Dataset Information

Transcriptome changes in undifferentiated Caco-2 cells exposed to food-grade titanium dioxide (E171): contribution of the nano- and micro- sized particles.

ABSTRACT: The food additive titanium dioxide (TiO2), or E171, is a white food colorant. Recent studies showed after E171 ingestion a significantly increased number of colorectal tumours in a colorectal cancer mouse model as well as inflammatory responses and dysregulation of the immune system in the intestine of rats. In the mouse colon, E171 induced gene expression changes related to oxidative stress, impairment of the immune system, activation of signalling and cancer-related processes. E171 comprises nanoparticles (NPs) and microparticles (MPs). Previous in vitro studies showed that E171, NPs and MPs induced oxidative stress responses, DNA damage and micronuclei formation. This study aimed to investigate the relative contribution of the NPs and MPs to effects of E171 at the transcriptome level in undifferentiated Caco-2 cells by genome wide microarray analysis. The results showed that E171, NPs, and MPs induce gene expression changes related to signalling, inflammation, immune system, transport and cancer. At the pathway level, metabolism of proteins with the insulin processing pathway and haemostasis were specific to E171 exposure. The gene expression changes associated with the immune system and inflammation induced by E171, MPs, and NPs suggest the creation of a favourable environment for colon cancer development.

SUBMITTER: Proquin H

PROVIDER: S-EPMC6893026 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Transcriptome changes in undifferentiated Caco-2 cells exposed to food-grade titanium dioxide (E171): contribution of the nano- and micro- sized particles.

Proquin Héloïse H Jonkhout Marloes C M MCM Jetten Marlon J MJ van Loveren Henk H de Kok Theo M TM Briedé Jacob J JJ

Scientific reports 20191204 1

The food additive titanium dioxide (TiO<sub>2</sub>), or E171, is a white food colorant. Recent studies showed after E171 ingestion a significantly increased number of colorectal tumours in a colorectal cancer mouse model as well as inflammatory responses and dysregulation of the immune system in the intestine of rats. In the mouse colon, E171 induced gene expression changes related to oxidative stress, impairment of the immune system, activation of signalling and cancer-related processes. E171 ...[more]

PMID: 31797963

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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: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:In the present study we investigate the effect of maternal pulmonary exposure to titanium dioxide (UV-Titan designed for use in the paint and lacquer industry) on prenatally exposed offspring. Time-mated mice (C57BL/6BomTac) were exposed by inhalation for 1 h/day to 42 mg UV-titan/m3 aerosolized powder or filtered air during gestation days (GD) 8-18. We evaluated levels of DNA strand breaks using the comet assay in bronchioalveolar lavage (BAL) cells and liver cells of the time-mated mice, and in liver cells of the offspring. In parallel, we analyzed changes in gene expression in the liver tissue of offspring using DNA microarrays. We demonstrate that UV-Titan did not induce DNA strand breaks in the time-mated mice or their offspring. Transcriptional profiling of newborn liver tissue revealed changes in the expression of genes related to the retinoic acid (RA) signalling pathway in the females, while gene expression in male offspring was relatively unaffected by exposure. Time-mated, nulliparous mice (C57BL/6BomTac, Taconic Europe, Ejby, Denmark) were exposed to filtered clean air or approximately 42 mg/m3 UV-Titan on GD 8M-bM-^@M-^S18 for 1 hr/day by a whole-body exposure.Delivery was expected on GD 20, and designated postnatal day (PND) 0. On PND 2, one offspring (M-bM-^@M-^\newbornM-bM-^@M-^]) per litter was killed by decapitation, to yield litters with at least 5 offspring per exposure group. The newborn offspring were collected two days after birth. On PND 23-24 (M-bM-^@M-^\at weaningM-bM-^@M-^]) one male and one female per litter were killed. Organs were dissected, weighed, placed in NUNC cryotubes, snap frozen in liquid N2 and stored at -80M-BM-0C until analysis. Exposed dams were killed on PND 24-25 (26-27 days after last exposure). DNA strad break detection was carried out in bronchoalveolar lavage fluid in dams by COMET assay. Total RNA was extracted from offspring livers and gene expression profiling was carried out on whole liver tissues from offspring. 9 UV-Titan treated and 7 controls mice consisting of 8 males and 8 females mRNA, hepatic, developmental, Toxicogenomics, nano-titanium dioxide

Dataset Information

Transcriptome changes in undifferentiated Caco-2 cells exposed to food-grade titanium dioxide (E171): contribution of the nano- and micro- sized particles.

Publications

Transcriptome changes in undifferentiated Caco-2 cells exposed to food-grade titanium dioxide (E171): contribution of the nano- and micro- sized particles.

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