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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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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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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