Perfluorobutanoic acid (PFBA) is an emerging contaminant that was demonstrated to exhibit estrogen effects via action on classic estrogen receptors (ERs) in a low-activity manner. The purpose of the present study is to reveal the estrogen disruption effect and mechanism of PFBA via estrogen-related receptor γ (ERRγ) pathways. In vivo experiment indicated that PFBA accumulated in zebrafish ovary and caused ovarian injury, with disturbing sex hormone levels and interfering gene expression related to estrogen synthesis and follicle regulation. In vitro, with cell proliferation assay, PFBA could promote estrogen-sensitive endometrial cancer cell Ishikawa proliferation at lowest observed effective concentrations (LOEC) 10 nM, which was close to human exposure levels. And cell proliferation was inhibited by ERRγ antagonist GSK5182. By fluorescence competitive binding assay, molecular docking and luciferase reporter gene assays, it demonstrated that PFBA could directly bind with ERRγ and activate ERRγ transcriptional activities with a LOEC of 10 nM. Furthermore, PFBA up-regulated the proliferation-related factors downstream of ERRγ and inhibited by PI3K/Akt inhibitor LY294002, which also suppressed the cell proliferation induced by PFBA. Taken together, the results revealed that PFBA had estrogen effects at the human-related exposure concentration, and demonstrated a new estrogen effects mechanism of PFBA via ERRγ pathway.

中文翻译：

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全氟丁酸：一种短链全氟烷基物质，通过雌激素相关受体γ途径表现出雌激素作用


全氟丁酸 （PFBA） 是一种新兴污染物，已被证明通过以低活性方式作用于经典雌激素受体 （ER） 而表现出雌激素作用。本研究的目的是揭示 PFBA 通过雌激素相关受体 γ （ERRγ） 通路的雌激素破坏作用和机制。体内实验表明，PFBA 在斑马鱼卵巢中积累并导致卵巢损伤，干扰性激素水平和干扰与雌激素合成和卵泡调节相关的基因表达。在体外，通过细胞增殖测定，PFBA 可以在最低观察到的有效浓度 （LOEC） 10 nM 下促进雌激素敏感的子宫内膜癌细胞 Ishikawa 增殖，这接近人类暴露水平。细胞增殖受到 ERRγ 拮抗剂 GSK5182 的抑制。通过荧光竞争性结合测定、分子对接和荧光素酶报告基因测定，证明 PFBA 可以直接与 ERRγ 结合并激活 ERRγ 转录活性，LOEC 为 10 nM。此外，PFBA 上调 ERRγ 下游的增殖相关因子，并被 PI3K/Akt 抑制剂 LY294002 抑制，这也抑制了 PFBA 诱导的细胞增殖。综上所述，结果显示 PFBA 在与人体相关的暴露浓度下具有雌激素作用，并证明了 PFBA 通过 ERRγ 通路的雌激素作用新机制。