替代阻燃剂 2-乙基己基二苯基磷酸盐 (EHDPP) 会破坏肝脂质体：来自人类 3D 肝球体细胞培养物的证据,Environmental Science & Technology

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替代阻燃剂 2-乙基己基二苯基磷酸盐 (EHDPP) 会破坏肝脂质体：来自人类 3D 肝球体细胞培养物的证据
Environmental Science & Technology ( IF 10.8 ) Pub Date : 2023-01-24 , DOI: 10.1021/acs.est.2c03998
Chander K Negi ₁ , Darshak Gadara ₁ , Jiri Kohoutek ₁ , Lola Bajard ₁ , Zdeněk Spáčil ₁ , Ludek Blaha ₁

Affiliation

本研究旨在评估反复接触磷酸 2-乙基己基二苯酯 (EHDPP) 对人类肝细胞的影响。体外利用三维 (3D) 肝球体细胞培养通过形态学、转录和生化测定探索 EHDPP 介导的代谢破坏的潜在机制。对单个肝细胞进行了脂质组学分析，以研究对细胞内脂质谱的影响，然后是肝细胞形态、生长、功能参数和细胞毒性评估。通过评估编码肝脏脂质代谢的关键基因的表达，使用基因水平分析描述了可能的机制。我们发现暴露于 1 μM 和 10 μM 的 EHDPP 7 天会改变人类 3D 肝球体的脂质分布。几种脂质类别的失调，包括甾醇脂质（胆固醇酯）、鞘脂（二氢神经酰胺、己糖神经酰胺、神经酰胺、鞘磷脂），甘油脂（甘油三酯）、甘油磷脂和脂肪酰基，以及 ACAT1、ACAT2、CYP27A1、ABCA1、GPAT2、PNPLA2、PGC1α 和 Nrf2 等基因的改变。我们的研究对 EHDPP 的代谢破坏作用提出了新的见解，并证明了类肝细胞作为一种药物的效用。体外细胞培养模型与组学技术（例如，脂质组学）相辅相成，用于机械毒性研究。

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Replacement Flame-Retardant 2-Ethylhexyldiphenyl Phosphate (EHDPP) Disrupts Hepatic Lipidome: Evidence from Human 3D Hepatospheroid Cell Culture

The present study aims to evaluate the effects of repeated exposure to 2-ethylhexyldiphenyl phosphate (EHDPP) on human liver cells. In vitro three-dimensional (3D) hepatospheroid cell culture was utilized to explore the potential mechanisms of EHDPP-mediated metabolic disruption through morphological, transcriptional, and biochemical assays. Lipidomics analysis was performed on the individual hepatospheroids to investigate the effects on intracellular lipid profiles, followed by hepatospheroid morphology, growth, functional parameters, and cytotoxicity evaluation. The possible mechanisms were delineated using the gene-level analysis by assessing the expression of key genes encoding for hepatic lipid metabolism. We revealed that exposure to EHDPP at 1 and 10 μM for 7 days alters the lipid profile of human 3D hepatospheroids. Dysregulation in several lipid classes, including sterol lipids (cholesterol esters), sphingolipids (dihydroceramide, hexosylceramide, ceramide, sphingomyelin), glycerolipids (triglycerides), glycerophospholipids, and fatty acyls, was noted along with alteration in genes including ACAT1, ACAT2, CYP27A1, ABCA1, GPAT2, PNPLA2, PGC1α, and Nrf2. Our study brings a novel insight into the metabolic disrupting effects of EHDPP and demonstrates the utility of hepatospheroids as an in vitro cell culture model complemented with omics technology (e.g., lipidomics) for mechanistic toxicity studies.

更新日期：2023-01-24

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