Li Chang-Lei, Yao Zhi-Yuan, Zhang Yin-Feng, Cui Xiao-Tong, Sun Ao, Cao Jing-Yu, Wang Zu-Sen
Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
Department of Thoracic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
Front Endocrinol (Lausanne). 2025 May 22;16:1606654. doi: 10.3389/fendo.2025.1606654. eCollection 2025.
Bisphenols (BPs), including bisphenol A (BPA) and its substitutes (BPS, BPF), are ubiquitous environmental contaminants with emerging links to metabolic disorders. This review synthesizes current evidence on the role of BP exposure in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), a global health crisis affecting 25% of adults worldwide. Epidemiological studies reveal significant positive associations between urinary/serum BP levels and NAFLD risk, particularly in males, with maternal exposure correlating to transgenerational metabolic dysfunction. Mechanistically, BPs disrupt hepatic lipid homeostasis by activating PPAR-γ and suppressing fatty acid oxidation while concurrently inducing insulin resistance via impaired IRS-1/PI3K/Akt signaling. Oxidative stress, NLRP3 inflammasome activation, and gut-liver axis perturbations further exacerbate steatosis and inflammation. Co-exposure with phthalates or high-fat diets amplifies hepatotoxicity, highlighting synergistic environmental risks. Critically, developmental and sex-specific susceptibility underscores the need for tailored interventions. We propose preventive strategies to mitigate NAFLD progression, including BP avoidance and policy reforms. This work bridges gaps between environmental epidemiology and molecular toxicology, emphasizing BPs as modifiable drivers of metabolic liver disease.
双酚类物质（BPs），包括双酚A（BPA）及其替代品（双酚S、双酚F），是普遍存在的环境污染物，与代谢紊乱的关联日益凸显。本综述综合了当前关于接触双酚类物质在非酒精性脂肪性肝病（NAFLD）发病机制中作用的证据，NAFLD是一场全球健康危机，影响着全球25%的成年人。流行病学研究表明，尿液/血清双酚类物质水平与NAFLD风险之间存在显著正相关，尤其是在男性中，母体接触双酚类物质与跨代代谢功能障碍相关。从机制上讲，双酚类物质通过激活过氧化物酶体增殖物激活受体γ（PPAR-γ）和抑制脂肪酸氧化来破坏肝脏脂质稳态，同时通过受损的胰岛素受体底物1（IRS-1）/磷脂酰肌醇-3激酶（PI3K）/蛋白激酶B（Akt）信号传导诱导胰岛素抵抗。氧化应激、NOD样受体蛋白3（NLRP3）炎性小体激活和肠-肝轴紊乱进一步加剧脂肪变性和炎症。与邻苯二甲酸盐或高脂饮食共同接触会放大肝毒性，突出了协同的环境风险。至关重要的是，发育和性别特异性易感性强调了采取针对性干预措施的必要性。我们提出了减轻NAFLD进展的预防策略，包括避免接触双酚类物质和政策改革。这项工作弥合了环境流行病学和分子毒理学之间的差距，强调双酚类物质是代谢性肝病的可改变驱动因素。
