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Toxicol In Vitro. 2014 Dec;28(8):1507-20. doi: 10.1016/j.tiv.2014.06.009. Epub 2014 Jul 2.

Potential involvement of chemicals in liver cancer progression: an alternative toxicological approach combining biomarkers and innovative technologies.

Author information

1
UMR 1331 TOXALIM (Research Centre in Food Toxicology), Institut National de la Recherche Agronomique (INRA), Laboratory of Xenobiotic's Cellular and Molecular Toxicology, 400 route des Chappes, BP 167, 06903 Sophia-Antipolis Cedex, France. Electronic address: ludovic.peyre@sophia.inra.fr.
2
UMR 1331 TOXALIM (Research Centre in Food Toxicology), Institut National de la Recherche Agronomique (INRA), Laboratory of Xenobiotic's Cellular and Molecular Toxicology, 400 route des Chappes, BP 167, 06903 Sophia-Antipolis Cedex, France.
3
GALDERMA R&D, Early Admet, 06902 Sophia Antipolis, France.
4
UMR 1331 TOXALIM (Research Centre in Food Toxicology), Institut National de la Recherche Agronomique (INRA), Laboratory of Xenobiotic's Cellular and Molecular Toxicology, 400 route des Chappes, BP 167, 06903 Sophia-Antipolis Cedex, France. Electronic address: Roger.rahmani@sophia.inra.fr.

Abstract

Pesticides as well as many other environmental pollutants are considered as risk factors for the initiation and the progression of cancer. In order to evaluate the in vitro effects of chemicals present in the diet, we began by combining viability, real-time cellular impedance and high throughput screening data to identify a concentration "zone of interest" for the six xenobiotics selected: endosulfan, dioxin, carbaryl, carbendazim, p'p'DDE and hydroquinone. We identified a single concentration of each pollutant allowing a modulation of the impedance in the absence of vital changes (nuclear integrity, mitochondrial membrane potential, cell death). Based on the number of observed modulations known to be involved in hepatic homeostasis dysfunction that may lead to cancer progression such as cell cycle and apoptosis regulators, EMT biomarkers and signal transduction pathways, we then ranked the pollutants in terms of their toxicity. Endosulfan, was able to strongly modulate all the studied cellular processes in HepG2 cells, followed by dioxin, then carbendazim. While p,p'DDE, carbaryl and hydroquinone seemed to affect fewer functions, their effects nevertheless warrant close scrutiny. Our in vitro data indicate that these xenobiotics may contribute to the evolution and worsening of hepatocarcinoma, whether via the induction of the EMT process and/or via the deregulation of liver key processes such as cell cycle and resistance to apoptosis.

KEYWORDS:

Cancer; Environmental pollutants; Epithelial–mesenchymal transition; Hepatic homeostasis dysregulation; High content screening; Real-time cellular impedance

PMID:
24997295
DOI:
10.1016/j.tiv.2014.06.009
[Indexed for MEDLINE]
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