Genome-wide methylation changes upon Caco-2 cells exposure to undigested and digested titanium dioxide nanoparticles

Ventura, Célia; Valente, Ana; Vieira, Luís; Silva, Catarina; Rolo, Dora; Silva, Maria Joao; Louro, Henriqueta

http://hdl.handle.net/10400.18/10727

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Ventura 2025 Genome-wide methylation changes upon Caco-2 cells exposure to undigested and digested titanium dioxide nanoparticles.pdf		6.96 MB	Adobe PDF	Ver/Abrir

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Introduction: Titanium dioxide nanoparticles (TiO2NPs) are relevant nanomaterials (NMs) for biomedicine and industry, which raise concerns about its effects on human health, particularly through ingestion. Several studies found that exposure to NMs can lead to DNA methylation changes. DNA methylation regulates gene expression, playing a vital role in development and disease, with aberrant methylation linked to cancer and other health conditions. Aim: We aimed at identifying DNA methylation changes in intestinal cells exposed to three TiO2NPs (NM-102, NM-103, NM-105), either digested or undigested. Their cellular effects were investigated by functional pathway and gene ontology (GO) analysis. Results: 48, 41, 55 differentially methylated genes (DMG) were identified after exposure to undigested NM-102, NM-103, NM-105; 71, 65, 55 DMG in the digested counterparts. Undigested TiO2NPs affected many G-proteins/adenylate cyclase-related pathways (PKA, glucagon, GPER1, CREB1, ADORA2B); the digested had lower impact. Cancer-related pathways were shared. Enriched molecular functions were mainly transcription-related; different biological processes were enriched if TiO2NPs were digested or not. Conclusions: TiO2NPs exposure causes DNA methylation changes that have a functional impact on intestinal cells, which differs with its physicochemical properties and digestion. NM-105 caused hypermethylation, unlike the other TiO2NPs. This study highlights DNA methylation relevance in assessing NMs’ toxicity.

Plain language summary: Titanium dioxide nanoparticles (TiO2NP) are widely present in our daily lives, including in food as a white pigment to make it better-looking and appealing. Although there are many toxicological studies on TiO2NP, few have focused on its effects on DNA methylation, which is a mechanism for regulating gene expression, and consequently, cellular functions. In this study, human intestinal cells were exposed to three different types of TiO2NP, before and after simulated digestion. Our results indicate that the physical-chemical characteristics of TiO2NP influence its effects and demonstrate the impact of digestion, relevant in the context of oral exposure. Moreover, they highlight the biological impact of TiO2NP on intestinal cells through DNA methylation changes and, consequently, the relevance of studying these changes when assessing the adverse effects of nanomaterials on human health.

Highlights: - TiO2NPs exposure caused DNA methylation changes on intestinal cells. - Simulated digestion of TiO2NPs caused methylation differences compared to undigested TiO2NPs. - Undigested TiO2NPs mainly affected G-proteins and adenylate cyclase pathways, while digested have a less obvious impact; both affected cancer-related pathways. - TiO2NPs with different physicochemical properties induced different DNA methylation changes. - NM-105 caused DNA hypermethylation, unlike the other TiO2NPs. - DNA methylation studies are relevant for assessing nanomaterials’ toxicity.