Food-grade TiO2 impairs intestinal and systemic immune homeostasis, initiates preneoplastic lesions and promotes aberrant crypt development in the rat colon

Sarah Bettini,Christel Cartier,Elisa Boutet-Robinet,Jean-Pierre Cravedi,Eric Gaultier,Jacques Dupuy,Fabrice H Pierre,Christine Coméra,Laurence Guzylack-Piriou,Solenn Reguer,Nathalie Thieriet,Patrick Grysan,Dominique Thiaudière,Jean-Nicolas Audinot,Matthieu Réfrégiers,Marie Carrière,Sylviane Taché,Nathalie Naud,Eric Houdeau

doi:10.1038/srep40373

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 TiO2 treatment, 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 TiO2 from dietary sources.

Highlights

(diameters of 30 to 400 nm), with up to 36% of particles falling below 100 nm in one dimension, i.e., nanoparticles (TiO2-NPs)[1,2,3]
Ti was detected in the gut lumen and Peyer’s patches (PP) (Fig. 1b) as well as in colon mucosa (Fig. 1c)
While recent reports based on NP models show that TiO2-NPs translocate through the intestinal epithelia, no in vivo study has been carried out to investigate the tissue distribution of food-grade TiO2 particles along the gut and whether the nanoscale fraction of E171 particles presents a specific risk via the oral route

Summary

Introduction

(diameters of 30 to 400 nm), with up to 36% of particles falling below 100 nm in one dimension, i.e., nanoparticles (TiO2-NPs)[1,2,3]. TiO2 particles of dietary origin have been found in the PP of patients suffering from inflammatory bowel disease (IBD)[17] including infants[18], and potent inflammasome activation has been reported in vitro using TiO2-NPs19. These studies point to possible contributions to chronic inflammatory processes in the gut if TiO2 particles accumulate in the cells of the PP through chronic dietary exposure, and this remains to be explored in vivo with the E171 food additive at relevant exposure levels for humans. The patterns of intestinal inflammation, preneoplastic lesion development and colonic aberrant crypt foci (ACF) promotion were assessed in rats with or without dimethylhydrazine (DMH)-induced carcinogenesis following oral E171 treatment at the same dosage delivered over 100 days

Methods

Results

Conclusion