Pillo Gelsomina, Aldrovandi Federico, Mescoli Ada, Maffei Giangabriele, Mascolo Maria Grazia, Vaccari Monica, Colacci Annamaria
Agency for Prevention, Environment and Energy (Arpae), Bologna, Italy.
Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy.
Front Toxicol. 2024 Jul 23;6:1389160. doi: 10.3389/ftox.2024.1389160. eCollection 2024.
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 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.
邻苯二甲酸二（2-乙基己基）酯（DEHP）是一种普遍存在的环境污染物，人类可通过多种途径接触到它。最近对该物质的人体健康风险评估进行了更新，重点关注其生殖毒性，包括被列为具有致癌性、致突变性或生殖毒性（CMR）的化学品清单中的DEHP。此外，基于DEHP在啮齿动物中的致癌性，它也被定义为可能对人类致癌。然而，DEHP的作用机制及其在人类中的相关性仍不清楚。啮齿动物数据表明，DEHP通过与多种分子信号相关的非基因毒性机制诱导癌症，这些信号包括PPARα激活、脂肪酸代谢紊乱、细胞增殖诱导、细胞凋亡减少、活性氧产生和氧化应激。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A31-1-1 BALB/c-3T3细胞系来评估DEHP的致癌潜力。此外，还进行了转录组分析，以探索分子反应并确定受影响的毒理学途径。虽然DEHP处理未在BALB/c-3T3细胞中诱导转化，但转录组结果显示与DEHP代谢、与全身代谢相关的组织特异性功能以及具有多效性结果的基础细胞信号传导相关的几种途径有显著调节。在这些信号通路中，可以突出细胞调节信号通路如Notch、Wnt和TGF-β的调节。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具体调节是众所周知的相互作用的基础，这可能对DEHP的作用机制至关重要。我们的研究结果提供了证据，支持这些模型在最大限度减少用于毒性评估的动物试验方面是有效的这一观点。
