Hui Qinming, Du Xinru, Li Maoxuan, Liu Sha, Wang Zhendong, Song Sisi, Gao Yancheng, Yang Ye, Zhou Chunxiao, Li Yuan
Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China.
The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.
Front Immunol. 2025 Mar 10;16:1552150. doi: 10.3389/fimmu.2025.1552150. eCollection 2025.
Hepatic osteodystrophy (HOD) is an important public health issue that severely affects human health. The pathogenesis of HOD is complex, and exposure to environmental pollutants plays an important role. Di-(2-ethylhexyl) phthalate (DEHP) is a persistent environmental endocrine toxicant that is present in many products, and the liver is an important target organ for its toxic effects. Our research aimed to investigate the effects of DEHP on HOD, and to reveal the underlying mechanisms and the potential key preventive approaches.
The daily intake EDI of DEHP and bone density indicators for men and women from 2009 to 2018 were screened and organized from the NHANES database to reveal the population correlation between EDI and BMD; C57BL/6 female and male mice were selected to construct an animal model of DEHP induced HOD, exploring the fuchtions and mechanisms of DEHP on osteoporosis; the novel small molecule inhibitor imICA was used to inhibit the process of DEHP induced osteoporosis, further exploring the targeted inhibition pathway of DEHP induced HOD.
Male and female populations were exposed to a relatively lower concentration of DEHP, and that only the male population exhibited a negative correlation between DEHP exposure and bone mineral density. An in vivo study confirmed that a low dose of DEHP caused liver lesions, disrupted liver function, and induced osteoporosis in male but not female C57BL/6J mice. Regarding the molecular mechanisms, a low dose of DEHP activated the hepatic 14-3-3η/nuclear factor κB (NF-κB) positive feedback loop, which in turn modified the secretory proteome associated with bone differentiation, leading to HOD. Finally, we revealed that targeting the 14-3-3η/ NF-κB feedback loop using our novel 14-3-3η inhibitor (imICA) could prevent DEHP-induced HOD.
A low dose of DEHP activated the hepatic 14-3-3η/ NF-κB positive feedback loop, which in turn modified the secretory proteome associated with bone differentiation and elevated IL-6 and CXCL1 levels, leading to HOD. Targeted 14-3-3η/NF-κB feedback loop using our novel 14-3-3η inhibitor, imICA, prevented DEHP-induced HOD.
肝性骨营养不良（HOD）是一个严重影响人类健康的重要公共卫生问题。HOD的发病机制复杂，环境污染物暴露在其中起重要作用。邻苯二甲酸二（2-乙基己基）酯（DEHP）是一种存在于许多产品中的持久性环境内分泌毒物，肝脏是其毒性作用的重要靶器官。我们的研究旨在探讨DEHP对HOD的影响，并揭示其潜在机制和可能的关键预防措施。
从美国国家健康与营养检查调查（NHANES）数据库中筛选并整理2009年至2018年男性和女性的DEHP每日摄入量估计每日摄入量（EDI）和骨密度指标，以揭示EDI与骨密度之间的人群相关性；选择C57BL/6雌性和雄性小鼠构建DEHP诱导的HOD动物模型，探讨DEHP对骨质疏松症的作用及机制；使用新型小分子抑制剂imICA抑制DEHP诱导的骨质疏松症过程，进一步探索DEHP诱导HOD的靶向抑制途径。
男性和女性人群接触的DEHP浓度相对较低，且仅男性人群中DEHP暴露与骨矿物质密度呈负相关。一项体内研究证实，低剂量的DEHP会导致雄性C57BL/6J小鼠肝脏损伤、肝功能紊乱并诱发骨质疏松症，而雌性小鼠未出现此情况。在分子机制方面，低剂量的DEHP激活了肝脏14-3-3η/核因子κB（NF-κB）正反馈回路，进而改变了与骨分化相关的分泌蛋白质组，导致HOD。最后，我们发现使用新型14-3-3η抑制剂（imICA）靶向14-3-3η/NF-κB反馈回路可预防DEHP诱导的HOD。
低剂量的DEHP激活了肝脏14-3-3η/NF-κB正反馈回路，进而改变了与骨分化相关的分泌蛋白质组，升高了白细胞介素-6（IL-6）和CXC趋化因子配体1（CXCL1）水平，导致HOD。使用我们的新型14-3-3η抑制剂imICA靶向14-3-3η/NF-κB反馈回路可预防DEHP诱导的HOD。
