Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany.
Department of GMP Process Development / ATMP Design, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany.
Environ Int. 2022 Jun;164:107279. doi: 10.1016/j.envint.2022.107279. Epub 2022 May 6.
The obesity pandemic is presumed to be accelerated by endocrine disruptors such as phthalate-plasticizers, which interfere with adipose tissue function. With the restriction of the plasticizer di-(2-ethylhexyl)-phthalate (DEHP), the search for safe substitutes gained importance. Focusing on the master regulator of adipogenesis and adipose tissue functionality, the peroxisome proliferator-activated receptor gamma (PPARγ), we evaluated 20 alternative plasticizers as well as their metabolites for binding to and activation of PPARγ and assessed effects on adipocyte lipid accumulation. Among several compounds that showed interaction with PPARγ, the metabolites MINCH, MHINP, and OH-MPHP of the plasticizers DINCH, DINP, and DPHP exerted the highest adipogenic potential in human adipocytes. These metabolites and their parent plasticizers were further analyzed in human preadipocytes and mature adipocytes using cellular assays and global proteomics. In preadipocytes, the plasticizer metabolites significantly increased lipid accumulation, enhanced leptin and adipsin secretion, and upregulated adipogenesis-associated markers and pathways, in a similar pattern to the PPARγ agonist rosiglitazone. Proteomics of mature adipocytes revealed that both, the plasticizers and their metabolites, induced oxidative stress, disturbed lipid storage, impaired metabolic homeostasis, and led to proinflammatory and insulin resistance promoting adipokine secretion. In conclusion, the plasticizer metabolites enhanced preadipocyte differentiation, at least partly mediated by PPARγ activation and, together with their parent plasticizers, affected the functionality of mature adipocytes similar to reported effects of a high-fat diet. This highlights the need to further investigate the currently used plasticizer alternatives for potential associations with obesity and the metabolic syndrome.
肥胖症大流行被认为是内分泌干扰物（如邻苯二甲酸酯类增塑剂）加速的，这些物质干扰脂肪组织功能。随着增塑剂邻苯二甲酸二（2-乙基己基）酯（DEHP）的限制，寻找安全替代品变得尤为重要。我们专注于脂肪生成和脂肪组织功能的主调控因子过氧化物酶体增殖物激活受体γ（PPARγ），评估了 20 种替代增塑剂及其代谢物与 PPARγ 的结合和激活，并评估了它们对脂肪细胞脂质积累的影响。在几种与 PPARγ 相互作用的化合物中，增塑剂 DINCH、DINP 和 DPHP 的代谢物 MINCH、MHINP 和 OH-MPHP 对人脂肪细胞表现出最高的成脂潜力。这些代谢物及其母体增塑剂在人前脂肪细胞和成熟脂肪细胞中进一步使用细胞测定和整体蛋白质组学进行了分析。在前脂肪细胞中，增塑剂代谢物显著增加了脂质积累，增强了瘦素和脂联素的分泌，并上调了与脂肪生成相关的标志物和途径，与 PPARγ 激动剂罗格列酮的作用模式相似。成熟脂肪细胞的蛋白质组学研究表明，增塑剂及其代谢物都诱导了氧化应激，扰乱了脂质储存，损害了代谢稳态，并导致促炎和胰岛素抵抗促进脂肪细胞因子的分泌。总之，增塑剂代谢物增强了前脂肪细胞的分化，至少部分是通过 PPARγ 激活介导的，与其母体增塑剂一起，影响成熟脂肪细胞的功能，类似于高脂肪饮食报道的作用。这凸显了需要进一步研究目前使用的增塑剂替代品，以调查它们与肥胖症和代谢综合征之间的潜在关联。
