邻苯二甲酸二(乙基己基)酯(DEHP)是一种普遍存在的环境污染物,人类通过多种途径暴露于其中。该物质的人体健康风险评估最近已经更新,关注生殖毒性,包括DEHP,在被归类为致癌的化学品清单中,诱变,或对生殖有毒(CMR)。此外,基于其在啮齿动物中的致癌性,DEHP也被定义为可能并且可能对人类致癌。然而,DEHP的作用机制及其在人类中的相关性尚不清楚。啮齿动物数据表明DEHP通过与多个分子信号相关的非基因毒性机制诱导癌症。包括PPARα激活,脂肪酸代谢的扰动,诱导细胞增殖,细胞凋亡减少,活性氧的产生,和氧化应激。根据DEHP毒理学数据集,已经使用不同的方案和细胞模型进行了几种体外细胞转化试验,以产生不同的结果。本研究旨在通过在标准细胞转化试验中使用A31-1-1BALB/c-3T3细胞系来评估DEHP的致癌潜力。此外,进行转录组学分析以探索分子反应并鉴定受影响的毒理学途径。尽管DEHP处理在BALB/c-3T3细胞中没有诱导转化,转录组学结果揭示了与DEHP代谢相关的几种途径的显着调节,与全身代谢相关的组织特异性功能,和具有多效性结果的基础细胞信号传导。在这些信号通路中,细胞调节信号通路的调节,比如Notch,Wnt,和TGF-β,可以突出显示。在代谢和神经生理学中具有双重功能的此类基因和途径的更特异性调节是众所周知的串扰的基础,这可能对DEHP的作用机制至关重要。我们的发现提供了证据来支持这样的观点,即这些模型在最大程度地减少使用动物试验进行毒性评估方面是有效的。
Di(ethylhexyl) phthalate (DEHP) is a ubiquitous environmental contaminant to which humans are exposed via multiple routes. Human health risk assessments for this substance have recently been updated, focusing on reproductive toxicity, including DEHP, in the list of chemicals classified as carcinogenic, mutagenic, or toxic to reproduction (CMR). Moreover, DEHP has also been defined as probably and possibly carcinogenic to humans based on its carcinogenicity in rodents. However, the mechanism of action of DEHP and its relevance in humans remain unclear. Rodent data suggests that DEHP induces cancer through non-genotoxic mechanisms related to multiple molecular signals, including PPARα activation, perturbation of fatty acid metabolism, induction of cell proliferation, decreased apoptosis, production of reactive oxygen species, and oxidative stress. According to the DEHP toxicological dataset, several in vitro cell transformation assays have been performed using different protocols and cellular models to produce different results. This study aimed to evaluate the carcinogenic potential of DEHP by using the A31-1-1 BALB/c-3T3 cell line in a standard cell transformation assay. Additionally, transcriptomic analysis was performed to explore the molecular responses and identify the affected toxicological pathways. Although DEHP treatment did not induce transformation in BALB/c-3T3 cells, the transcriptomic results revealed significant modulation of several pathways associated with DEHP metabolism, tissue-specific functions related to systemic metabolism, and basal cellular signaling with pleiotropic outcomes. Among these signaling pathways, modulation of cell-regulating signaling pathways, such as Notch, Wnt, and TGF-β, can be highlighted. More specific modulation of such genes and pathways with double functions in metabolism and neurophysiology underlies the well-known crosstalk that may be crucial for the mechanism of action of DEHP. Our findings offer evidence to support the notion that these models are effective in minimizing the use of animal testing for toxicity assessment.