Molina-Molina José-Manuel, Escande Aurélie, Pillon Arnaud, Gomez Elena, Pakdel Farzad, Cavaillès Vincent, Olea Nicolás, Aït-Aïssa Sélim, Balaguer Patrick
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France; INSERM, U896, Montpellier, F-34298, France.
Toxicol Appl Pharmacol. 2008 Nov 1;232(3):384-95. doi: 10.1016/j.taap.2008.07.017. Epub 2008 Jul 29.
Benzophenone (BP) derivatives, BP1 (2,4-dihydroxybenzophenone), BP2 (2,2',4,4'-tetrahydroxybenzophenone), BP3 (2-hydroxy-4-methoxybenzophenone), and THB (2,4,4'-trihydroxybenzophenone) are UV-absorbing chemicals widely used in pharmaceutical, cosmetics, and industrial applications, such as topical sunscreens in lotions and hair sprays to protect skin and hair from UV irradiation. Studies on their endocrine disrupting properties have mostly focused on their interaction with human estrogen receptor alpha (hERalpha), and there has been no comprehensive analysis of their potency in a system allowing comparison between hERalpha and hERbeta activities. The objective of this study was to provide a comprehensive ER activation profile of BP derivatives using ER from human and fish origin in a battery of in vitro tests, i.e., competitive binding, reporter gene based assays, vitellogenin (Vtg) induction in isolated rainbow trout hepatocytes, and proliferation based assays. The ability to induce human androgen receptor (hAR)-mediated reporter gene expression was also examined. All BP derivatives tested except BP3 were full hERalpha and hERbeta agonists (BP2>THB>BP1) and displayed a stronger activation of hERbeta compared with hERalpha, the opposite effect to that of estradiol (E2). Unlike E2, BPs were more active in rainbow trout ERalpha (rtERalpha) than in hERalpha assay. All four BP derivatives showed anti-androgenic activity (THB>BP2>BP1>BP3). Overall, the observed anti-androgenic potencies of BP derivatives, together with their proposed greater effect on ERbeta versus ERalpha activation, support further investigation of their role as endocrine disrupters in humans and wildlife.
二苯甲酮（BP）衍生物，BP1（2,4 - 二羟基二苯甲酮）、BP2（2,2',4,4'-四羟基二苯甲酮）、BP3（2 - 羟基 - 4 - 甲氧基二苯甲酮）和THB（2,4,4'-三羟基二苯甲酮）是紫外线吸收化学品，广泛用于制药、化妆品和工业应用，如乳液和发胶中的局部防晒霜，以保护皮肤和头发免受紫外线照射。关于它们的内分泌干扰特性的研究大多集中在它们与人类雌激素受体α（hERα）的相互作用上，并且在一个能够比较hERα和hERβ活性的系统中，尚未对它们的效力进行全面分析。本研究的目的是通过一系列体外试验，即竞争性结合、基于报告基因的测定、分离的虹鳟肝细胞中的卵黄蛋白原（Vtg）诱导以及基于增殖的测定，利用人和鱼来源的雌激素受体，提供BP衍生物的全面雌激素受体激活概况。还检测了诱导人类雄激素受体（hAR）介导的报告基因表达的能力。除BP3外，所有测试的BP衍生物都是完全的hERα和hERβ激动剂（BP2>THB>BP1），并且与hERα相比，对hERβ的激活更强，这与雌二醇（E2）的作用相反。与E2不同，BP在虹鳟雌激素受体α（rtERα）中的活性比在hERα测定中更高。所有四种BP衍生物均表现出抗雄激素活性（THB>BP2>BP1>BP3）。总体而言，观察到的BP衍生物的抗雄激素效力，以及它们对ERβ激活相对于ERα激活的更大影响，支持进一步研究它们作为人类和野生动物内分泌干扰物的作用。
