Tian Yaru, Xu Miao, Shang Hailin, You Lijuan, Yang Jing, Jia Xudong, Yang Hui, Wu Yongning, Yang Xingfen, Wan Yi
Food Safety and Health Research Center, School of Public Health, Southern Medical University, Guangzhou 510515, China.
NHC Key Laboratory of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment, Beijing 100021, China.
Toxics. 2024 Mar 14;12(3):214. doi: 10.3390/toxics12030214.
Phthalic acid esters (PAEs), commonly used as plasticizers, are pervasive in the environment, leading to widespread human exposure. The association between phthalate exposure and metabolic disorders has been increasingly recognized, yet the precise biological mechanisms are not well-defined. In this study, we explored the effects of monoethylhexyl phthalate (MEHP) and monocyclohexyl phthalate (MCHP) on glucose and lipid metabolism in human hepatocytes and adipocytes. In hepatocytes, MEHP and MCHP were observed to enhance lipid uptake and accumulation in a dose-responsive manner, along with upregulating genes involved in lipid biosynthesis. Transcriptomic analysis indicated a broader impact of MEHP on hepatic gene expression relative to MCHP, but MCHP particularly promoted the expression of the gluconeogenesis key enzymes G6PC and FBP1. In adipocytes, MEHP and MCHP both increased lipid droplet formation, mimicking the effects of the Peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone (Rosi). Transcriptomic analysis revealed that MEHP predominantly altered fatty acid metabolism pathways in mature adipocytes (MA), whereas MCHP exhibited less impact. Metabolic perturbations from MEHP and MCHP demonstrate shared activation of the PPARs pathway in hepatocytes and adipocytes, but the cell-type discrepancy might be attributed to the differential expression of PPARγ. Our results indicate that MEHP and MCHP disrupt glucose and lipid homeostasis in human liver and adipose through mechanisms that involve the PPAR and adenosine monophosphate-activated protein kinase (AMPK) signaling pathways, highlighting the nuanced cellular responses to these environmental contaminants.
邻苯二甲酸酯（PAEs）常用作增塑剂，在环境中广泛存在，导致人类普遍暴露。邻苯二甲酸酯暴露与代谢紊乱之间的关联已得到越来越多的认识，但其确切的生物学机制尚不清楚。在本研究中，我们探讨了邻苯二甲酸单乙基己酯（MEHP）和邻苯二甲酸单环己酯（MCHP）对人肝细胞和脂肪细胞葡萄糖和脂质代谢的影响。在肝细胞中，观察到MEHP和MCHP以剂量反应方式增强脂质摄取和积累，同时上调参与脂质生物合成的基因。转录组分析表明，相对于MCHP，MEHP对肝脏基因表达的影响更广泛，但MCHP特别促进了糖异生关键酶G6PC和FBP1的表达。在脂肪细胞中，MEHP和MCHP均增加脂滴形成，模拟过氧化物酶体增殖物激活受体γ（PPARγ）激动剂罗格列酮（Rosi）的作用。转录组分析显示，MEHP主要改变成熟脂肪细胞（MA）中的脂肪酸代谢途径，而MCHP的影响较小。MEHP和MCHP引起的代谢紊乱表明，肝细胞和脂肪细胞中PPARs途径共同激活，但细胞类型差异可能归因于PPARγ的差异表达。我们的结果表明，MEHP和MCHP通过涉及PPAR和腺苷单磷酸激活蛋白激酶（AMPK）信号通路的机制破坏人肝脏和脂肪组织中的葡萄糖和脂质稳态，突出了细胞对这些环境污染物的细微反应。
