title: Low-Dose Pesticide Mixture Induces Senescence in Normal Mesenchymal Stem Cells (MSC) and Promotes Tumorigenic Phenotype in Premalignant MSC.
abstract: Humans are chronically exposed to multiple environmental pollutants such as pesticides with no significant evidence about the safety of such poly-exposures. We exposed mesenchymal stem cells (MSC) to very low doses of mixture of seven pesticides frequently detected in food samples for 21 days in vitro. We observed a permanent phenotype modification with a specific induction of an oxidative stress-related senescence. Pesticide mixture also induced a shift in MSC differentiation towards adipogenesis but did not initiate a tumorigenic transformation. In modified MSC in which a premalignant phenotype was induced, the exposure to pesticide mixture promoted tumorigenic phenotype both in vitro and in vivo after cell implantation, in all nude mice. Our results suggest that a common combination of pesticides can induce a premature ageing of adult MSC, and as such could accelerate age-related diseases. Exposure to pesticide mixture may also promote the tumorigenic transformation in a predisposed stromal environment. Abstract Video Link: https://youtu.be/mfSVPTol-Gk Stem Cells 2017;35:800-811.
authors.affiliation: Centre de Recherche en Cancérologie Nantes Angers UMR INSERM 892, CNRS 6299 - Equipe 9, Université de Nantes, Nantes, France.|Faculté de Médecine, Université de Nantes, Nantes, France.
authors.forename: Mazene
authors.initials: M
authors.lastname: Hochane
authors.affiliation: Faculté de Médecine, Université de Nantes, Nantes, France.|INSERM, UMR 957, Equipe Ligue 2012, Nantes, France.|Faculty of Medicine, Pathophysiology of Bone Resorption Laboratory and Therapy of Primary Bone Tumours University of Nantes, Nantes, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Trichet
authors.affiliation: Centre de Recherche en Cancérologie Nantes Angers UMR INSERM 892, CNRS 6299 - Equipe 9, Université de Nantes, Nantes, France.|Faculté de Médecine, Université de Nantes, Nantes, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Pecqueur
authors.affiliation: Faculté de Médecine, Université de Nantes, Nantes, France.|INSERM, UMR 957, Equipe Ligue 2012, Nantes, France.|Faculty of Medicine, Pathophysiology of Bone Resorption Laboratory and Therapy of Primary Bone Tumours University of Nantes, Nantes, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Avril
authors.affiliation: Centre de Recherche en Cancérologie Nantes Angers UMR INSERM 892, CNRS 6299 - Equipe 9, Université de Nantes, Nantes, France.|Faculté de Médecine, Université de Nantes, Nantes, France.|CHU de Nantes, Nantes, France.
authors.forename: Lisa
authors.initials: L
authors.lastname: Oliver
authors.affiliation: Centre de Recherche en Cancérologie Nantes Angers UMR INSERM 892, CNRS 6299 - Equipe 9, Université de Nantes, Nantes, France.|Faculté de Médecine, Université de Nantes, Nantes, France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Denis
authors.affiliation: Faculté de Médecine, Université de Nantes, Nantes, France.|INSERM, UMR 957, Equipe Ligue 2012, Nantes, France.|Faculty of Medicine, Pathophysiology of Bone Resorption Laboratory and Therapy of Primary Bone Tumours University of Nantes, Nantes, France.|CHU de Nantes, Nantes, France.
authors.forename: Regis
authors.initials: R
authors.lastname: Brion
authors.affiliation: Faculté de Médecine, Université de Nantes, Nantes, France.|INSERM, UMR 957, Equipe Ligue 2012, Nantes, France.|Faculty of Medicine, Pathophysiology of Bone Resorption Laboratory and Therapy of Primary Bone Tumours University of Nantes, Nantes, France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Amiaud
authors.affiliation: Department of Pharmacology and Toxicology, University Hospital of Nantes, Nantes, France.|Service de toxicologie, Faculté de pharmacie de Nantes.
authors.forename: Alain
authors.initials: A
authors.lastname: Pineau
authors.affiliation: Faculté de Médecine, Université de Nantes, Nantes, France.|INSERM UMR 913, IMAD, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Naveilhan
authors.affiliation: Faculté de Médecine, Université de Nantes, Nantes, France.|INSERM, UMR 957, Equipe Ligue 2012, Nantes, France.|Faculty of Medicine, Pathophysiology of Bone Resorption Laboratory and Therapy of Primary Bone Tumours University of Nantes, Nantes, France.|CHU de Nantes, Nantes, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
authors.affiliation: Centre de Recherche en Cancérologie Nantes Angers UMR INSERM 892, CNRS 6299 - Equipe 9, Université de Nantes, Nantes, France.|Faculté de Médecine, Université de Nantes, Nantes, France.|LaBCT, Institut de Cancérologie de l'Ouest, Nantes, France.
authors.forename: François M
authors.initials: FM
authors.lastname: Vallette
authors.affiliation: Centre de Recherche en Cancérologie Nantes Angers UMR INSERM 892, CNRS 6299 - Equipe 9, Université de Nantes, Nantes, France.|Service de toxicologie, Faculté de pharmacie de Nantes.
authors.forename: Christophe
authors.initials: C
authors.lastname: Olivier
mesh_terms: D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D019069:Cell Respiration; D016922:Cellular Senescence; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008819:Mice, Nude; D010575:Pesticides / Q000633:toxicity*; D010641:Phenotype; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D010575:Pesticides; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53
keywords: mesenchymal stem cells; pesticide mixture; pesticides; senescence; tumorigenesis