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

Murugadoss, Sivakumar; Vinković Vrček, Ivana; Schaffert, Alexandra; Paparella, Martin; Pem, Barbara; Sosnowska, Anita; Stępnik, Maciej; Martens, Marvin; Willighagen, Egon L.; Puzyn, Tomasz; Cimpan, Mihaela Roxana; Lemaire, Frauke; Mertens, Birgit; Dusinska, Maria; Fessard, Valérie; Hoet, Peter H. (2024) Linking nanomaterial-induced mitochondrial dysfunction to existing adverse outcome pathways for chemicals. ALTEX - Alternatives to Animal Experimentation, 41 (1). pp. 76-90. ISSN 1868-596X

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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.

Item Type:	Article
Uncontrolled Keywords:	nanosafety; mitochondrial toxicity; adverse outcome pathways; new approach methodologies; risk assessment
Subjects:	NATURAL SCIENCES > Chemistry
Divisions:	Division of Organic Chemistry and Biochemistry
Projects:	Project title Project leader Project code Project type Siguran pristup za razvoj nano-sustava za ciljanu isporuku lijekova u mozak-SENDER Ivana Vinković Vrček; Marija Ćurlin; Željko Debeljak PZS-2019-02-4323 HRZZ
Depositing User:	Ivana Vuglec
Date Deposited:	26 Mar 2026 09:40
URI:	http://fulir.irb.hr/id/eprint/11485
DOI:	10.14573/altex.2305011

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