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Transcriptomics effects of ingestion of food additive titanium dioxide (E171) in the colon of a chemically induced colorectal cancer model

ABSTRACT: Titanium dioxide, a white colorant, is the mineral the most produced worldwide. It is used in food under the name of E171. Previous studies showed that in a chemically induced colorectal cancer mouse model, E171 increase significantly the number of tumours. The aim of this study was to understand the molecular mechanisms behind these effects of E171 exposure. BALB/c mice were exposed by gavage to 5 mg/kg bw/day of E171 for 2, 7, 14 and 21 days. Whole genome mRNA microarray analyses on the distal colon were performed. The results show that E171 induced a downregulation of genes involved in the innate and adaptive immune system, suggesting impairment of this system. In addition, over time, signalling genes involved in colorectal cancer and other types of cancers were modulated. In relation to cancer development, effects potentially associated with oxidative stress were observed through modulation of genes related to antioxidant production. E171 affected genes involved in biotransformation of xenobiotics which can form reactive intermediates resulting in toxicological effects. These transcriptomics data reflect the early biological responses induced by E171 which precede tumour formation in an AOM/DSS mouse model.

ORGANISM(S): Mus musculus

PROVIDER: GSE109520 | GEO | 2018/07/15

REPOSITORIES: GEO

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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: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.

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Transcriptomics effects of ingestion of food additive titanium dioxide (E171) in the colon of a chemically induced colorectal cancer model

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