The food additive titanium dioxide hinders intestinal production of TGF-β and IL-10 in mice, and long-term exposure in adults or from perinatal life blocks oral tolerance to ovalbumin

Lamas, Bruno; Chevalier, Laurence; Gaultier, Eric; Cartier, Christel; Weingarten, Laurent; Blanc, Xavier; Fisicaro, Paola; Oster, Caroline; Noireaux, Johanna; Evariste, Lauris; Breyner, Natalia Martins; Houdeau, Eric

doi:10.1016/j.fct.2023.113974

Cited by 8 publications

(5 citation statements)

References 61 publications

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“…The fg -TiO 2 was purchased as powder from the website of a French commercial supplier of food colouring agents, and was already characterized in previous studies as a representative E171 sample in the anatase crystal form that has been placed on the EU market [ 15 , 20 , 25 , 33 , 34 , 35 ]. Briefly, to obtain a stable dispersion of TiO 2 particles, the fg -TiO 2 stock suspension (10 mg/mL) was sonicated in an ice bath for 16 min at 30% amplitude with a VCX 750-230 V (Sonics&Materials, Newton, CT, USA), then stocked at 4 °C during 15 days maximum before use.…”

Section: Methodsmentioning

confidence: 99%

“…In EU, the precautionary principle led to public policies banning the use of the fg -TiO 2 in 2022 [ 4 , 31 ] based on its capacity to induce oxidative stress [ 18 ] and genotoxicity [ 32 , 33 ], as well as its potential to cause developmental impacts when in utero exposure occurs via the mother’s diet [ 15 , 16 , 34 , 35 , 36 ]. However, the use of fg -TiO 2 is still authorised outside Europe, and food safety agencies worldwide have asked for additional studies.…”

Section: Introductionmentioning

confidence: 99%

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Validating Enteroid-Derived Monolayers from Murine Gut Organoids for Toxicological Testing of Inorganic Particles: Proof-of-Concept with Food-Grade Titanium Dioxide

Malaisé,

Casale,

Pettes-Duler

et al. 2024

IJMS

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Human exposure to foodborne inorganic nanoparticles (NPs) is a growing concern. However, identifying potential hazards linked to NP ingestion often requires long-term exposure in animals. Owing these constraints, intestinal organoids are a promising alternative to in vivo experiments; as such, an in vitro approach should enable a rapid and reliable assessment of the effects of ingested chemicals on the gut. However, this remains to be validated for inorganic substances. In our study, a transcriptomic analysis and immunofluorescence staining were performed to compare the effects of food-grade TiO2 (fg-TiO2) on enteroid-derived monolayers (EDMs) from murine intestinal organoids to the known impacts of TiO2 on intestinal epithelium. After their ability to respond to a pro-inflammatory cytokine cocktail was validated, EDMs were exposed to 0, 0.1, 1, or 10 µg fg-TiO2/mL for 24 h. A dose-related increase of the muc2, vilin 1, and chromogranin A gene markers of cell differentiation was observed. In addition, fg-TiO2 induced apoptosis and dose-dependent genotoxicity, while a decreased expression of genes encoding for antimicrobial peptides, and of genes related to tight junction function, was observed. These results validated the use of EDMs as a reliable model for the toxicity testing of foodborne NPs likely to affect the intestinal barrier.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Validating Enteroid-Derived Monolayers from Murine Gut Organoids for Toxicological Testing of Inorganic Particles: Proof-of-Concept with Food-Grade Titanium Dioxide

Malaisé,

Casale,

Pettes-Duler

et al. 2024

IJMS

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“… 9 – 11 In this context, chronic exposure to inorganic nanoparticles (NPs) from various household sources, including their use as food additives, has gained increasing attention due to the potential immune system alterations that they can induce. 11 , 12 Notably, studies in rats 13 and mice 14 , 15 have demonstrated that silicon and titanium dioxide NPs can disrupt OT 14 , 15 or alter immune cell populations involved in OT induction, 13 respectively. Thus, foodborne NPs may be linked to the recent prevalence increase in food sensitivities in the industrialized world.…”

Section: Introductionmentioning

confidence: 99%

Evaluating the Effects of Chronic Oral Exposure to the Food Additive Silicon Dioxide on Oral Tolerance Induction and Food Sensitivities in Mice

Lamas,

Martins Breyner,

Malaisé

et al. 2024

Environ Health Perspect

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Background: The increasing prevalence of food sensitivities has been attributed to changes in gut microenvironment; however, ubiquitous environmental triggers such as inorganic nanoparticles (NPs) used as food additives have not been thoroughly investigated. Objectives: We explored the impact of the NP-structured food-grade silicon dioxide ( ) on intestinal immune response involved in oral tolerance (OT) induction and evaluated the consequences of oral chronic exposure to this food-additive using a mouse model of OT to ovalbumin (OVA) and on gluten immunopathology in mice expressing the celiac disease risk gene, HLA-DQ8. Methods: Viability, proliferation, and cytokine production of mesenteric lymph node (MLN) cells were evaluated after exposure to . C57BL/6J mice and a mouse model of OT to OVA were orally exposed to or vehicle for 60 d. Fecal lipocalin-2 (Lcn-2), anti-OVA IgG, cytokine production, and immune cell populations were analyzed. Nonobese diabetic (NOD) mice expressing HLA-DQ8 (NOD/DQ8), exposed to or vehicle, were immunized with gluten and immunopathology was investigated. Results: MLN cells exposed to presented less proliferative T cells and lower secretion of interleukin 10 (IL-10) and transforming growth factor beta ( ) by T regulatory and cells compared to control, two factors mediating OT. Mice given exhibited intestinal Lcn-2 level and interferon gamma ( ) secretion, showing inflammation and less production of IL-10 and . These effects were also observed in OVA-tolerized mice exposed to , in addition to a breakdown of OT and a lower intestinal frequency of T cells. In NOD/DQ8 mice immunized with gluten, the villus-to-crypt ratio was decreased while the intraepithelial lymphocyte counts and the Th1 inflammatory response were aggravated after treatment. Discussion: Our results suggest that chronic oral exposure to blocked oral tolerance induction to OVA, and worsened gluten-induced immunopathology in NOD/DQ8 mice. The results should prompt investigation on the link between exposure and food sensitivities in humans. https://doi.org/10.1289/EHP12758

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“…In EU, the precautionary principle led to public policies banning the use of the fg-TiO 2 in 2022 [4,31] based on its capacity to induce oxidative stress [18] and genotoxicity [32,33], as well as its potential to cause developmental impacts when in utero exposure occurs via the mother's diet [15,16,[34][35][36]. However, the use of fg-TiO 2 is still authorised outside Europe, and food safety agencies worldwide have asked for additional studies.…”

Section: Introductionmentioning

confidence: 99%

Validating Enteroid-Derived Monolayers From Murine Gut Organoids for Toxicological Testing of Inorganic Particles: Proof-of-Concept With Food Grade Titanium Dioxide

Malaisé,

Casale,

Pettes-Duler

et al. 2024

Preprint

View full text Add to dashboard Cite

Human exposure to foodborne inorganic nanoparticles (NPs) is a growing concern. However, identifying potential hazards linked to NP ingestion often requires long-term exposure in animals. Owing these constraints, intestinal organoids are a promising alternative to in vivo experiments, as such an in vitro approach should enable rapid and reliable assessment of the effects on the gut of ingested chemicals. However, this remains to be validated for inorganic substances. In our study, a transcriptomic analysis and immunofluorescence staining were performed to compare the effects of food-grade TiO2 (fg-TiO2) on enteroid-derived monolayers (EDMs) from murine intestinal organoids to known impacts of TiO2 on intestinal epithelium. After validating their ability to dose-dependently respond to a pro-inflammatory cytokine cocktail, EDMs were exposed to 0.1, 1 or 10 µg fg-TiO2/mL for 24h. In line with known data, a dose-related increase of muc2, vilin 1 and chromogranin A gene markers of cell differentiation was observed. In addition, fg-TiO2 induced apoptosis and dose-dependent genotoxicity, while a decreased expression of genes encoding for antimicrobial peptides, and of genes related to tight junction function was observed. These results validated the use of EDMs as a reliable model for toxicity testing of foodborne NPs likely to affect the intestinal barrier.

show abstract

The food additive titanium dioxide hinders intestinal production of TGF-β and IL-10 in mice, and long-term exposure in adults or from perinatal life blocks oral tolerance to ovalbumin

Cited by 8 publications

References 61 publications

Validating Enteroid-Derived Monolayers from Murine Gut Organoids for Toxicological Testing of Inorganic Particles: Proof-of-Concept with Food-Grade Titanium Dioxide

Validating Enteroid-Derived Monolayers from Murine Gut Organoids for Toxicological Testing of Inorganic Particles: Proof-of-Concept with Food-Grade Titanium Dioxide

Evaluating the Effects of Chronic Oral Exposure to the Food Additive Silicon Dioxide on Oral Tolerance Induction and Food Sensitivities in Mice

Validating Enteroid-Derived Monolayers From Murine Gut Organoids for Toxicological Testing of Inorganic Particles: Proof-of-Concept With Food Grade Titanium Dioxide

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