Yang Liwei, Ju Aipeng, Huang Yawen, Jiang Huibin, Ye Jiaming, Qi Wen, Zhou Liting
Department of Occupational and Environmental Health, School of Public Health, Jilin University, Changchun, China.
Department of Human Anatomy, College of Basic Medical Sciences, Jilin University, Changchun, China.
Front Toxicol. 2025 Jul 1;7:1623830. doi: 10.3389/ftox.2025.1623830. eCollection 2025.
Environmental endocrine disruptors (EEDs) had been proved as significant risk factors for liver fibrosis. However, which specific pollutants predominantly related to liver fibrosis remain unidentified. This study was aimed to screen in the specific EEDs using NHANES data and further validate the findings in BRL-3A hepatocytes.
A total of 5,843 adult participants (≥18 years) incorporating data on EEDs/metabolites, demographics, lifestyle factors, and vibration-controlled transient elastography (VCTE) measurements were gated from the NHANES. Advanced analytical methods including LASSO regression, multivariable logistic regression, and restricted cubic spline (RCS) modeling were implemented for pollutant screening. validation involved treating BRL-3A hepatocytes with identified EEDs, followed by comprehensive assessment of fibrotic markers through quantitative PCR, Western blotting, and extracellular matrix component analysis.
Di-n-butyl phthalate (DBuP), the metabolites of tributyl phosphate (TBP), was demonstrated to be the strongest EEDs associated with liver fibrosis ( < 0.05). Mechanistic studies revealed that 1 μM TBP significantly elevated extracellular matrix components (HA: +130%, Ⅳ-Col: +22%) through MMP9 upregulation at both transcriptional (1.8-fold increase) and translational (1.73-fold increase) levels in hepatocytes.
Our findings establish TBP as a novel environmental determinant positively correlated with liver fibrosis in U.S. adults. The profibrotic effects appear mediated through transcriptional activation of extracellular matrix remodeling genes, particularly via MMP9 pathway modulation.
环境内分泌干扰物（EEDs）已被证明是肝纤维化的重要风险因素。然而，哪些特定污染物与肝纤维化的主要关联仍不明确。本研究旨在利用美国国家健康与营养检查调查（NHANES）数据筛选特定的环境内分泌干扰物，并在BRL-3A肝细胞中进一步验证研究结果。
从NHANES中选取了总共5843名成年参与者（≥18岁），纳入了环境内分泌干扰物/代谢物、人口统计学、生活方式因素以及振动控制瞬时弹性成像（VCTE）测量数据。采用包括套索回归、多变量逻辑回归和受限立方样条（RCS）建模在内的先进分析方法进行污染物筛选。验证过程包括用已确定的环境内分泌干扰物处理BRL-3A肝细胞，随后通过定量PCR、蛋白质印迹法和细胞外基质成分分析对纤维化标志物进行全面评估。
邻苯二甲酸二正丁酯（DBuP），即磷酸三丁酯（TBP）的代谢物，被证明是与肝纤维化关联最强的环境内分泌干扰物（<0.05）。机制研究表明，1μM TBP通过在肝细胞转录水平（增加1.8倍）和翻译水平（增加1.73倍）上调基质金属蛋白酶9（MMP9），显著提高细胞外基质成分（透明质酸：增加130%，Ⅳ型胶原：增加22%）。
我们的研究结果确定TBP是一种与美国成年人肝纤维化呈正相关的新型环境决定因素。促纤维化作用似乎是通过细胞外基质重塑基因的转录激活介导的，特别是通过MMP9途径调节。
