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/kgbw/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/kgbw/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.

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“…In parallel, a Th1-mediated inflammatory response was observed in the small bowel of adult mice exposed for 10 days to TiO 2 -NP ( 159 ), whereas chronic exposure for 100 days to the food-grade form (E171) led to low-grade inflammation and immunosuppression in the colon ( 154 , 160 ). Further studies have confirmed the down-expression of genes involved in the innate and adaptive immune responses in the distal colon of mice treated for 21 days with E171 ( 161 ).…”

Correction: Bischoff et al. 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. Nanomaterials 2022, 12, 1256

“…In the published publication [1], there was an error regarding the affiliation for Yannick Schrooders (yannickschrooders@xs4all.nl). The affiliation 4 was wrongly added, and the updated affiliation only includes affiliation 1.…”

“…There was an error in the original publication [1]. The original publication stated that lymphoid hyperplasia was observed in the histopathology samples of the pilot study.…”

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“…Very recently, using an Apc-gene-knockout model, which spontaneously develops colorectal tumors, E171 exposure induced an increase, statistically nonsignificant, 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, while modulation of events related to inflammation, activation of immune responses, cell cycle, and cancer signaling were shown by whole-genome mRNA analysis [180]. Conversely, food-grade titanium dioxide (E171) induced adenomas in colon and goblet cells hyperplasia in a regular diet model and microvesicular steatosis in a high fat diet model in mice [181].…”