Publications by authors named "Yann Landkocz"

14 Publications

  • Page 1 of 1

Toxicological responses of BEAS-2B cells to repeated exposures to benzene, toluene, m-xylene, and mesitylene using air-liquid interface method.

J Appl Toxicol 2020 Dec 2. Epub 2020 Dec 2.

Unité de Chimie Environnementale et Interactions sur le Vivant, SFR Condorcet FR CNRS 3417, Université du Littoral Côte d'Opale, Dunkirk, France.

In order to reduce exposure to toxic chemicals, the European REACH regulation (1907/2006) recommends substituting toxic molecules with compounds that are less harmful to human health and the environment. Toluene is one of the most frequently used solvents in industries despite its toxicity. The objective of this study is to better understand and compare the toxicity of toluene and its homologues in a bronchial cell model. Thus, human bronchial BEAS-2B cells were exposed to steams of toluene, m-xylene, mesitylene (1,3,5-trimethylbenzene), and benzene (20 and 100 ppm). Exposure was carried out using an air-liquid interface (ALI) system (Vitrocell) during 1 h/day for 1, 3, or 5 days. Cytotoxicity, xenobiotic metabolism enzyme gene expression, and inflammatory response were evaluated following cell exposures. BEAS-2B cell exposure to toluene and its homologues revealed the involvement of major (CYP2E1) and minor metabolic pathways (CYP1A1). A late induction of genes (EPHX1, DHDH, ALDH2, and ALDH3B1) was measured from Day 3 and can be linked to the formation of metabolites. An increase in the secretion level of inflammatory markers (TNF-α, IL-6, IL-8, MCP-1, and GM-CSF) was also observed. In parallel, regulation between inflammatory mediators and the expression of transmembrane glycoprotein mucin MUC1 was also studied. This in vitro approach with ALI system points out the relevance of conducting repeated exposures to detect potential late effects. The difference recorded after cell exposure to toluene and its homologues highlights the importance of substitution principle.
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http://dx.doi.org/10.1002/jat.4113DOI Listing
December 2020

Atmospheric fine particulate matter and epithelial mesenchymal transition in pulmonary cells: state of the art and critical review of the studies.

J Toxicol Environ Health B Crit Rev 2020 10 13;23(7):293-318. Epub 2020 Sep 13.

Unité de Chimie Environnementale et Interactions sur le Vivant, UCEIV UR4492, SFR Condorcet FR-CNRS-3417, Univ. Littoral Côte d'Opale (ULCO) , Dunkerque, France.

Exposure to fine particulate matter (PM) has been associated with several diseases including asthma, chronic obstructive pulmonary disease (COPD) and lung cancer. Mechanisms such as oxidative stress and inflammation are well-documented and are considered as the starting point of some of the pathological responses. However, a number of studies also focused on epithelial-mesenchymal transition (EMT), which is a biological process involved in fibrotic diseases and cancer progression notably via metastasis induction. Up until now, EMT was widely reported and in various cell types but investigations dealing with studies of PM induced EMT in pulmonary cells are limited. Further, few investigations combined the necessary endpoints for validation of the EMT state in cells: such as expression of several surface, cytoskeleton or extracellular matrix biomarkers and activation of transcription markers and epigenetic factors. Studies explored various cell types, cultured under differing conditions and exposed for various durations to different doses. Such unharmonized protocols (1) might introduce bias, (2) make difficult comparison of results and (3) preclude reaching a definitive conclusion regarding the ability of airborne PM to induce EMT in pulmonary cells. Some questions remain, in particular the specific PM components responsible for EMT triggering. The aim of this review is to examine the available PM induced EMT studies on pulmonary cells with special emphasis on the critical parameters considered to carry out future research in this field. This clarification appears necessary for production of reliable and comparable results.
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http://dx.doi.org/10.1080/10937404.2020.1816238DOI Listing
October 2020

Toxicity of fine and quasi-ultrafine particles: Focus on the effects of organic extractable and non-extractable matter fractions.

Chemosphere 2020 Mar 22;243:125440. Epub 2019 Nov 22.

Unité de Chimie Environnementale et Interactions sur le Vivant, UCEIV EA4492, FR CNRS 3417, Univ. Littoral Côte d'Opale, Dunkerque, France.

To date no study has been able to clearly attribute the observed toxicological effects of atmospheric particles (PM) to a specific class of components. The toxicity of both the organic extractable matter (OEM) and non-extractable matter (NEM) of fine particles (PM) was compared to that of PM in its entirety on normal human epithelial bronchial BEAS-2B cells in culture. The specific effect of the quasi-ultrafine fraction (PM) was assessed, by comparing the responses of cells exposed to the PM and PM organic extractable matter, OEM and OEM respectively. Chemically, PAH, O-PAH, and N-PAH were respectively 43, 17, and 4 times more concentrated in PM than in PM, suggesting thereby a predominant influence of anthropogenic activities and combustion sources. BEAS-2B cells exposed to PM, NEM, EOM and OEM lead to different profiles of expression of selected genes and proteins involved in the metabolic activation of PAH, O-PAH, and N-PAH, and in the genotoxicity pathways. Specifically, OEM was the most inducer for phase I and phase II enzymes implicated in the metabolic activation of PAH (AHR, AHRR, ARNT, CYP1A1, CYP1B1, EPHX-1, GSTA-4) thereby producing the highest DNA damage, felt by ATR and, thereafter, a cascade of protein phosphorylation (CHK1/CHK2/MDM2) closely related to the cell cycle arrest (P21 and P53 induction). This study underlined the crucial role played by the organic chemicals present in PM. These results should be considered in any future study looking for the main chemical determinants responsible for the toxicity of ambient fine PM.
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http://dx.doi.org/10.1016/j.chemosphere.2019.125440DOI Listing
March 2020

A prospective pilot study of the T-lymphocyte response to fine particulate matter exposure.

J Appl Toxicol 2020 05 23;40(5):619-630. Epub 2020 Jan 23.

EA 4492 - UCEIV - Unité de Chimie Environnementale et Interactions sur le Vivant, Université du Littoral Côte d'Opale, SFR Condorcet FR CNRS 3417, Dunkerque, France.

Exposure to air pollution is associated with increased morbidity and mortality. Once the fine atmospheric particulate matter (FP) is inhaled, some of its compounds can pass through the lungs and reach the bloodstream where they can come into contact with immune cells. Exposure to FP particularly affects sensitive populations such as the elderly. Aging affects the immune system, making the elderly more vulnerable. The project aims to determine the effects of FP exposure on human T cells while looking for biomarkers associated with exposure. Blood samples from 95 healthy subjects in three different age groups (20-30, 45-55 and 70-85 years) were collected to determine a potential age effect. T lymphocytes were isolated to be exposed ex vivo for 72 hours to 45 μg/mL of FP collected in Dunkirk and chemically characterized. Overexpression of the CYP1A1, CYP1B1 and CYP2S1 genes was therefore measured after exposure of the T cells to FP. These genes code for enzymes known to be involved in the metabolic activation of organic compounds such as polycyclic aromatic hydrocarbons detected in the FP sample. T-cell profiling allowed us to suggest a mixed T-helper 1/2 profile caused by exposure to FP. With regard to the influence of age, we have observed differences in the expression of certain genes, as well as an increase in interleukin-4 and -13 concentrations in the elderly. These results showed that exposure of T lymphocytes to FP causes effects on both transcriptomic and cytokine secretion levels.
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http://dx.doi.org/10.1002/jat.3932DOI Listing
May 2020

Cellular response and extracellular vesicles characterization of human macrophages exposed to fine atmospheric particulate matter.

Environ Pollut 2019 Nov 25;254(Pt A):112933. Epub 2019 Jul 25.

University of Littoral Côte d'Opale, Unit of Environmental Chemistry and Interactions with Life, UCEIV EA4492, SFR Condorcet FR CNRS 3417, Dunkerque, France. Electronic address:

Exposure to fine atmospheric Particulate Matter (PM) is one of the major environmental causes involved in the development of inflammatory lung diseases, such as chronic obstructive pulmonary disease (COPD) or asthma. When PM is penetrating in the pulmonary system, alveolar macrophages represent the first line of defense, in particular by triggering a pro-inflammatory response, and also by their ability to recruit infiltrating macrophages from the bone marrow. The aim of this in vitro study was to evaluate the gene expression and cytokine production involved in the toxicological and inflammatory responses of infiltrating macrophages, as well as the Extracellular Vesicles (EVs) production, after their exposure to PM. The ability of these EVs to convey information related to PM exposure from exposed macrophages to pulmonary epithelial cells was also evaluated. Infiltrating macrophages respond to fine particles exposure in a conventional manner, as their exposure to PM induced the expression of Xenobiotic Metabolizing Enzymes (XMEs) such as CYP1A1 and CYP1B1, the enzymes involved in oxidative stress SOD2, NQO1 and HMOX as well as pro-inflammatory cytokines in a dose-dependent manner. Exposure to PM also induced a greater release of EVs in a dose-dependent manner. In addition, the produced EVs were able to induce a pro-inflammatory phenotype on pulmonary epithelial cells, with the induction of the release of IL6 and TNFα proinflammatory cytokines. These results suggest that infiltrating macrophages participate in the pro-inflammatory response induced by PM exposure and that EVs could be involved in this mechanism.
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http://dx.doi.org/10.1016/j.envpol.2019.07.101DOI Listing
November 2019

In vitro toxicological evaluation of emissions from catalytic oxidation removal of industrial VOCs by air/liquid interface (ALI) exposure system in repeated mode.

Toxicol In Vitro 2019 Aug 22;58:110-117. Epub 2019 Mar 22.

UCEIV - EA4492, Unité de Chimie Environnementale et Interactions sur le Vivant, SFR Condorcet FR CNRS 3417, Université du Littoral Côte d'Opale, Dunkerque, France.

Toxicity of toluene and by-products formed during its catalytic oxidative degradation was studied in human bronchial BEAS-2B cells repeatedly exposed. BEAS-2B cells were exposed using an Air-Liquid Interface (ALI) System (Vitrocell®) for 1 h per day during 1, 3 or 5 days to gaseous flows: toluene vapors (100 and 1000 ppm) and outflow after catalytic oxidation of toluene (10 and 100%). After exposure to gaseous flow, cytotoxicity, inflammatory response and Xenobiotic Metabolism Enzymes (XME) gene expression were investigated. No significant cytotoxicity was found after 5 days for every condition of exposure. After cells exposure to catalytic oxidation flow, IL-6 level increased no significantly in a time- and dose-dependent way, while an inverted U-shaped profile of IL-8 secretion was observed. XME genes induction, notably CYP2E1 and CYP2F1 results were in line with the presence of unconverted toluene and benzene formed as a by-product, detected by analytical methods. Exposure to pure toluene also demonstrated the activation of these XMEs involved in its metabolism. Repeated exposure permits to show CYP1A1, CYP1B1 and CY2S1 expression, probably related to the formation of other by-products, as PAHs, not detected by standard analytical methods used for the development of catalysts.
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http://dx.doi.org/10.1016/j.tiv.2019.03.030DOI Listing
August 2019

Chemical characterization of fine and ultrafine PM, direct and indirect genotoxicity of PM and their organic extracts on pulmonary cells.

J Environ Sci (China) 2018 Sep 27;71:168-178. Epub 2018 Apr 27.

University of the Littoral Opal Coast, Unit of Environmental Chmistry and Interactions with Living Organisms, UCEIV EA4492, SFR Condorcet FR CNRS 3417, Dunkerque, France.

Particulate matter in ambient air constitutes a complex mixture of fine and ultrafine particles composed of various chemical compounds including metals, ions, and organics. A multidisciplinary approach was developed by studying physico-chemical characteristics and mechanisms involved in the toxicity of particulate atmospheric pollution. PM and PM including ultrafine particles were sampled in Dunkerque, a French industrialized seaside city. PM samples were characterized from a chemical and toxicological point of view. Physico-chemical characterization evidenced that PM comes from several sources: natural ones, such as soil resuspension and marine sea-salt emissions, as well as anthropogenic ones, such as shipping traffic, road traffic, and industrial activities. Human BEAS-2B lung cells were exposed to PM, or to the Extractable Organic Matter (EOM) of PM and PM. These exposures induced several mechanisms of action implied in the genotoxicity, such as oxidative DNA adducts and DNA Damage Response. The toxicity of PM-EOM was higher for the sample including the ultrafine fraction (PM) containing also higher concentrations of polycyclic aromatic hydrocarbons. These results evidenced the major role of organic compounds in the toxicity of PM.
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http://dx.doi.org/10.1016/j.jes.2018.04.022DOI Listing
September 2018

Influence of aging in the modulation of epigenetic biomarkers of carcinogenesis after exposure to air pollution.

Exp Gerontol 2018 09 31;110:125-132. Epub 2018 May 31.

Unité de Chimie Environnementale et Interactions sur le Vivant (EA4492), Université du Littoral Côte d'Opale, Dunkerque 59140, France.

Background: Classified as carcinogenic to humans by the IARC in 2013, fine air particulate matter (PM) can be inhaled and retained into the lung or reach the systemic circulation. This can cause or exacerbate numerous pathologies to which the elderly are often more sensitive.

Methods: In order to estimate the influence of age on the development of early cellular epigenetic alterations involved in carcinogenesis, peripheral blood mononuclear cells sampled from 90 patients from three age classes (25-30, 50-55 and 75-80 years old) were ex vivo exposed to urban PM.

Results: Particles exposure led to variations in telomerase activity and telomeres length in all age groups without any influence of age. Conversely, P16 gene expression increased significantly with age after exposure to PM. Age could enhance MGMT gene expression after exposure to particles, by decreasing the level of promoter methylation in the oldest people.

Conclusion: Hence, our results demonstrated several tendencies in cells modification depending on age, even if all epigenetic assays were carried out after a limited exposure time allowing only one or two cell cycles. Since lung cancer symptoms appear only at an advanced stage, our results underline the needs for further investigation on the studied biomarkers for early diagnosis of carcinogenesis to improve survival.
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http://dx.doi.org/10.1016/j.exger.2018.05.018DOI Listing
September 2018

Comparative study of diesel and biodiesel exhausts on lung oxidative stress and genotoxicity in rats.

Environ Pollut 2018 Apr 8;235:514-524. Epub 2018 Jan 8.

Normandie Univ, UNICAEN, UNIROUEN, ABTE, 14000 Caen et 76000, Rouen, France; Centre François Baclesse, Caen, France. Electronic address:

The contribution of diesel exhaust to atmospheric pollution is a major concern for public health, especially in terms of occurrence of lung cancers. The present study aimed at addressing the toxic effects of a repeated exposure to these emissions in an animal study performed under strictly controlled conditions. Rats were repeatedly exposed to the exhaust of diesel engine. Parameters such as the presence of a particle filter or the use of gasoil containing rapeseed methyl ester were investigated. Various biological parameters were monitored in the lungs to assess the toxic and genotoxic effects of the exposure. First, a transcriptomic analysis showed that some pathways related to DNA repair and cell cycle were affected to a limited extent by diesel but even less by biodiesel. In agreement with occurrence of a limited genotoxic stress in the lungs of diesel-exposed animals, small induction of γ-H2AX and acrolein adducts was observed but not of bulky adducts and 8-oxodGuo. Unexpected results were obtained in the study of the effect of the particle filter. Indeed, exhausts collected downstream of the particle filter led to a slightly higher induction of a series of genes than those collected upstream. This result was in agreement with the formation of acrolein adducts and γH2AX. On the contrary, induction of oxidative stress remained very limited since only SOD was found to be induced and only when rats were exposed to biodiesel exhaust collected upstream of the particle filter. Parameters related to telomeres were identical in all groups. In summary, our results point to a limited accumulation of damage in lungs following repeated exposure to diesel exhausts when modern engines and relevant fuels are used. Yet, a few significant effects are still observed, mostly after the particle filter, suggesting a remaining toxicity associated with the gaseous or nano-particular phases.
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http://dx.doi.org/10.1016/j.envpol.2017.12.077DOI Listing
April 2018

Physicochemical characteristics, mutagenicity and genotoxicity of airborne particles under industrial and rural influences in Northern Lebanon.

Environ Sci Pollut Res Int 2017 Aug 15;24(23):18782-18797. Epub 2017 Jun 15.

Unité de Chimie Environnementale et Interactions sur le Vivant, UCEIV, EA 4492, Université du Littoral Côte d'Opale, Dunkerque, France.

In this work, the main objectives were to assess the mutagenic and genotoxic effects of fine particulate matter collected in an industrial influenced site in comparison with a non-industrial influenced one (rural site) and to relate the particulate matter (PM) composition to the observed genotoxic effects. At the industrial influenced site, higher concentrations of phosphates, trace metals, and polycyclic aromatic hydrocarbons (PAHs) in particles could be related to the contributions of quarries, fertilizer producer, cement plants, and tires burning. Gasoline and diesel combustion contributions were evidenced in particles collected at both sites. Particles collected under industrial influence showed a higher mutagenic potential on three tested strains of Salmonella typhimurium (TA98, YG1041, and TA102), and especially on the YG1041, compared to particles from the rural site. Furthermore, only particles collected in the vicinity of the industrial site showed a tendency to activate the SOS responses in Escherichia coli PQ37, which is indicative of DNA damage as a result of exposure of the bacteria cells to the action of mutagenic samples. The mutagenicity and genotoxicity of the industrial PM particulates may be attributed to its composition especially in organic compounds. This study showed that proximity of industries can affect local PM composition as well as PM genotoxic and mutagenic potential.
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http://dx.doi.org/10.1007/s11356-017-9389-3DOI Listing
August 2017

Smoker extracellular vesicles influence status of human bronchial epithelial cells.

Int J Hyg Environ Health 2017 04 30;220(2 Pt B):445-454. Epub 2016 Dec 30.

Unité de Chimie Environnementale et Interactions sur le Vivant (UCEIV), EA4492, Université du Littoral Côte d'Opale (ULCO), Dunkerque, France. Electronic address:

Cigarette smoking is a habit that has spread all over the world and is a significant risk factor for many diseases including cardiovascular disease, chronic obstructive pulmonary disease (COPD), asthma and lung cancer. Evaluation and understanding of tobacco health effects are of major interest worldwide and answer to important societal concerns. Identification of new biomarkers of exposure to tobacco smoke potentially implicated in COPD or lung carcinogenesis would allow a better observation of tobacco exposed population, thanks to screening establishment at reversible stages of pathological processes. In this study, we questioned whether cigarette smoking alters miRNA profiles of Extracellular Vesicles (EVs) present in human Broncho Alveolar Lavages (BALs), which could affect surrounding normal bronchial epithelial cells status. To this aim, BALs were carried out on 10 Smokers and 10 Non-Smokers, and EVs were isolated from the supernatants and characterized. We then compared the amount of 10 microRNAs (miRNAs) present in Smokers versus Non-Smokers BAL EVs and performed statistical analysis to discuss the biological significance by the smoking status and to evaluate BAL EV miRNAs as potential biomarkers of tobacco exposure. Finally, we tested the effects of smokers versus non-smokers EVs on human bronchial epithelial cells (BEAS-2B) to compare their influence on the cells status. Our study shows for the first time in human samples that smoking can alter lung EV profile that can influence surrounding bronchial epithelial cells.
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http://dx.doi.org/10.1016/j.ijheh.2016.12.010DOI Listing
April 2017

Fine and ultrafine atmospheric particulate matter at a multi-influenced urban site: Physicochemical characterization, mutagenicity and cytotoxicity.

Environ Pollut 2017 Feb 30;221:130-140. Epub 2016 Nov 30.

Univ. Littoral Côte d'Opale, EA 4492 - UCEIV - Unité de Chimie Environnementale et Interactions sur le Vivant, F-59140, Dunkerque, France.

Particulate Matter (PM) air pollution is one of the major concerns for environment and health. Understanding the heterogeneity and complexity of fine and ultrafine PM is a fundamental issue notably for the assessment of PM toxicological effects. The aim of this study was to evaluate mutagenicity and cytotoxicity of a multi-influenced urban site PM, with or without the ultrafine fraction. For this purpose, PM (PM with aerodynamic diameter ranging from 0.3 to 2.5 μm) and PM were collected in Dunkerque, a French coastal industrial city and were extensively characterized for their physico-chemical properties, including inorganic and organic species. In order to identify the possible sources of atmospheric pollution, specific criteria like Carbon Preference Index (CPI) and PAH characteristic ratios were investigated. Mutagenicity assays using Ames test with TA98, TA102 and YG1041 Salmonella strains with or without S9 activation were performed on native PM sample and PM organic extracts and water-soluble fractions. BEAS-2B cell viability and cell proliferation were evaluated measuring lactate dehydrogenase release and mitochondrial dehydrogenase activity after exposure to PM and their extracts. Several contributing sources were identified in PM: soil resuspension, marine emissions including sea-salt or shipping, road traffic and industrial activities, mainly related to steelmaking or petro-chemistry. Mutagenicity of PM was evidenced, especially for PM, including ultrafine fraction, in relation to PAHs content and possibly nitro-aromatics compounds. PM induced cytotoxic effects at relatively high doses, while alteration of proliferation with low PM doses could be related to underlying mechanisms such as genotoxicity.
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http://dx.doi.org/10.1016/j.envpol.2016.11.054DOI Listing
February 2017

Usefulness of toxicological validation of VOCs catalytic degradation by air-liquid interface exposure system.

Environ Res 2017 Jan 9;152:328-335. Epub 2016 Nov 9.

Unité de Chimie Environnementale et Interactions sur le Vivant EA4492, Université du Littoral Côte d'Opale, 189A Avenue Maurice Schumann, 59140 Dunkerque, France. Electronic address:

Toluene is one of the most used Volatile Organic Compounds (VOCs) in the industry despite its major health impacts. Catalytic oxidation represents an efficient remediation technique in order to reduce its emission directly at the source, but it can release by-products. To complete the classical performance assessment using dedicated analytical chemistry methods, we propose to perform an untargeted toxicological validation on two efficient catalysts. Using biological system allows integrating synergy and antagonism in toxic effects of emitted VOCs and by-products, often described in case of multi-exposure condition. Catalysts Pd/α-AlO and Pd/γ-AlO developed for the oxidation of toluene were both coupled to a Vitrocell Air-Liquid Interface (ALI) system, for exposure of human A549 lung cells during 1h to toluene or to catalysts exhaust before quantification of xenobiotics metabolizing enzymes. This study validated initially the Vitrocell as an innovative, direct and dynamic model of ALI exposure in the assessment of the performances of new catalysts, showing the presence of chemically undetected by-products. The comparison of the two catalysts showed then that fewer organic compounds metabolizing genes were induced by Pd/γ-AlO in comparison to Pd/α-AlO, suggesting that Pd/γ-AlO is more efficient for toluene total oxidation from a toxicological point of view.
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http://dx.doi.org/10.1016/j.envres.2016.10.027DOI Listing
January 2017

Transcriptomic effects of di-(2-ethylhexyl)-phthalate in Syrian hamster embryo cells: an important role of early cytoskeleton disturbances in carcinogenesis?

BMC Genomics 2011 Oct 25;12:524. Epub 2011 Oct 25.

CNRS UMR7146, Laboratoire I.E.B.E., Rue General Delestraint, 57070 Metz, France.

Background: Di-(2-ethylhexyl)-phthalate (DEHP) is a commonly used plasticizer in polyvinylchloride (PVC) formulations and a potentially non-genotoxic carcinogen. The aim of this study was to identify genes whose level of expression is altered by DEHP by using a global wide-genome approach in Syrian hamster embryo (SHE) cells, a model similar to human cells regarding their responses to this type of carcinogen. With mRNA Differential Display (DD), we analysed the transcriptional regulation of SHE cells exposed to 0, 12.5, 25 and 50 μM of DEHP for 24 hrs, conditions which induced neoplastic transformation of these cells. A real-time quantitative polymerase chain reaction (qPCR) was used to confirm differential expression of genes identified by DD.

Results: Gene expression profiling showed 178 differentially-expressed fragments corresponding to 122 genes after tblastx comparisons, 79 up-regulated and 43 down-regulated. The genes of interest were involved in many biological pathways, including signal transduction, regulation of the cytoskeleton, xenobiotic metabolism, apoptosis, lipidogenesis, protein conformation, transport and cell cycle. We then focused particularly on genes involved in the regulation of the cytoskeleton, one of the processes occurring during carcinogenesis and in the early steps of neoplastic transformation. Twenty one cytoskeleton-related genes were studied by qPCR. The down-regulated genes were involved in focal adhesion or cell junction. The up-regulated genes were involved in the regulation of the actin cytoskeleton and this would suggest a role of cellular plasticity in the mechanism of chemical carcinogenesis. The gene expression changes identified in the present study were PPAR-independent.

Conclusion: This study identified a set of genes whose expression is altered by DEHP exposure in mammalian embryo cells. This is the first study that elucidates the genomic changes of DEHP involved in the organization of the cytoskeleton. The latter genes may be candidates as biomarkers predictive of early events in the multistep carcinogenic process.
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http://dx.doi.org/10.1186/1471-2164-12-524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3218109PMC
October 2011