<br>2,4-二叔丁基苯酚暴露损害成骨分化,Toxicology and Applied Pharmacology

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2,4-二叔丁基苯酚暴露损害成骨分化
Toxicology and Applied Pharmacology ( IF 3.3 ) Pub Date : 2023-01-20 , DOI: 10.1016/j.taap.2023.116386
Thanh-Bình Dương ₁ , Raj Dwivedi ₁ , Lisa J Bain ₁

Affiliation

2,4-二叔丁基苯酚（2,4-DTBP）是一种合成抗氧化剂，用于聚乙烯交联聚合物（PEX）配水管道和食品相关塑料。2,4-DTBP 可以从塑料材料中浸出，已在母乳、脐带血和胎盘组织中发现，因此人们担心这种化合物可能会干扰胎儿发育。本研究的目的是评估 2,4-DTBP 对细胞分化的影响。在 40 天内将人诱导多能干细胞（HiPS）分化为成骨细胞或成肌细胞，并分析体节、皮肤肌节、菌核、成肌细胞和成骨细胞发育的标志物。当作为干细胞培养时，2,4-DTBP 不会改变细胞活力和标志物表达（NANOG， OCT4）。然而，在分化为体节样细胞后，2,4-DTBP 的 MEOX1 和 TBX6 转录本水平降低，而 NANOG 和 OCT4 又以剂量依赖性方式上调。在菌核组样阶段，0.5 μM 和 1.0 μM 2,4-DTBP 暴露组的 PAX9 mRNA 降低了 2 倍。分化成成骨细胞样谱系 40 天后，暴露于 2,4-DTBP 以剂量依赖性方式显著降低成骨转录本 RUNX2 和 OSX 的表达。此外，0.5 μM 和 1.0 μM 处理组钙沉积物的茜素红染色降低。相比之下，肌生成不受 2,4-DTBP 暴露的影响。有趣的是，KEAP1 表达在硬化切开样细胞中显著增加，但在皮肤动植物样细胞中表达降低，这可能表明一种作用机制。总体而言，这项研究表明，2,4-DTBP 可以延迟硬化切开器和成骨细胞发育过程中的关键过程，从而导致暴露个体可能出现骨骼发育问题。

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2,4-di-tert-butylphenol exposure impairs osteogenic differentiation

2,4-di-tert-butylphenol (2,4-DTBP) is a synthetic antioxidant used in polyethylene crosspolymer (PEX) water distribution pipes and food-related plastics. 2,4-DTBP can leach from plastic materials and has been found in breast milk, cord blood, and placental tissue, giving rise to the concern that this compound may interfere with fetal development. The objective of this study is to assess the impacts of 2,4-DTBP on cellular differentiation. Human induced pluripotent stem (HiPS) cells were differentiated into osteoblasts or myoblasts over 40 days, and analyzed for markers of somite, dermomyotome, sclerotome, myoblast, and osteoblast development. When cultured as stem cells, 2,4-DTBP did not alter cell viability and expression of markers (NANOG, OCT4). However, upon differentiation into somite-like cells, 2,4-DTBP had reduced levels of MEOX1 and TBX6 transcripts, while NANOG and OCT4 were in turn upregulated in a dose-dependent manner. At the sclerotome-like stage, PAX9 mRNA decreased by 2-fold in the 0.5 μM and 1.0 μM 2,4-DTBP exposure groups. After 40 days of differentiation into an osteoblast-like lineage, exposure to 2,4-DTBP significantly reduced expression of the osteogenesis transcripts RUNX2 and OSX in a dose-dependent manner. Further, Alizarin Red staining of calcium deposits was decreased in the 0.5 μM and 1.0 μM treatment groups. In contrast, myogenesis was not affected by 2,4-DTBP exposure. Interestingly, KEAP1 expression was significantly increased in the sclerotomal-like cells, but decreased in the dermomytomal-like cells, which may suggest a mechanism of action. Overall, this study shows that 2,4-DTBP can delay key processes during sclerotome and osteoblast development, leading to a potential for bone developmental issues in exposed individuals.

更新日期：2023-01-20

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