Abstract
BackgroundFood-grade TiO2 (E171 in the EU) is widely used as a coloring agent in foodstuffs, including sweets. Chronic dietary exposure raises concerns for human health due to proinflammatory properties and the ability to induce and promote preneoplastic lesions in the rodent gut. Characterization of intestinal TiO2 uptake is essential for assessing the health risk in humans. We studied in vivo the gut absorption kinetics of TiO2 in fasted mice orally given a single dose (40 mg/kg) to assess the ability of intestinal apical surfaces to absorb particles when available without entrapment in the bolus. The epithelial translocation pathways were also identified ex vivo using intestinal loops in anesthetized mice.ResultsThe absorption of TiO2 particles was analyzed in gut tissues by laser-reflective confocal microscopy and ICP-MS at 4 and 8 h following oral administration. A bimodal pattern was detected in the small intestine: TiO2 absorption peaked at 4 h in jejunal and ileal villi before returning to basal levels at 8 h, while being undetectable at 4 h but significantly present at 8 h in the jejunal Peyer’s patches (PP). Lower absorption occurred in the colon, while TiO2 particles were clearly detectable by confocal microscopy in the blood at 4 and 8 h after treatment. Ex vivo, jejunal loops were exposed to the food additive in the presence and absence of pharmacological inhibitors of paracellular tight junction (TJ) permeability or of transcellular (endocytic) passage. Thirty minutes after E171 addition, TiO2 absorption by the jejunal villi was decreased by 66% (p < 0.001 vs. control) in the presence of the paracellular permeability blocker triaminopyrimidine; the other inhibitors had no significant effect. Substantial absorption through a goblet cell (GC)-associated pathway, insensitive to TJ blockade, was also detected.ConclusionsAfter a single E171 dose in mice, early intestinal uptake of TiO2 particles mainly occurred through the villi of the small intestine, which, in contrast to the PP, represent the main absorption surface in the small intestine. A GC-associated passage and passive diffusion through paracellular TJ spaces between enterocytes appeared to be major absorption routes for transepithelial uptake of dietary TiO2.
Highlights
Food-grade TiO2 (E171 in the European Union (EU)) is widely used as a coloring agent in foodstuffs, including sweets
The kinetics and absorption rates for TiO2 particle uptake along the gut remain to be specified, the respective contributions of diffuse Peyer’s patches (PP) sites compared to absorptive enterocytes, the latter of which represent most of the surface area of the gut epithelium
Kinetic of TiO2 absorption along the intestine and systemic passage The primary particle size distribution in the E171 batch used has been previously characterized by transmission electronic microscopy (TEM), and ranged between 20 and 340 nm in diameter [6, 7]
Summary
Food-grade TiO2 (E171 in the EU) is widely used as a coloring agent in foodstuffs, including sweets. Food safety authorities recommended additional toxicity testing to establish a health-based guidance value for food-grade TiO2 [3] This requires supplemental studies designed to determine in vivo the absorption sites of TiO2 particles from the food additive E171 as it passes through the gut, along with information on the mechanisms of particle uptake. Bimodal passage into the bloodstream has been reported after a single oral dose of food-grade TiO2 given to volunteers, with an identifiable absorption starting at 1 h and peaking at 6 h after ingestion [13] Such long-lasting intestinal absorption with a delayed peak for lumen-to-blood passage led the authors to hypothesize two routes for particle uptake from the gut that remain to be precised in vivo. Trans- and paracellular routes for transepithelial TiO2 passage were studied ex vivo on isolated intestinal loops in anesthetized mice in the presence and absence of selective pharmacological blockades
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