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

INTRODUCTION: Titanium dioxide nanoparticles (TiO(2)NPs) 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 TiO(2)NPs (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 TiO(2)NPs 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 TiO(2)NPs were digested or not. CONCLUSIONS: TiO(2)NPs 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 TiO(2)NPs. This study highlights DNA methylation relevance in assessing NMs' toxicity.