Adverse outcome pathways (AOPs) for radiation-induced reproductive effects in environmental species: state of science and identification of a consensus AOP network

Figures & data

Figure 1. Example of a generic linear Adverse Outcome Pathway (AOP) that is the basis for developing sets of interlinked AOPs into AOP networks (AOPNs), schematics adapted from the user’s handbook for AOP development (OECD 2018).

Figure 2. Workflow for integrating individual taxon- or species group-specific adverse outcome pathways (AOPs) into a consensus AOP (cAOP) and potential applications. Created with BioRender.com.

Table 1. Definition of events, detections methods and studies used to populate a consensus Adverse Outcome Pathway Network (AOPN) for reproductive effects in environmental species.

Type	Event ID	Title	Parameter measured	Taxon	Reference
MIE	1686	Deposition of Energy	Fluorescent Nuclear Track Detector (FNTD); Nanodots dosimetry; Liquid scintillation counting; RPL dosimetry; TLDs dosimetry	PP, PN, HA, PC, OF	Dubois et al. 2019; Dufourcq‐sekatcheff et al. 2021; Gomes et al. 2017; Guédon et al. 2021; Hurem, Gomes et al. 2018; Maremonti, Brede et al. 2020; Maremonti et al. 2019; Maremonti, Eide et al. 2020; Nilsson and Brahme 1983; Rahmanian et al. 2017; Smith et al. 2012; Song, Xie, Lee, Brede et al. 2020; Van Hoeck et al. 2015a, b; Xie et al. 2019
KE	1632	Increase in RONS	Fluorescent probe assays (H2DCFDA, DHR123); Antioxidant gene expression; Antioxidant enzyme activities; GSSG/GSH imbalance, In vivo measurements of H2O2; Indirect measurement as oxidative DNA damage	PP, PN, HA, PC, OF	Gagnaire et al. 2021; Gagnaire et al. 2015; Gomes et al. 2017; Guédon et al. 2021; Guirandy et al. 2019; Hertel-Aas, Oughton et al. 2011; Hurem, Gomes et al. 2017; Hurem, Gomes et al. 2018; Hurem, Martín et al. 2018; Kariuki et al. 2019; Maremonti, Brede et al. 2020; Maremonti, Eide et al. 2020; Olsvik et al. 2010; Reisz et al. 2014; Shin et al. 2011; Song et al. 2014; Song, Xie, Lee, Brede et al. 2020; Song, Xie, Lee, Tollefsen et al. 2020; Van Hoeck et al. 2015a, b; Xie et al. 2019
KE	1194	Increase, DNA damage	Comet assay; Expression of DNA damage related genes and proteins; Increase, Oxidative damage to DNA; 8-oxo-G ELISA assay	PP, PN, HA, PC, OF	Adam-Guillermin et al. 2012; Azzam et al. 2012; Blagojevic et al. 2019; Dubois et al. 2019; Gagnaire et al. 2015; Gomes et al. 2017; Guédon et al. 2021; Hertel-Aas, Oughton et al. 2011; Hurem, , Martín et al. 2017; Kariuki et al. 2019; Maremonti et al. 2019; Oladosu et al. 2016; Pereira et al. 2011; Song et al. 2014; Van Hoeck et al. 2015a, b; Vanhoudt et al. 2014
KE	1505	Cell cycle, disrupted	Cell cycle arrest; Expression of relevant genes and proteins	PN, OF	Dubois et al. 2019; Guédon et al. 2021; Hurem, Martín et al. 2017; Hurem, Martín et al. 2018; Maremonti, Brede et al. 2020; Maremonti et al. 2019; Maremonti, Eide et al. 2020
KE	1864	Increase, Programed cell death	TUNEL assay; Cell division and cell cycle arrest relevant genes; Flow cytometry of endoploidy levels; Atrophy of seminal vesicles and testes; CED-1 fluorescent reporter strain for DNA damage-induced germ cell apoptosis	PP, PN, HA, PC, OF	Biermans et al. 2015; Guédon et al. 2021; Hertel-Aas, Oughton et al. 2011; Hurem, Martín et al. 2017; Hurem, Martín et al. 2018; Kariuki et al. 2019; Maremonti, Brede et al. 2020; Maremonti, Eide et al. 2020; Rusin et al. 2019; Scaldaferro et al. 2013; Song, Xie, Lee, Brede et al. 2020; Song, Xie, Lee, Tollefsen et al. 2020; Sowmithra et al. 2015; Van Hoeck et al. 2015a, b; Xie et al. 2020
KE	1366	Decrease, Oogenesis	Egg-laying rate; Increase in pre-vitellogenic follicles; Regression of gonads; Reduction in visual eggs	PN, PC, OF	Dufourcq‐sekatcheff et al. 2021 ; Hurem, Gomes et al. 2018; Hurem, Martín et al. 2018
KE	752	Altered, Meiotic chromosome dynamics	Cytological analysis; Expression of relevant genes and proteins	PP, PN	Chu and Shakes 2013; Maremonti et al. 2019; Rao and Rao 1977
KE	1798	Decrease, spermatogenesis	Sperm count; atrophy of seminal vesicles and testes; Regression of testis; Reduction in spermatogonia; Increase in pollen abnormalities; Decrease pollen viability; Pollen shape analysis	PP, PN, HA, OF	Dufourcq‐sekatcheff et al. 2021; Guédon et al. 2021; Hertel-Aas et al. 2007; Hurem, Martín et al. 2018; Hyodo Taguchi and Egami 1976; Maremonti et al. 2019; Møller et al. 2016; Nurmansyah et al. 2018
AO	1863	Decrease, Reproduction	Reduced fertility, Reduced egg count, Reduced fertility, Reduced fecundity, changes to germination characteristics	PP, PN, HA, PC, OF	Amirikhah et al. 2021; Cheng et al. 2018; Dubois et al. 2018; Dufourcq‐sekatcheff et al. 2021; Guédon et al. 2021; Guirandy et al. 2022; Guirandy et al. 2019; Hertel-Aas, Brunborg et al. 2011; Hinton et al. 2004; Hurem, Martín et al. 2018; Maremonti et al. 2019; Song, Xie, Lee, Brede et al. 2020; Sowmithra et al. 2015; Xie et al. 2019
AO	360	Decrease, Population growth rate	Reduction in plant area and numbers; Reduction in offspring over several generations; Dynamic energy-based predictive modeling; population modeling	PP, PN, HA, PC, OF	Alonzo et al. 2016; Cheng et al. 2018; Guédon et al. 2021; Guirandy et al. 2022; Guirandy et al. 2019; Hertel-Aas et al. 2007; Hurem, Gomes et al. 2018; Hurem, Martín et al. 2018; Lecomte-Pradines et al. 2017; Xie et al. 2019

MIE: molecular initiating event; KE: key event; AO: adverse outcome.

Figure 3. Integration of data from individual taxa into a network of consensus Adverse Outcome Pathways (cAOPs) spanning primary producers (PP), androdioecious nematodes (PN), hermaphroditic annelids (HA), parthenogenic crustaceans (PC) and oviparous fish (OF) on basis of existing model species data. The solid lines indicate key event relationships (KERs) with broad taxonomic applicability, whereas the broken arrows represent KERs with limited empirical evidence from different species. Created with BioRender.com.

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