Molecular and cell phenotype programs in oral epithelial cells directed by co-exposure to arsenic and smokeless tobacco.

Autor:	Das S; Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, Lyon, France., Thakur S; Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, Lyon, France.; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK., Cahais V; Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, Lyon, France., Virard F; Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, Lyon, France.; University Claude Bernard Lyon 1, INSERM U1052-CNRS UMR5286, Cancer Research Center, Centre Léon Bérard, Lyon, France.; University of Lyon, Faculty of Odontology, Hospices Civils de Lyon, Lyon, France., Claeys L; Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, Lyon, France.; Centre of Excellence in Mycotoxicology and Public Health, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium., Renard C; Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, Lyon, France., Cuenin C; Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, Lyon, France., Cros MP; Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, Lyon, France., Keïta S; Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, Lyon, France., Venuti A; Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, Lyon, France., Sirand C; Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, Lyon, France., Ghantous A; Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, Lyon, France., Herceg Z; Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, Lyon, France., Korenjak M; Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, Lyon, France., Zavadil J; Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, Lyon, France.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Oct 15. Date of Electronic Publication: 2024 Oct 15.
DOI:	10.1101/2024.10.14.618077
Abstrakt:	Chronic arsenic exposure can lead to various health issues, including cancer. Concerns have been mounting about the enhancement of arsenic toxicity through co-exposure to various prevalent lifestyle habits. Smokeless tobacco products are commonly consumed in South Asian countries, where their use frequently co-occurs with exposure to arsenic from contaminated groundwater. To decipher the in vitro molecular and cellular responses to arsenic and/or smokeless tobacco, we performed temporal multi-omics analysis of the transcriptome and DNA methylome remodelling in exposed hTERT-immortalized human normal oral keratinocytes (NOK), as well as arsenic and/or smokeless tobacco genotoxicity and mutagenicity investigations in NOK cells and in human p53 knock-in murine embryonic fibroblasts (Hupki MEF). RNAseq results from acute exposures to arsenic alone and in combination with smokeless tobacco extract revealed upregulation of genes with roles in cell cycle changes, apoptosis and inflammation responses. This was in keeping with global DNA hypomethylation affecting genes involved in the same processes in response to chronic treatment in NOK cells. At the phenotypic level, we observed a dose-dependent decrease in NOK cell viability, induction of DNA damage, cell cycle changes and increased apoptosis, with the most pronounced effects observed under arsenic and SLT co-exposure conditions. Live-cell imaging experiments indicated that the DNA damage likely resulted from induction of apoptosis, an observation validated by a lack of exome-wide mutagenesis in response to chronic exposure to arsenic and/or smokeless tobacco. In sum, our integrative omics study provides novel insights into the acute and chronic responses to arsenic and smokeless tobacco (co-)exposure, with both types of responses converging on several key mechanisms associated with cancer hallmark processes. The generated rich catalogue of molecular programs in oral cells regulated by arsenic and smokeless tobacco (co-)exposure may provide bases for future development of biomarkers for use in molecular epidemiology studies of exposed populations at risk of developing oral cancer. Competing Interests: DECLARATION OF COMPETING INTEREST The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Databáze:	MEDLINE
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