 P450c17 和 P450scc 的表达，而降低了 StAR 和 3β-HSD 的表达。有趣的是，BP2 影响类固醇生成酶基因的表达方式与 T3 信号相反。BP2 下调了 TRα/T3 对 P450c17 和 P450scc 表达的激活，同时增强了 TRα/T3 对 StAR 和 3β-HSD 表达的抑制。启动子-报告基因构建体的瞬时转染分析表明，BP2 通过影响 P450c17、StAR 和 3β-HSD 的 cAMP 和 Nur77 激活启动子活性来改变类固醇生成酶基因的表达。用小鼠进行的动物实验表明，BP2 通过影响体内一些类固醇生成酶基因的表达，降低了睾丸中睾酮的产生。总之，这些发现阐明了 BP2 作用于睾丸类固醇生成的分子机制，并表明 BP2 部分作为一种甲状腺拮抗剂，影响睾丸中的类固醇生成。
