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ORIGINAL RESEARCH article

Front. Toxicol.
Sec. In Vitro Toxicology
Volume 6 - 2024 | doi: 10.3389/ftox.2024.1389160
This article is part of the Research Topic Reducing Animal Use in Carcinogenicity Testing View all 6 articles

An insight into carcinogenic activity and molecular mechanisms of Bis(2-ethylhexyl) phthalate

Provisionally accepted
Annamaria Colacci Annamaria Colacci 1*Gelsomina Pillo Gelsomina Pillo 1*Federico Aldrovandi Federico Aldrovandi 2Ada Mescoli Ada Mescoli 2*Giangabriele Maffei Giangabriele Maffei 2Maria Grazia Mascolo Maria Grazia Mascolo 1MONICA VACCARI MONICA VACCARI 1
  • 1 Agency for Prevention, Environment and Energy (Arpae), Emilia-Romagna, Italy, Bologna, Emilia-Romagna, Italy
  • 2 University of Bologna, Bologna, Emilia-Romagna, Italy

The final, formatted version of the article will be published soon.

    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 PPAR-α 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.

    Keywords: bis(2-ethylhexyl) phthalate1, non-genotoxic carcinogens2, alternative methods3, Transcriptomics4, toxicogenomics5, cell transformation assay6, Cytotoxicity7, transformics8

    Received: 21 Feb 2024; Accepted: 03 May 2024.

    Copyright: © 2024 Colacci, Pillo, Aldrovandi, Mescoli, Maffei, Mascolo and VACCARI. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Annamaria Colacci, Agency for Prevention, Environment and Energy (Arpae), Emilia-Romagna, Italy, Bologna, Emilia-Romagna, Italy
    Gelsomina Pillo, Agency for Prevention, Environment and Energy (Arpae), Emilia-Romagna, Italy, Bologna, Emilia-Romagna, Italy
    Ada Mescoli, University of Bologna, Bologna, 40126, Emilia-Romagna, Italy

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