Okazaki Hiroyuki, Takeda Shuso, Kakizoe Kazuhiro, Taniguchi Aya, Tokuyasu Miki, Himeno Taichi, Ishii Hiroyuki, Kohro-Ikeda Eriko, Haraguchi Koichi, Watanabe Kazuhito, Aramaki Hironori
Department of Molecular Biology, Daiichi University of Pharmacy.
Laboratory of Xenobiotic Metabolism and Environmental Toxicology, Faculty of Pharmaceutical Sciences, Hiroshima International University (HIU).
Biol Pharm Bull. 2017;40(11):1909-1916. doi: 10.1248/bpb.b17-00427.
Bisphenols are endocrine disruptors that are widely found in the environment. Accumulating experimental evidence suggests an adverse interaction between bisphenols and estrogen signaling. Most studies have performed experiments that focused on estrogen receptor (ER) engagement by bisphenols. Therefore, the effects of bisphenols on the expression of ERα (ESR1) and ERβ (ESR2) remain largely unknown. In the present study, we examined the effects of four bisphenols: bisphenol A (BPA), bisphenol B (BPB), bisphenol S (BPS), and bisphenol AF (BPAF), on estrogen signaling in two human breast cancer cell lines (MCF-7 and SK-BR-3). Among these bisphenols, BPAF up-regulated the expression of ERβ, and this was coupled with the abrogation of estrogen response element (ERE)-mediated transcriptional activities as well as the down-regulation of Cdc2 expression in MCF-7 cells, without influencing the expression of ERα. BPAF functioned as an agonist of ERα at lower concentrations (nanomolar order), but did not exhibit any modulatory action on ERα transiently expressed in SK-BR-3 cells in the presence or absence of 17β-estradiol (E2) at higher concentrations (micromolar order). The introduction of ERβ cDNA resulted in greater reductions in MCF-7 cell viability than with BPAF alone. Since ERβ is a suppressive molecule of ERα function, these results provide rational evidence for BPAF functioning as an anti-estrogenic compound via the induction of ERβ at higher concentrations.
双酚是环境中广泛存在的内分泌干扰物。越来越多的实验证据表明双酚与雌激素信号之间存在不良相互作用。大多数研究进行的实验都集中在双酚与雌激素受体（ER）的结合上。因此，双酚对雌激素受体α（ESR1）和雌激素受体β（ESR2）表达的影响在很大程度上仍然未知。在本研究中，我们检测了四种双酚：双酚A（BPA）、双酚B（BPB）、双酚S（BPS）和双酚AF（BPAF）对两种人乳腺癌细胞系（MCF-7和SK-BR-3）中雌激素信号的影响。在这些双酚中，BPAF上调了ERβ的表达，这与雌激素反应元件（ERE）介导的转录活性的消除以及MCF-7细胞中Cdc2表达的下调相关，而不影响ERα的表达。在较低浓度（纳摩尔级）下，BPAF作为ERα的激动剂发挥作用，但在较高浓度（微摩尔级）下，无论是否存在17β-雌二醇（E2），对SK-BR-3细胞中瞬时表达的ERα均未表现出任何调节作用。引入ERβ cDNA导致MCF-7细胞活力的降低比单独使用BPAF时更大。由于ERβ是ERα功能的抑制分子，这些结果为BPAF在较高浓度下通过诱导ERβ发挥抗雌激素化合物的作用提供了合理证据。
