Dataset Information

The Effects of the Food Additive Titanium Dioxide (E171) on Tumor Formation and Gene Expression in the Colon of a Transgenic Mouse Model for Colorectal Cancer.

ABSTRACT: Titanium dioxide (TiO₂) is present in many different food products as the food additive E171, which is currently scrutinized due to its potential adverse effects, including the stimulation of tumor formation in the gastrointestinal tract. We developed a transgenic mouse model to examine the effects of E171 on colorectal cancer (CRC), using the Cre-LoxP system to create an Apc-gene-knockout model which spontaneously develops colorectal tumors. A pilot study showed that E171 exposed mice developed colorectal adenocarcinomas, which were accompanied by enhanced hyperplasia in epithelial cells, lymphatic nodules at the base of the polyps, and increased tumor size. In the main study, tumor formation was studied following the exposure to 5 mg/kg_bw/day of E171 for 9 weeks (Phase I). E171 exposure showed a statistically nonsignificant increase in the number of colorectal tumors in these transgenic mice, as well as a statistically nonsignificant increase in the average number of mice with tumors. Gene expression changes in the colon were analyzed after exposure to 1, 2, and 5 mg/kg_bw/day of E171 for 2, 7, 14, and 21 days (Phase II). Whole-genome mRNA analysis revealed the modulation of genes in pathways involved in the regulation of gene expression, cell cycle, post-translational modification, nuclear receptor signaling, and circadian rhythm. The processes associated with these genes might be involved in the enhanced tumor formation and suggest that E171 may contribute to tumor formation and progression by modulation of events related to inflammation, activation of immune responses, cell cycle, and cancer signaling.

SUBMITTER: Bischoff NS

PROVIDER: S-EPMC9027218 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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The Effects of the Food Additive Titanium Dioxide (E171) on Tumor Formation and Gene Expression in the Colon of a Transgenic Mouse Model for Colorectal Cancer.

Bischoff Nicolaj S NS Proquin Héloïse H Jetten Marlon J MJ Schrooders Yannick Y Jonkhout Marloes C M MCM Briedé Jacco J JJ van Breda Simone G SG Jennen Danyel G J DGJ Medina-Reyes Estefany I EI Delgado-Buenrostro Norma L NL Chirino Yolanda I YI van Loveren Henk H de Kok Theo M TM

Nanomaterials (Basel, Switzerland) 20220407 8

Titanium dioxide (TiO<sub>2</sub>) is present in many different food products as the food additive E171, which is currently scrutinized due to its potential adverse effects, including the stimulation of tumor formation in the gastrointestinal tract. We developed a transgenic mouse model to examine the effects of E171 on colorectal cancer (CRC), using the Cre-LoxP system to create an <i>Apc</i>-gene-knockout model which spontaneously develops colorectal tumors. A pilot study showed that E171 expo ...[more]

PMID: 35457963

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Project description:The present opinion deals with an updated safety assessment of the food additive titanium dioxide (E 171) based on new relevant scientific evidence considered by the Panel to be reliable, including data obtained with TiO2 nanoparticles (NPs) and data from an extended one-generation reproductive toxicity (EOGRT) study. Less than 50% of constituent particles by number in E 171 have a minimum external dimension < 100 nm. In addition, the Panel noted that constituent particles < 30 nm amounted to less than 1% of particles by number. The Panel therefore considered that studies with TiO2 NPs < 30 nm were of limited relevance to the safety assessment of E 171. The Panel concluded that although gastrointestinal absorption of TiO2 particles is low, they may accumulate in the body. Studies on general and organ toxicity did not indicate adverse effects with either E 171 up to a dose of 1,000 mg/kg body weight (bw) per day or with TiO2 NPs (> 30 nm) up to the highest dose tested of 100 mg/kg bw per day. No effects on reproductive and developmental toxicity were observed up to a dose of 1,000 mg E 171/kg bw per day, the highest dose tested in the EOGRT study. However, observations of potential immunotoxicity and inflammation with E 171 and potential neurotoxicity with TiO2 NPs, together with the potential induction of aberrant crypt foci with E 171, may indicate adverse effects. With respect to genotoxicity, the Panel concluded that TiO2 particles have the potential to induce DNA strand breaks and chromosomal damage, but not gene mutations. No clear correlation was observed between the physico-chemical properties of TiO2 particles and the outcome of either in vitro or in vivo genotoxicity assays. A concern for genotoxicity of TiO2 particles that may be present in E 171 could therefore not be ruled out. Several modes of action for the genotoxicity may operate in parallel and the relative contributions of different molecular mechanisms elicited by TiO2 particles are not known. There was uncertainty as to whether a threshold mode of action could be assumed. In addition, a cut-off value for TiO2 particle size with respect to genotoxicity could not be identified. No appropriately designed study was available to investigate the potential carcinogenic effects of TiO2 NPs. Based on all the evidence available, a concern for genotoxicity could not be ruled out, and given the many uncertainties, the Panel concluded that E 171 can no longer be considered as safe when used as a food additive.

Project description:The prospective use of food additive titanium dioxide (E171 TiO2) in a variety of fields (food, pharmaceutics, and cosmetics) prompts proper cellular cytotoxicity and transcriptomic assessment. Interestingly, smaller-sized E171 TiO2 can translocate in bloodstream and induce a diverse immunological response by activating the immune system, which can be either pro-inflammatory or immune-suppressive. Nevertheless, their cellular or immunologic responses in a heterogeneous population of the immune system following exposure of food additive E171 TiO2 is yet to be elucidated. For this purpose, we have used male Sprague-Dawley rats to deliver E171 TiO2 (5 mg/kg bw per day) via non-invasive intratracheal instillation for 13 weeks. After the 4 weeks recovery period, 3 mL of blood samples from both treated and untreated groups were collected for scRNAseq analysis. Firstly, granulocyte G1 activated innate immune response through the upregulation of genes involved in pro-inflammatory cytokine mediated cytotoxicity. Whereas NK cells resulted in heterogeneity role depending on the subsets where NK1 significantly inhibited cytotoxicity, whereas NK2 and NK3 subsets activated pro-B cell population & inhibited T cell mediated cytotoxicity respectively. While NKT_1 activated innate inflammatory responses which was confirmed by cytotoxic CD8+ T killer cell suppression. Similarly, NKT_2 cells promote inflammatory response by releasing lytic granules and MHC-I complex inhibition to arrest cytotoxic T killer cell responses. Conversely, NKT_3 suppressed inflammatory response by release of anti-inflammatory cytokines suggesting the functional heterogeneity of NKT subset. The formation of MHC-I or MHC-II complexes with T-cell subsets resulted in neither B and T cell dysfunction nor cytotoxic T killer cell inhibition suppressing adaptive immune response. Overall, our research offers an innovative high-dimensional approach to reveal immunological and transcriptomic responses of each cell types at the single cell level in a complex heterogeneous cellular environment by reassuring a precise assessment of immunological response of E171 TiO2.

Project description:Interventions: This study is a cross-over design, including only healthy volunteers. A cross-over design was chosen because it is the most appropriate design for this study: it will reduce the individual differences by allowing every subject to be his own control. This study will be done in 4 weeks and include 2 periods. The volunteers will be randomized in two groups: one group will start with the intervention period and the other one will start with the control period. After, these 2 weeks of intervention or control periods, the volunteers will start the control period and intervention period respectively for another 2 weeks. The time of exposure is 2 weeks. Indeed, it takes 5 to 7 days for the turnover of the epithelial cells in the gut. This will ensure the exposure of all the cells of the luminal surface of the colon. The control period, is meant to reduce to a minimum the ingestion of E171 in order to have all the volunteers to start the same level of E171. During this period the volunteers will receive a list of products to avoid like cookies, chewing gum, certain toothpaste that are known to contain a significant amount of E171. The intervention period, is meant to control the amount of E171 that the volunteers will ingest. A concentration, 0.82 mg/kg bw/day, corresponding to a normal daily consumption will be given to the volunteers. The quantity will be adjusted to the body weight and dispersed in yoghurt that will be eaten at breakfast, lunch and dinner. In order to verify the compliance of the subjects, once in every period the subjects will prepare a package that include exactly what they ate and drank all day. This food package will be mixed and tested for TiO2 content. Primary outcome(s): The primary outcome parameters are differences in transcriptomic markers after consumption of food additive E171. These outcomes in humans will shed light on the relevance of markers identified in preclinical studies, and how the animal data on the risk of facilitation of tumour growth can be extrapolated to humans Study Design: Randomized controlled trial, Single blinded (masking used), N/A , unknown, Crossover

Project description:ObjectiveUp to 44% of particulates of food-grade titanium dioxide (TiO2) are in nanoscale, while the effect and combined effect of which with other substances on intestinal barrier haven't been fully understood yet. This study is aimed to study the effect of two kinds of TiO2 nanoparticles (TiO2 NPs and TiO2 MPs) on intestinal barrier functions, to reveal the combined effect of TiO2 NPs and Lipopolysaccharide (LPS) on intestinal barrier.MethodsMale ICR mice were randomly divided into 18 groups (3 feed types * 3 exposure length * 2 LPS dosage) and were fed with normal or TiO2-mixed feed (containing 1% (mass fraction, w/w) TiO2 NPs or TiO2 MPs) for 1, 3, 6 months, followed by a single oral administration of 0 or 10 mg/(kg body weight) LPS. Four hours later, the transportation of TiO2, the intestinal barrier functions and the inflammatory response were evaluated.ResultsBoth TiO2 notably increased the intestinal villi height / crypt depth ratios after 1 and 3 months of exposure, and increased the expression of ileal tight junction proteins (ZO-1 and occludin) after 1 month of exposure. After 6 months of exposure, TiO2 NPs led to reduced feed consumption, TiO2 MPs caused spare microvilli in small intestine and elevated Ti content in the blood cells. The intestinal permeability didn't change in both TiO2 exposed groups. After LPS administration, we observed altered intestinal villi height / crypt depth ratios, lowered intestinal permeability (DAO) and upregulated expression of ileal ZO-1 in both (TiO2 +LPS) exposed groups. There are no significant changes of ileal or serum cytokines except for a higher serum TNF-α level in LPS treated group. The antagonistic effect was found between TiO2 NPs and LPS, but there are complicated interactions between TiO2 MPs and LPS.ConclusionLong-term intake of food additive TiO2 could alter the intestinal epithelial structure without influencing intestinal barrier function. Co-exposure of TiO2 and LPS would enhance intestinal barrier function without causing notable inflammatory responses, and there is antagonistic effect between TiO2 NPs and LPS. All the minor effects observed might associate with the gentle exposure method where TiO2 being ingested with feed.

Dataset Information

The Effects of the Food Additive Titanium Dioxide (E171) on Tumor Formation and Gene Expression in the Colon of a Transgenic Mouse Model for Colorectal Cancer.

Publications

The Effects of the Food Additive Titanium Dioxide (E171) on Tumor Formation and Gene Expression in the Colon of a Transgenic Mouse Model for Colorectal Cancer.

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