Graduate Program in Genetics, Department of Genetics, Federal University of Paraná (UFPR), Curitiba, PR, Brazil.
Laboratory of Toxicology, Department of Pharmacological and Biomolecular Sciences 'Rodolfo Paoletti', Università Degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy.
Arch Toxicol. 2024 Jul;98(7):2153-2171. doi: 10.1007/s00204-024-03738-x. Epub 2024 May 28.
Diisopentyl phthalate (DiPeP) is primarily used as a plasticizer or additive within the production of polyvinyl chloride (PVC), and has many additional industrial applications. Its metabolites were recently found in urinary samples of pregnant women; thus, this substance is of concern as relates to human exposure. Depending upon the nature of the alcohol used in its synthesis, DiPeP may exist either as a mixture consisting of several branched positional isomers, or as a single defined structure. This article investigates the skin sensitization potential and immunomodulatory effects of DiPeP CAS No. 84777-06-0, which is currently marketed and classified as a UVCB substance, by in silico and in vitro methods. Our findings showed an immunomodulatory effect for DiPeP in LPS-induced THP-1 activation assay (increased CD54 expression). In silico predictions using QSAR TOOLBOX 4.5, ToxTree, and VEGA did not identify DiPeP, in the form of a discrete compound, as a skin sensitizer. The keratinocyte activation (Key Event 2 (KE2) of the adverse outcome pathway (AOP) for skin sensitization) was evaluated by two different test methods (HaCaT assay and RHE assay), and results were discordant. While the HaCaT assay showed that DiPeP can activate keratinocytes (increased levels of IL-6, IL-8, IL-1α, and ILA gene expression), in the RHE assay, DiPeP slightly increased IL-6 release. Although inconclusive for KE2, the role of DiPeP in KE3 (dendritic cell activation) was demonstrated by the increased levels of CD54 and IL-8 and TNF-α in THP-1 cells (THP-1 activation assay). Altogether, findings were inconclusive regarding the skin sensitization potential of the UVCB DiPeP-disagreeing with the results of DiPeP in the form of discrete compound (skin sensitizer by the LLNA assay). Additional studies are needed to elucidate the differences between DiPeP isomer forms, and to better understand the applicability domains of non-animal methods in identifying skin sensitization hazards of UVCB substances.
邻苯二甲酸二异戊酯（DiPeP）主要用作聚氯乙烯（PVC）生产中的增塑剂或添加剂，并有许多其他工业用途。最近在孕妇尿液样本中发现了其代谢物；因此，这种物质与人类接触有关，值得关注。根据其合成中使用的醇的性质，DiPeP 可能存在于由几种支链位置异构体组成的混合物中，或者作为单一的定义结构。本文通过体内和体外方法研究了 DiPeP（CAS 号 84777-06-0）的皮肤致敏潜力和免疫调节作用，目前市场上和分类为 UVCB 物质。我们的研究结果表明，DiPeP 在 LPS 诱导的 THP-1 激活试验中具有免疫调节作用（增加 CD54 表达）。使用 QSAR TOOLBOX 4.5、ToxTree 和 VEGA 的体内预测并未将 DiPeP 确定为离散化合物，因此不是皮肤致敏剂。角质形成细胞激活（皮肤致敏不良结局途径（AOP）的关键事件 2（KE2））通过两种不同的测试方法（HaCaT 测定和 RHE 测定）进行评估，结果不一致。虽然 HaCaT 测定表明 DiPeP 可以激活角质形成细胞（增加 IL-6、IL-8、IL-1α 和 ILA 基因表达），但在 RHE 测定中，DiPeP 略微增加了 IL-6 的释放。虽然对于 KE2 尚无定论，但 DiPeP 在 THP-1 细胞中增加 CD54 和 IL-8 和 TNF-α水平表明，在 KE3（树突状细胞激活）中起作用（THP-1 激活测定）。总之，关于 UVCB DiPeP 的皮肤致敏潜力的研究结果不一致——与 DiPeP 离散化合物形式的结果不一致（通过 LLNA 测定为皮肤致敏剂）。需要进一步研究以阐明 DiPeP 异构体形式之间的差异，并更好地理解非动物方法在识别 UVCB 物质皮肤致敏危害方面的适用范围。
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