Cheng Wei, Zhou Yue, Xie Yichun, Li Yan, Zhou Ren, Wang Hui, Feng Yan, Wang Yan
School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Sci Total Environ. 2023 Jan 1;854:158585. doi: 10.1016/j.scitotenv.2022.158585. Epub 2022 Sep 8.
Human are exposed to microplastics (MP) via inhalation or ingestion daily and inevitably. The liver is an important target organ of MP. Bisphenol A (BPA) is one of commonly used plasticizers. It is added in plastics, but also generally detected in the biological samples of human beings. However, the combined toxic effect of MP and BPA on human liver is unclear. In this study, a novel 3D in vitro model, the liver organoid (LO) derived from human-pluripotent stem cells, has been utilized to explore the 1 μm polystyrene (PS)-induced hepatotoxicity with BPA individually and jointly. Conclusively, all the changes in the cytotoxicity, cellular and molecular makers regarding the energy supplement, hepatic injury, oxidative stress, inflammatory response, disruption in the lipid accumulation, as well as epigenetics regulation induced by BPA or PS on the LOs individually were comparable to previous study. The BPA levels in the culture medium were declined by the added PS. The combined adverse effect of PS and BPA on the LOs was identified to be synergistic upon deteriorated hepatotoxicity and interfered the gene panels related to multiple processes of lipid metabolism, together with the proteins of HNF4A, CD36, ACC1, CPT1A, CYP2E1, ERα and ERβ. Specifically, PS didn't change the ERα or ERβ individually, but when the LOs were co-exposed to PS and BPA, the ERα further elevated significantly and synergistically. Our findings highlight the metabolic-related health risk due to co-exposure to MP and BPA, even at low-doses equivalent to human internal exposure level. Based on these findings, the potential adverse outcome pathway related to PS and BPA singly and jointly were proposed, predicting two possible outcomes to be hepatic steatosis. Moreover, the ERα and HNF4A were proposed to be potential candidate markers to investigate the "vector-like effect" of PS in the present of BPA.
人类每天不可避免地通过吸入或摄入接触微塑料（MP）。肝脏是MP的重要靶器官。双酚A（BPA）是常用的增塑剂之一。它被添加到塑料制品中，并且在人类生物样本中也普遍被检测到。然而，MP和BPA对人类肝脏的联合毒性作用尚不清楚。在本研究中，一种新型的三维体外模型，即源自人多能干细胞的肝类器官（LO），已被用于探究1μm聚苯乙烯（PS）单独及与BPA联合诱导的肝毒性。总之，BPA或PS单独对LO诱导的细胞毒性、与能量补充、肝损伤、氧化应激、炎症反应、脂质蓄积破坏以及表观遗传调控相关的细胞和分子标志物的所有变化与先前研究相当。添加的PS使培养基中的BPA水平下降。PS和BPA对LO的联合不良作用被确定为协同作用，表现为肝毒性恶化，并干扰了与脂质代谢多个过程相关的基因谱，以及肝细胞核因子4α（HNF4A）、脂肪酸转运蛋白CD36、乙酰辅酶A羧化酶1（ACC1）、肉碱/有机阳离子转运体1A（CPT1A）、细胞色素P450 2E1（CYP2E1）、雌激素受体α（ERα）和雌激素受体β（ERβ）的蛋白。具体而言，PS单独并未改变ERα或ERβ，但当LO同时暴露于PS和BPA时，ERα进一步显著且协同升高。我们的研究结果强调了即使在相当于人类体内暴露水平的低剂量下，共同接触MP和BPA所带来的与代谢相关的健康风险。基于这些发现，提出了与PS和BPA单独及联合作用相关的潜在不良结局途径，预测了两种可能的结局为肝脂肪变性。此外，提出ERα和HNF4A作为潜在的候选标志物，以研究在BPA存在下PS的“载体样效应”。
