Advanced lung and liver models for hazard characterization of nanomaterials
Abstract
Humans are constantly exposed to particles from the surrounding environment, including nanomaterials (NMs) which are small particles with size <100 nm. After inhalation, some NMs can deposit in the lungs, cross the lung-blood barrier, and reach other target organs such as the liver. New approach methodologies are being developed for hazard assessment of NMs, including advanced in vitro models based on cell cultures in more physiologically relevant conditions. Of special importance is the application of these models for genotoxicity testing, to evaluate the ability of the NMs to alter the genetic information. The aim of this work was to contribute to the development of advanced lung and liver models, representing a first-contact and secondary target organ of inhaled NMs, respectively. The performance of the models in genotoxicity testing was compared to traditional models. Advanced lung models were constructed with bronchial or alveolar epithelial cells in mono- or cocultures with endothelial cells and macrophages at the air-liquid interface. An advanced liver model was constructed with hepatocytes cultured in spheroids, allowing increased cell-to-cell interactions and signaling. Both advanced models and traditional models were exposed to NMs or chemicals for 24 hours, before cellular viability, genotoxicity, inter-laboratory variability, and other endpoints were analyzed. This work has shown that the culturing conditions of the cells affected the toxic response to chemicals and NMs. This thesis contributed to new knowledge on advanced in vitro models by application of genotoxicity testing after NM exposures. Comet assay was applied to HepG2 spheroids and micronucleus assay to ALI cocultures for the first time to our knowledge. The advanced models are promising 3D models for use in genotoxicity studies and can support the hazard and risk assessment of NMs in compliance with the 3R´s for next generation risk assessment.List of papers
Paper I. Laura M. A. Camassa, Elisabeth Elje, Espen Mariussen, Eleonora M. Longhin, Maria Dusinska, Shan Zienolddiny-Narui, Elise Rundén-Pran. Advanced Respiratory Models for Hazard Assessment of Nanomaterials—Performance of Mono-, Co- and Tricultures. Nanomaterials, 2022; 12; 2609; doi: 10.3390/nano12152609. The article is included in the thesis. Also available at: https://doi.org/10.3390/nano12152609 |
Paper II. Elise Rundén-Pran, Espen Mariussen, Elisabeth Elje, Aline Chary, Eleonora Marta Longhin, Naouale El Yamani, Maria Dusinska, Arno C. Gutleb, Tommaso Serchi. Hazard assessment of spherical and rod-shaped silver nanomaterials by an advanced lung model at the air-liquid interface. (Manuscript) To be published. The paper is not available in DUO awaiting publishing. |
Paper III. Elisabeth Elje, Espen Mariussen, Erin McFadden, Maria Dusinska, Elise Rundén-Pran. Different sensitivity of advanced bronchial and alveolar mono- and coculture models for hazard assessment of nanomaterials. Nanomaterials, 2023; 13; 407; doi: 10.3390/nano13030407. The article is included in the thesis. Also available at: https://doi.org/10.3390/nano13030407 |
Paper IV. Elisabeth Elje, Michelle Hesler, Elise Rundén-Pran, Pascal Mann, Espen Mariussen, Sylvia Wagner, Maria Dusinska, Yvonne Kohl. The comet assay applied to HepG2 liver spheroids. Mutat Res Gen Tox En, 2019; 845; 403033; doi:10.1016/j.mrgentox.2019.03.006. The article is included in the thesis. Also available at: https://doi.org/10.1016/j.mrgentox.2019.03.006 |
Paper V. Elisabeth Elje, Espen Mariussen, Oscar H. Moriones, Neus G. Bastús, Victor Puntes, Yvonne Kohl, Maria Dusinska and Elise Rundén-Pran. Hepato(Geno)Toxicity Assessment of Nanoparticles in a HepG2 Liver Spheroid Model. Nanomaterials, 2020; 10; 545; doi: 10.3390/nano10030545. The article is included in the thesis. Also available at: https://doi.org/10.3390/nano10030545 |