揭示ESR1功能障碍协调了与多基基物质暴露与骨关节炎的联系:来自多层次证据的见解
Jingyi Dang1, Xiaolong Shao1, Debin Cheng2
1Department of Joint Surgery, Xi'an Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710054, China.
Ecotoxicology and environmental safety
|December 10, 2025
概括
包括PFOA和PFOS在内的Per-和多基物质 (PFAS) 暴露与骨关节炎 (OA) 有关. 这项研究揭示了ESR1功能障碍作为一个关键机制,表明拉洛西芬作为一种潜在的治疗策略.
科学领域:
- 环境健康 环境健康
- 毒理学 毒理学 毒理学
- 分子生物学分子生物学
背景情况:
- 和多醇基物质 (PFAS) 是持久性污染物,与各种健康问题有关.
- 流行病学数据表明,PFAS暴露与骨关节炎 (OA) 患病率之间存在联系.
- PFAS诱导的OA背后的精确机制和分子标在很大程度上是未知的.
研究的目的:
- 阐明 perfluorooctanoic 酸 (PFOA) 和 perfluorooctanesulfonic 酸 (PFOS) 在骨关节炎发病过程中的作用.
- 确定在OA中受到PFAS暴露影响的关键分子标和途径.
- 探索与PFAS相关的OA的潜在治疗干预措施.
主要方法:
- 网络毒理学,转录组分析和机器学习的整合.
- 在PFAS暴露和OA之间确定共同的目标.
- 使用体外和单细胞转录组分析进行实验验证.
- 分子对接和动力学模拟以评估PFOA/PFOS与ESR1结合的情况.
- 对一种ESR1激动剂 (raloxifene) 的治疗潜力的评估.
主要成果:
- 确定了PFOA/PFOS和OA的38个常见目标,富含氧化应激,内分泌代谢和衰老途径.
- 确定ESR1是将PFOA/PFOS暴露与OA联系在一起的核心目标.
- 酸和酸直接与ESR1结合,降低其在冠状细胞中的表达,并加剧氧化应激和衰老.
- 低调ESR1导致软骨矩阵降解.
- 拉洛西芬治疗逆转了PFOA/PFOS对软骨细胞和软骨同质化的有害影响.
结论:
- ESR1功能障碍是PFAS暴露相关的骨关节炎的一个关键分子事件.
- 暴露于PFAS会通过氧化应激和老化,通过ESR1下调调节调节,导致OA病原发生.
- 用拉洛西芬等激动剂向ESR1可能为环境病因驱动的OA提供一种新的治疗策略.
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