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- Early-stage nanosafety assessment as a critical tool for innovative nanomaterials developmentPublication . Louro, Henriqueta; Ventura, Célia; Rolo, Dora; Vital, Nádia; Pinto, Fátima; Silva, Maria JoãoThe perspectives of innovation through the use of nanomaterials (NMs) in key sectors such as agriculture, food industry, medicine, energy, environment, and electronics, has exponentially increased their development, production, and application. However, a major concern for public health is that some materials for long being considered safe for humans, e.g., titanium dioxide or cellulose fibers, can acquire different properties at the nanoscale that, despite being more attractive for industrial applications, may also elicit nano-bio interactions and toxic effects. Furthermore, their physicochemical properties can be influenced by the surrounding matrix or by physiological processes, such as digestion or inhalation, that modify their primary physicochemical properties. These secondary features may also influence the NMs toxicity and associated adverse health outcomes, such chronic inflammation and/or cancer. Therefore, the safety assessment of NMs must be conducted early in their development process and follow the nanotoxicology principles, in order to unveil the most relevant physicochemical characteristics that determine their potential adverse effects. In this work, the nanotoxicological investigation for the case studies of titanium dioxide NMs and nanocelluloses are presented. They illustrate the establishment of relationships between NMs characteristics and their toxicological properties and how they may direct the synthesis of innovative and safer NMs. If such tool is used at an early stage of NMs or product development, it moves industry towards a safe and sustainable by design (SSBD) approach that will enable safety to keep pace with innovation for the benefit of citizens. The Portuguese ISO/CEN Technical Commission for Nanotechnologies (CT194) is acknowledged for its role in bridging the gap between science and industry.
- Cellular and Molecular Mechanisms of Toxicity of Ingested Titanium Dioxide NanomaterialsPublication . Vieira, Adriana; Gramacho, Ana; Rolo, Dora; Vital, Nádia; Silva, Maria João; Louro, HenriquetaAn exponential increase in products containing titanium dioxide nanomaterials (TiO2), in agriculture, food and feed industry, lead to increased oral exposure to these nanomaterials (NMs). Thus, the gastrointestinal tract (GIT) emerges as a possible route of exposure that may drive systemic exposure, if the intestinal barrier is surpassed. NMs have been suggested to produce adverse outcomes, such as genotoxic effects, that are associated with increased risk of cancer, leading to a concern for public health. However, to date, the differences in the physicochemical characteristics of the NMs studied and other variables in the test systems have generated contradictory results in the literature. Processes like human digestion may change the NMs characteristics, inducing unexpected toxic effects in the intestine. Using TiO2 as case-study, this chapter provides a review of the works addressing the interactions of NMs with biological systems in the context of intestinal tract and digestion processes, at cellular and molecular level. The knowledge gaps identified suggest that the incorporation of a simulated digestion process for in vitro studies has the potential to improve the model for elucidating key events elicited by these NMs, advancing the nanosafety studies towards the development of an adverse outcome pathway for intestinal effects.
- Titanium dioxide nanomaterials - induced DNA damage in intestinal cells following simulated in vitro digestionPublication . Vieira, Adriana; Rolo, Dora; Vital, Nádia; Martins, Carla; Assunção, Ricardo; Alvito, Paula; Gonçalves, Lídia; Bettencourt, Ana; Silva, Maria João; Louro, HenriquetaIntroduction: The increased use of titanium dioxide nanomaterials (TiO2) in food products has raised oral exposure to those nanomaterials, with subsequent risks to human health, particularly genotoxicity and, ultimately, cancer development. In humans, the digestion process may modify the physicochemical properties of TiO2, thereby shaping the potential biological outcomes. Thus, such process should be considered when assessing their hazard upon oral exposure. This work aimed to investigate the genotoxic effects of three TiO2 (NM-102, NM-103 and NM-105, JRC repository) after the simulation of the human digestive process using the standardized INFOGEST in vitro digestion method. The secondary physicochemical properties and DNA damage levels, using the comet assay, were analysed in two intestinal cell lines exposed for 24h to digested or undigested TiO2. Results: An increase in the level of DNA strand breaks in two intestinal cell lines(Caco-2 and HT29-MTX-E12) was observed after exposure to digested NM-105, concomitantly with a decrease in its hydrodynamic size, comparatively to the undigested nanomaterial. Moreover, the digested NM-103 induced DNA damage in Caco-2 cells whereas the undigested nanomaterial did not. The FPG-modified comet assay also revealed an increase in oxidative DNA lesions upon treatment of Caco-2 with NM-103 and HT29-MTX-E12 with NM-102. Conclusions: One of the digested TiO2(NM-105) can be classified as potentially genotoxic in both cell lines, while the digested NM-103 induced an equivocal genotoxic response in Caco-2 cells. Therefore, the digestion simulation is of relevance to investigate the potential genotoxic effects of ingested nanomaterials.
- Aula 9: Vias de Efeitos Adversos e Avaliação de RiscoPublication . Rolo, Dora; Silva, Maria João; Louro, HenriquetaSobre Vias de Efeitos Adversos e Avaliação de Risco.
- Cellular effects of Titanium Dioxide Nanoparticles in the intestinePublication . Rolo, Dora; Pereira, Joana F.S.; Matos, Paulo; Gonçalves, Lídia; Bettencourt, Ana Francisca; Jordan, Peter; Silva, Maria João; Louro, HenriquetaIntroduction: The increased use of titanium dioxide nanoparticles (TiO2-NPs) as a food additive demands a thorough assessment of their potential risk for human health. Via oral exposure they may lead to adverse local or systemic outcomes, and few studies have focused on the cellular internalization mechanisms (endocytosis) of TiO2-NPs. The objective was to analyze the mechanisms by which TiO2-NPs (NM-102, NM-103 and NM-105, JRC repository) translocate by the intestinal epithelium layer, using monolayers of human intestinal cell lines (Caco-2 and HT29-MTX), as well as polarized Caco-2 cells, and co-cultures of both cells. Results: We evaluated cell differentiation by transepithelial resistance measurements and the translocation of TiO2-NPs tagged with alizarin through the intestinal barrier by confocal microscopy and we confirmed the internalization of the TiO2-NPs in both cell line models. Co-localization studies suggested that the smallest TiO2-NPs were internalized into EEA1-positive early-endosomes and accumulate in late endosomes (Rab7), with only a small fraction following the degradative pathway to the lysosome (LAMP1). This suggested that at least part of the TiO2-NPs could be redirected to the secretory pathway. Consistently, we detected fluorescence passing from the apical (AP) to the basolateral (BL) chamber, depending on the characteristics of cell model and TiO2-NPs tested. Conclusions: Small TiO2-NPs were endocytosed by Caco-2 cells, with an increase in particle diameter suggesting intracellular aggregation, whereas larger agglomerates deposited mainly extracellularly. Following endocytosis, TiO2 NPs were trafficked through different intracellular compartments including early and late endosomes/endo-lysosomes, with part being subjected to AP to BL transport.