Bischoff Nicolaj S, Proquin Héloïse, Jetten Marlon J, Schrooders Yannick, Jonkhout Marloes C M, Briedé Jacco J, van Breda Simone G, Jennen Danyel G J, Medina-Reyes Estefany I, Delgado-Buenrostro Norma L, Chirino Yolanda I, van Loveren Henk, de Kok Theo M
Department of Toxicogenomics, GROW School for Oncology and Reproduction, Maastricht University Medical Center, 6229 ER Maastricht, The Netherlands.
National Institute for Public Health and Environment (RIVM), Bilthoven, 3721 MA De Bilt, The Netherlands.
Nanomaterials (Basel). 2022 Apr 7;12(8):1256. doi: 10.3390/nano12081256.
Titanium dioxide (TiO) 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 -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/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/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.
二氧化钛（TiO）作为食品添加剂E171存在于许多不同的食品中，目前因其潜在的不良影响而受到审查，这些影响包括刺激胃肠道肿瘤形成。我们开发了一种转基因小鼠模型来研究E171对结直肠癌（CRC）的影响，使用Cre-LoxP系统创建一个自发发生结直肠肿瘤的基因敲除模型。一项初步研究表明，暴露于E171的小鼠发生了结直肠腺癌，伴有上皮细胞增生增强、息肉底部的淋巴小结以及肿瘤大小增加。在主要研究中，研究了在9周内每天暴露于5 mg/kg的E171后的肿瘤形成情况（第一阶段）。在这些转基因小鼠中，E171暴露导致结直肠肿瘤数量在统计学上无显著增加，以及患肿瘤小鼠的平均数量在统计学上无显著增加。在暴露于每天1、2和5 mg/kg的E171 2、7、14和21天后（第二阶段），分析了结肠中的基因表达变化。全基因组mRNA分析揭示了参与基因表达调控、细胞周期、翻译后修饰、核受体信号传导和昼夜节律的途径中的基因调控。与这些基因相关的过程可能参与了肿瘤形成的增强，并表明E171可能通过调节与炎症、免疫反应激活、细胞周期和癌症信号传导相关的事件来促进肿瘤形成和进展。
