title: Food-grade TiO2impairs intestinal and systemic immune homeostasis, initiates preneoplastic lesions and promotes aberrant crypt development in the rat colon.
abstract: Food-grade titanium dioxide (TiO2) containing a nanoscale particle fraction (TiO2-NPs) is approved as a white pigment (E171 in Europe) in common foodstuffs, including confectionary. There are growing concerns that daily oral TiO2-NP intake is associated with an increased risk of chronic intestinal inflammation and carcinogenesis. In rats orally exposed for one week to E171 at human relevant levels, titanium was detected in the immune cells of Peyer's patches (PP) as observed with the TiO2-NP model NM-105. Dendritic cell frequency increased in PP regardless of the TiO2treatment, while regulatory T cells involved in dampening inflammatory responses decreased with E171 only, an effect still observed after 100 days of treatment. In all TiO2-treated rats, stimulation of immune cells isolated from PP showed a decrease in Thelper (Th)-1 IFN-γ secretion, while splenic Th1/Th17 inflammatory responses sharply increased. E171 or NM-105 for one week did not initiate intestinal inflammation, while a 100-day E171 treatment promoted colon microinflammation and initiated preneoplastic lesions while also fostering the growth of aberrant crypt foci in a chemically induced carcinogenesis model. These data should be considered for risk assessments of the susceptibility to Th17-driven autoimmune diseases and to colorectal cancer in humans exposed to TiO2from dietary sources.
authors.affiliation: Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bettini
authors.affiliation: Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France.
authors.forename: Elisa
authors.initials: E
authors.lastname: Boutet-Robinet
authors.affiliation: Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France.
authors.forename: Christel
authors.initials: C
authors.lastname: Cartier
authors.affiliation: Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Coméra
authors.affiliation: Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Gaultier
authors.affiliation: Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Dupuy
authors.affiliation: Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Naud
authors.affiliation: Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France.
authors.forename: Sylviane
authors.initials: S
authors.lastname: Taché
authors.affiliation: Luxembourg Institute of Science and Technology (LIST), Materials Research and Technology (MRT), Advanced Instrumentation for Ion Nano-Analytics (IANA), L-4362 Esch-sur-Alzette, Luxembourg.
authors.forename: Patrick
authors.initials: P
authors.lastname: Grysan
authors.affiliation: Synchrotron SOLEIL, F-91192 Gif-sur-Yvette, France.
authors.forename: Solenn
authors.initials: S
authors.lastname: Reguer
authors.affiliation: French Agency for Food, Environmental and Occupational Health and Safety (ANSES), F-94701 Maisons-Alfort, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Thieriet
authors.affiliation: Synchrotron SOLEIL, F-91192 Gif-sur-Yvette, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Réfrégiers
authors.affiliation: Synchrotron SOLEIL, F-91192 Gif-sur-Yvette, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Thiaudière
authors.affiliation: Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Cravedi
authors.affiliation: Université Grenoble-Alpes, INAC-LCIB, Laboratoire Lésions des Acides Nucléiques, 17 rue des Martyrs, F-38000 Grenoble, France.|CEA, INAC-SCIB, Laboratoire Lésions des Acides Nucléiques, 17 rue des Martyrs, F-38000 Grenoble, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Carrière
authors.affiliation: Luxembourg Institute of Science and Technology (LIST), Materials Research and Technology (MRT), Advanced Instrumentation for Ion Nano-Analytics (IANA), L-4362 Esch-sur-Alzette, Luxembourg.
authors.forename: Jean-Nicolas
authors.initials: JN
authors.lastname: Audinot
authors.affiliation: Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France.
authors.forename: Fabrice H
authors.initials: FH
authors.lastname: Pierre
authors.affiliation: Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Guzylack-Piriou
authors.affiliation: Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Houdeau
mesh_terms: D000284:Administration, Oral; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D002469:Cell Separation; D003106:Colon / Q000276:immunology* / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D004249:DNA Damage; D003713:Dendritic Cells / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005502:Food; D006706:Homeostasis; D007107:Immune System / Q000276:immunology*; D007249:Inflammation / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D010539:Permeability; D010581:Peyer's Patches / Q000473:pathology; D011230:Precancerous Conditions / Q000473:pathology*; D017208:Rats, Wistar; D013347:Subcellular Fractions / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D014018:Tissue Distribution; D014025:Titanium / Q000008:administration & dosage / Q000737:chemistry*
chemical_list: D016207:Cytokines; C009495:titanium dioxide; D014025:Titanium