Linking nanomaterial-induced mitochondrial dysfunction to existing adverse outcome pathways for chemicals

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Sivakumar Murugadoss, Ivana Vinković Vrček, Alexandra Schaffert, Martin Paparella, Barbara Pem, Anita Sosnowska, Maciej Stępnik, Marvin Martens, Egon L. Willighagen, Tomasz Puzyn, Mihaela Roxana Cimpan, Frauke Lemaire, Birgit Mertens, Maria Dusinska, Valérie Fessard, Peter H. Hoet
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Abstract

The adverse outcome pathway (AOP) framework plays a crucial role in the paradigm shift of tox­icity testing towards the development and use of new approach methodologies. AOPs developed for chemicals are in theory applicable to nanomaterials (NMs). However, only initial efforts have been made to integrate information on NM-induced toxicity into existing AOPs. In a previous study, we identified AOPs in the AOP-Wiki associated with the molecular initiating events (MIEs) and key events (KEs) reported for NMs in scientific literature. In a next step, we analyzed these AOPs and found that mitochondrial toxicity plays a significant role in several of them at the molecular and cellular levels. In this study, we aimed to generate hypothesis-based AOPs related to NM-induced mitochondrial toxicity. This was achieved by integrating knowledge on NM-induced mitochondrial toxicity into all existing AOPs in the AOP-Wiki, which already includes mitochondrial toxicity as a MIE/KE. Several AOPs in the AOP-Wiki related to the lung, liver, cardiovascular and nervous system, with extensively defined KEs and key event relationships (KERs), could be utilized to develop AOPs that are relevant for NMs. However, the majority of the studies included in our literature review were of poor quality, particularly in reporting NM physicochemical characteristics, and NM-relevant mitochondrial MIEs were rarely reported. This study highlights the potential role of NM-induced mitochondrial toxicity in human-relevant adverse outcomes and identifies useful AOPs in the AOP-Wiki for the development of AOPs for NMs.


Plain language summary
This article investigates commonalities in the toxicity pathways of chemicals and nanomaterials. Nanomaterials have been found to affect the function of mitochondria, the powerhouses within every human cell. Mitochondrial dysfunction may cause harmful effects such as cellular damage and inflammation. By linking these findings to existing adverse outcome pathways for chemicals, the research provides valuable insights for assessing the risks associated with nanomaterial exposure. This work is crucial for understanding the potential health implications of nanomaterials and can contribute to informed decision-making in regulatory and risk assessment processes without the use of animals.

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How to Cite
Murugadoss, S., Vinković Vrček, I., Schaffert, A., Paparella, M. ., Pem, B. ., Sosnowska, A., Stępnik, M., Martens, M. ., Willighagen, E. L., Puzyn, T. ., Roxana Cimpan, M. ., Lemaire, F. ., Mertens, B. ., Dusinska, M. ., Fessard, V. . and Hoet, P. H. . (2024) “Linking nanomaterial-induced mitochondrial dysfunction to existing adverse outcome pathways for chemicals”, ALTEX - Alternatives to animal experimentation, 41(1), pp. 76–90. doi: 10.14573/altex.2305011.
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References

Alimohammadi, M., Meyburg, B., Ückert, A.-K. et al. (2023). EFSA pilot project on new approach methodologies (NAMs) for tebufenpyrad risk assessment. Part 2. Hazard characterisation and identification of the reference point. EFSA Support Publ 20, 7794E. doi:10.2903/sp.efsa.2023.en-7794

Backer, J. M. and Weinstein, I. B. (1980). Mitochondrial DNA is a major cellular target for a dihydrodiol-epoxide derivative of benzo[a]pyrene. Science 209, 297-299. doi:10.1126/science.6770466

Bajard, L., Adamovsky, O., Audouze, K. et al. (2023). Application of AOPs to assist regulatory assessment of chemical risks – Case studies, needs and recommendations. Environ Res 217, 114650. doi:10.1016/j.envres.2022.114650

Barbir, R., Jiménez, R. R., Martín-Rapún, R. et al. (2021). Interaction of differently sized, shaped, and functionalized silver and gold nanoparticles with glycosylated versus nonglycosylated transferrin. ACS Appl Mater Interfaces 13, 27533-27547. doi:10.1021/acsami.1c04063

Bessa, M. J., Brandão, F., Fokkens, P. H. B. et al. (2021). In vitro toxicity of industrially relevant engineered nanoparticles in human alveolar epithelial cells: Air-liquid interface versus submerged cultures. Nanomaterials (Basel) 11, 3225. doi:10.3390/nano11123225

Brand, W., Peters, R. J. B., Braakhuis, H. M. et al. (2020). Possible effects of titanium dioxide particles on human liver, intestinal tissue, spleen and kidney after oral exposure. Nanotoxicology 14, 985-1007. doi:10.1080/17435390.2020.1778809

Brescia, S., Alexander-White, C., Li, H. et al. (2023). Risk assessment in the 21st century: Where are we heading? Toxicol Res (Camb), 1-11. doi:10.1093/toxres/tfac087

Burden, N., Sewell, F., Andersen, M. E. et al. (2015). Adverse outcome pathways can drive non-animal approaches for safety assessment. J Appl Toxicol 35, 971-975. doi:10.1002/jat.3165

Cabral-Costa, J. V. and Kowaltowski, A. J. (2020). Neurological disorders and mitochondria. Mol Aspects Med 71, 100826. doi:10.1016/j.mam.2019.10.003

Cheimarios, N., Pem, B., Tsoumanis, A. et al. (2022). An in vitro dosimetry tool for the numerical transport modeling of engineered nanomaterials powered by the Enalos RiskGONE Cloud Platform. Nanomaterials 1, 3935. doi:10.3390/nano12223935

Cohen, B. H. (2010). Pharmacologic effects on mitochondrial function. Dev Disabil Res Rev 16, 189-199. doi:10.1002/ddrr.106

Daiber, A., Kuntic, M., Hahad, O. et al. (2020). Effects of air pollution particles (ultrafine and fine particulate matter) on mitochondrial function and oxidative stress – Implications for cardiovascular and neurodegenerative diseases. Arch Biochem Biophys 696, 108662. doi:10.1016/j.abb.2020.108662

Deloid, G. M., Cohen, J. M., Pyrgiotakis, G. et al. (2017). Preparation, characterization, and in vitro dosimetry of dispersed, engineered nanomaterials. Nat Protoc 12, 355-371. doi:10.1038/nprot.2016.172

Delp, J., Cediel-Ulloa, A., Suciu, I. et al. (2021). Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol 95, 591-615. doi:10.1007/s00204-020-02970-5

Diabaté, S., Armand, L., Murugadoss, S. et al. (2020). Air-liquid interface exposure of lung epithelial cells to low doses of nanoparticles to assess pulmonary adverse effects. Nanomaterials 11, 65. doi:10.3390/nano11010065

Dreier, D. A., Mello, D. F., Meyer, J. N. et al. (2019). Linking mitochondrial dysfunction to organismal and population health in the context of environmental pollutants: Progress and considerations for mitochondrial adverse outcome pathways. Environ Toxicol Chem 38, 1625-1634. doi:10.1002/etc.4453

Ede, J. D., Lobaskin, V., Vogel, U. et al. (2020). Translating scientific advances in the AOP framework to decision making for nanomaterials. Nanomaterials 10, 1229. doi:10.3390/nano10061229

Fernández-Cruz, M. L., Hernández-Moreno, D., Catalán, J. et al. (2018). Quality evaluation of human and environmental toxicity studies performed with nanomaterials – The GUIDEnano approach. Environ Sci Nano 5, 381-397. doi:10.1039/c7en00716g

Fetterman, J. L., Sammy, M. J. and Ballinger, S. W. (2017). Mitochondrial toxicity of tobacco smoke and air pollution. Toxicology 391, 18-33. doi:10.1016/j.tox.2017.08.002

Gerloff, K., Landesmann, B., Worth, A. et al. (2017). The adverse outcome pathway approach in nanotoxicology. Comput Toxicol 1, 3-11. doi:10.1016/j.comtox.2016.07.001

Gorini, S., De Angelis, A., Berrino, L. et al. (2018). Chemotherapeutic drugs and mitochondrial dysfunction: Focus on doxorubicin, trastuzumab, and sunitinib. Oxid Med Cell Longev 2018, 7582730. doi:10.1155/2018/7582730

Halappanavar, S., Van Den Brule, S., Nymark, P. et al. (2020a). Adverse outcome pathways as a tool for the design of testing strategies to support the safety assessment of emerging advanced materials at the nanoscale. Part Fibre Toxicol 17, 16. doi:10.1186/s12989-020-00344-4

Halappanavar, S., Ede, J. D., Mahapatra, I. et al. (2020b). A methodology for developing key events to advance nanomaterial-relevant adverse outcome pathways to inform risk assessment. Nanotoxicology 15, 289-310. doi:10.1080/17435390.2020.1851419

Hartmann, N. B., Jensen, K. A., Baun, A. et al. (2015). Techniques and protocols for dispersing nanoparticle powders in aqueous media – Is there a rationale for harmonization? J Toxicol Environ Health B Crit Rev 18, 299-326. doi:10.1080/10937404.2015.1074969

Hayden, M. R. (2022). The mighty mitochondria are unifying organelles and metabolic hubs in multiple organs of obesity, insulin resistance, metabolic syndrome, and type 2 diabetes: An observational ultrastructure study. Int J Mol Sci 23, 4820. doi:10.3390/ijms23094820

ISO (2012). ISO – ISO/TR 13014:2012 – Nanotechnologies – Guidance on physico-chemical characterization of engineered nanoscale materials for toxicologic assessment. https://www.iso.org/standard/52334.html (accessed 26.02.2020)

Jacobs, M. N., Colacci, A., Corvi, R. et al. (2020). Chemical carcinogen safety testing: OECD expert group international consensus on the development of an integrated approach for the testing and assessment of chemical non-genotoxic carcinogens. Arch Toxicol 94, 2899-2923. doi:10.1007/s00204-020-02784-5/tables/2

Jayasundara, N. (2017). Ecological significance of mitochondrial toxicants. Toxicology 391, 64-74. doi:10.1016/j.tox.2017.07.015

Khalifa, A. A., Rashad, R. M. and El-Hadidy, W. F. (2021). Thymoquinone protects against cardiac mitochondrial DNA loss, oxidative stress, inflammation and apoptosis in isoproterenol-induced myocardial infarction in rats. Heliyon 7, e07561. doi:10.1016/j.heliyon.2021.e07561

Kirichenko, T. V., V., Borisov, E. E., Shakhpazyan, N. K. et al. (2022). Mitochondrial implications in cardiovascular aging and diseases: The specific role of mitochondrial dynamics and shifts. Int J Mol Sci 23, 2951. doi:10.3390/ijms23062951

Kubickova, B. and Jacobs, M. N. (2023). Development of a reference and proficiency chemical list for human steatosis endpoints in vitro. Front Endocrinol (Lausanne) 14, 848. doi:10.3389/fendo.2023.1126880

Li, A., Gao, M., Liu, B. et al. (2022). Mitochondrial autophagy: Molecular mechanisms and implications for cardiovascular disease. Cell Death Dis 13, 444. doi:10.1038/s41419-022-04906-6

Massart, J., Borgne-Sanchez, A. and Fromenty, B. (2018). Drug-induced mitochondrial toxicity. In P. Oliveira (ed.), Mitochondrial Biology and Experimental Therapeutics (269-295). Cham, Switzerland: Springer. doi:10.1007/978-3-319-73344-9_13

Mech, A., Rauscher, H., Rasmussen, K. et al. (2020). The NanoDefine methods manual. Part 3, Standard operating procedures (SOPs). Publications Office of the EU. https://op.europa.eu/en/publication-detail/-/publication/b8bf4c68-4246-11ea-9099-01aa75ed71a1/language-en (accessed 15.08.2023)

Meyer, J. N., Leung, M. C. K., Rooney, J. P. et al. (2013). Mitochondria as a target of environmental toxicants. Toxicol Sci 134, 1-17. doi:10.1093/toxsci/kft102

Meyer, J. N., Hartman, J. H. and Mello, D. F. (2018). Mitochondrial toxicity. Toxicol Sci 162, 15-23. doi:10.1093/toxsci/kfy008

Murugadoss, S., Brassinne, F., Sebaihi, N. et al. (2020a). Agglomeration of titanium dioxide nanoparticles increases toxicological responses in vitro and in vivo. Part Fibre Toxicol 17, 10. doi:10.1186/s12989-020-00341-7

Murugadoss, S., Van Den Brule, S., Brassinne, F. et al. (2020b). Is aggregated synthetic amorphous silica toxicologically relevant? Part Fibre Toxicol 17, 1. doi:10.1186/s12989-019-0331-3

Murugadoss, S. (2021). A strategy towards the generation of testable adverse outcome pathways for nanomaterials. ALTEX 38, 1-13. doi:10.14573/altex.2102191

Murugadoss, S., Das, N., Godderis, L. et al. (2021a). Identifying nanodescriptors to predict the toxicity of nanomaterials: A case study on titanium dioxide. Environ Sci Nano 8, 580-590. doi:10.1039/d0en01031f

Murugadoss, S., Vrček, I. V., Pem, B. et al. (2021b). A strategy towards the generation of testable adverse outcome pathways for nanomaterials. ALTEX 38, 580-594. doi:10.14573/altex.2102191

Norat, P., Soldozy, S., Sokolowski, J. D. et al. (2020). Mitochondrial dysfunction in neurological disorders: Exploring mitochondrial transplantation. NPJ Regen Med 5, 22. doi:10.1038/s41536-020-00107-x

Nymark, P., Kohonen, P., Hongisto, V. et al. (2018). Toxic and genomic influences of inhaled nanomaterials as a basis for predicting adverse outcome. Ann Am Thorac Soc 15, Suppl 2, S91-S97. doi:10.1513/annalsats.201706-478mg

OECD (2017). Guidance Document on the Reporting of Defined Approaches and Individual Information Sources to be Used within Integrated Approaches to Testing and Assessment (IATA) for Skin Sensitisation. Series on Testing and Assessment, No. 256. OECD Publishing, Paris. doi:10.1787/9789264279285-en

OECD (2020a). OECD Guidelines for the Testing of Chemicals, Section 4 : Health Effects. https://www.oecd-ilibrary.org/environment/oecd-guidelines-for-the-testing-of-chemicals-section-4-health-effects_20745788 (accessed 03.04.2023)

OECD (2020b). Report on Considerations from Case Studies on Integrated Approaches for Testing and Assessment (IATA). Series on Testing and Assessment, No. 328. OECD Publishing, Paris. https://one.oecd.org/document/env/jm/mono(2020)24/en/pdf (accessed 28.04.2023)

Pal, A. K., Bello, D., Cohen, J. et al. (2015). Implications of in vitro dosimetry on toxicological ranking of low aspect ratio engineered nanomaterials. Nanotoxicology 9, 871-885. doi:10.3109/17435390.2014.986670

Pyrgiotakis, G., Blattmann, C. O., Pratsinis, S. et al. (2013). Nanoparticle-nanoparticle interactions in biological media by atomic force microscopy. Langmuir 29, 11385-11395. doi:10.1021/la4019585

Qu, K., Yan, F., Qin, X. et al. (2022). Mitochondrial dysfunction in vascular endothelial cells and its role in atherosclerosis. Front Physiol 13, 1084604. doi:10.3389/fphys.2022.1084604

Rolo, D., Tavares, A., Vital, N. et al. (2022). Overview of adverse outcome pathways and current applications on nanomaterials. Adv Exp Med Biol 1357, 415-439. doi:10.1007/978-3-030-88071-2_17/cover

Roubicek, D. A. and de Souza-Pinto, N. C. (2017). Mitochondria and mitochondrial DNA as relevant targets for environmental contaminants. Toxicology 391, 100-108. doi:10.1016/j.tox.2017.06.012

Russell, W. M. S. and Burch, R. L. (1959). The Principles of Humane Experimental Technique by W. M. S. Russell and R. L. Burch. https://caat.jhsph.edu/principles/the-principles-of-humane-experimental-technique (accessed 14.04.2023)

Schaffert, A., Murugadoss, S., Mertens, B. et al. (2023). Cardiotoxicity of chemicals: Current regulatory guidelines, knowledge gaps, and needs. ALTEX 40, 337-340. doi:10.14573/altex.2301121

Singh, K. P. and Gupta, S. (2014). Nano-QSAR modeling for predicting biological activity of diverse nanomaterials. RSC Adv 4, 13215-13230. doi:10.1039/c4ra01274g

Tang, X., Wang, Z., Hu, S. et al. (2022). Assessing drug-induced mitochondrial toxicity in cardiomyocytes: implications for preclinical cardiac safety evaluation. Pharmaceutics 14, 1313. doi:10.3390/pharmaceutics14071313

Thomas, D. G., Smith, J. N., Thrall, B. D. et al. (2018). ISD3: A particokinetic model for predicting the combined effects of particle sedimentation, diffusion and dissolution on cellular dosimetry for in vitro systems. Part Fibre Toxicol 15, 6. doi:10.1186/S12989-018-0243-7

van der Zalm, A. J., Barroso, J., Browne, P. et al. (2022). A framework for establishing scientific confidence in new approach methodologies. Arch Toxicol 96, 2865. doi:10.1007/s00204-022-03365-4

Vietti, G., Lison, D. and van den Brule, S. (2016). Mechanisms of lung fibrosis induced by carbon nanotubes: Towards an adverse outcome pathway (AOP). Part Fibre Toxicol 13, 1-23. doi:10.1186/s12989-016-0123-y

Vuda, M. and Kamath, A. (2016). Drug induced mitochondrial dysfunction: Mechanisms and adverse clinical consequences. Mitochondrion 31, 63-74. doi:10.1016/j.mito.2016.10.005

Vyas, S., Zaganjor, E. and Haigis, M. C. (2016). Mitochondria and cancer. Cell 166, 555-566. doi:10.1016/j.cell.2016.07.002

Wallace, D. C. (2012). Mitochondria and cancer. Nat Rev Cancer 12, 685-698. doi:10.1038/nrc3365

Wang, Z. M., Ying, Z., Bosy-Westphal, A. et al. (2010). Specific metabolic rates of major organs and tissues across adulthood: Evaluation by mechanistic model of resting energy expenditure. Am J Clin Nutr 92, 1369. doi:10.3945/ajcn.2010.29885

Werbner, B., Tavakoli-Rouzbehani, O. M., Fatahian, A. N. et al. (2023). The dynamic interplay between cardiac mitochondrial health and myocardial structural remodeling in metabolic heart disease, aging, and heart failure HHS Public Access. J Cardiovasc Aging 3, 9. doi:10.20517/jca.2022.42

West, A. P. (2017). Mitochondrial dysfunction as a trigger of innate immune responses and inflammation. Toxicology 391, 54-63. doi:10.1016/j.tox.2017.07.016

Wu, D., Ma, Y., Cao, Y. et al. (2020). Mitochondrial toxicity of nanomaterials. Sci Total Environ 702, 134994. doi:10.1016/j.scitotenv.2019.134994

Zolkipli-Cunningham, Z. and Falk, M. J. (2017). Clinical effects of chemical exposures on mitochondrial function. Toxicology 391, 90-99. doi:10.1016/j.tox.2017.07.009

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