AOP: 505

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Reactive Oxygen Species (ROS) formation leads to cancer via inflammation pathway

Short name

A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help

ROS formation leads to cancer via inflammation pathway

The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help

Handbook Version v2.5

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help

Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Of the originating work: Jaeseong Jeong and Jinhee Choi, School of Environmental Engineering, University of Seoul, Seoul, Republic of Korea

Of the content populated in the AOP-Wiki: John R. Frisch and Travis Karschnik, General Dynamics Information Technology, Duluth, Minnesota; Daniel L. Villeneuve, US Environmental Protection Agency, Great Lakes Toxicology and Ecology Division, Duluth, MN

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section. More help

Evgeniia Kazymova (email point of contact)

Contributors

Users with write access to the AOP page. Entries in this field are controlled by the Point of Contact. More help

John Frisch
Evgeniia Kazymova

Coaches

This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help

OECD Information Table

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OECD Project #	OECD Status	Reviewer's Reports	Journal-format Article	OECD iLibrary Published Version

This AOP was last modified on September 25, 2023 16:27

Revision dates for related pages

Page	Revision Date/Time
Increased, Reactive oxygen species	July 26, 2023 14:34
Oxidative Stress	March 21, 2023 15:16
Increase, Inflammation	August 10, 2023 14:43
General Apoptosis	April 04, 2018 14:51
Increase, Cancer	August 10, 2023 14:59
Increased, Reactive oxygen species leads to Oxidative Stress	August 15, 2023 10:05
Oxidative Stress leads to Increase, Inflammation	August 15, 2023 10:38
Increase, Inflammation leads to General Apoptosis	August 15, 2023 14:39
General Apoptosis leads to Increase, Cancer	August 15, 2023 14:56
Polyethylene AS low Mol.Wt.	July 31, 2023 09:43
Polyvinyl chloride	July 31, 2023 09:45

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

Reactive oxygen species (ROS) are derived from oxygen molecules and can occur as free radicals (ex. superoxide, hydroxyl, peroxyl) or non-radicals (ex. ozone, singlet oxygen). ROS production occurs via a variety of normal cellular process; however, in stress situations (ex. exposure to radiation, chemical or biological stressors) reactive oxygen species levels dramatically increase and cause damage to cellular components. In this Adverse Outcome Pathway (AOP) we focus on the inflammation response to increases in oxidative stress. Inflammation pathways include a molecular response (ex. interleukins, cytokines, interferons) and produces visible tissue swelling during histology examinations. In this AOP we focus on the apoptosis response to cellular damage. Pathways leading to apoptosis, or single cell death, have traditionally been studied as both independent and simultaneous from pathways leading to necrosis, or tissue-wide cell death, with both overlap and distinct mechanisms (Elmore 2007). For the purposes of this AOP, we are characterizing cancer due to widespread cell-death, and recognize the complications in separating the related apoptosis and necrosis pathways.

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

This Adverse Outcome Pathway (AOP) focuses on the pathway in which an established molecular disruption, increased levels of reactive oxygen species (ROS), leads to increased cancer through inflammation and cell/death/apoptosis. Environmental stressors leading to increased reactive oxygen species result in a variety of stress responses, visible through inflammation. These stress responses have been studied in many eukaryotes, including mammals (humans, lab mice, lab rats), teleost fish, and invertebrates (cladocerans, mussels).

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components. Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

This AOP was developed as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki. Jeong and Choi (2020) and Jeong and Choi (2019) provided initial network analysis from microplastic stressors, guided by weight of evidence from ToxCast assays of mammalian gene data. This publication, and the work cited within, were used create and support this AOP and its respective KE and KER pages.

The AOP-wiki authors did a further evaluation of published peer-reviewed literature to provide additional evidence in support of the AOP. Companion adverse outcome pathways are planned for two additional pathways initiated by reactive oxygen species (ROS), leading to increased cancer: 1. Decreased, PPARalpha transactivation of gene expression leads to Alteration, lipid metabolism and 2. Acetylcholinesterase (AchE) Inhibition leads to Decrease, Mitochondrial ATP production.

Summary of the AOP

This section is for information that describes the overall AOP.The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)

An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help

Key Events (KE)

A measurable event within a specific biological level of organisation. More help

Adverse Outcomes (AO)

An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

Type	Event ID	Title	Short name

MIE

1115

Increased, Reactive oxygen species

KE	1392	Oxidative Stress	Oxidative Stress
KE	149	Increase, Inflammation	Increase, Inflammation
KE	1513	General Apoptosis	General Apoptosis

885

Increase, Cancer

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Title	Adjacency	Evidence	Quantitative Understanding

Increased, Reactive oxygen species leads to Oxidative Stress	adjacent	High	Low
Oxidative Stress leads to Increase, Inflammation	adjacent	High	Low
Increase, Inflammation leads to General Apoptosis	adjacent	High	Low
General Apoptosis leads to Increase, Cancer	adjacent	High	Low

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Name
Polyethylene AS low Mol.Wt.
Polyvinyl chloride

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Life stage	Evidence
All life stages	High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help

Term	Scientific Term	Evidence	Link
human	Homo sapiens	High	NCBI
mouse	Mus musculus	High	NCBI
rat	Rattus norvegicus	High	NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help

Sex	Evidence
Unspecific	High

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

The biological plausibility of KERs is strong due to the available mechanistic evidence present in studies from a wide variety of taxa. Increases in reactive oxygen (ROS) levels cause a variety of cellular responses. Jeong et al. (2020) used a weight-of-evidence approach in analyzing TOXCAST data, and proposed the putative AOP pathway from MIE Increased Reactive Oxygen Species to KE Oxidative Stress to KE Increase, Inflammation to KE General Apoptosis to AO Increase, Cancer.

The essentiality of KERs is strong due to a variety of evidence from different controlled experimental designs with controls. Exposure to a variety of chemical, physical, and biological stressors have induced oxidative stress from increases in reactive oxygen species (ROS) levels. In this AOP we are focusing on the KERs between oxidative stress, inflammation, apoptosis, and cancer, as strongly supported by a variety of studies. Other oxidative stress pathways lead to apoptosis and cancer (ex. peroxisome proliferator-activated receptors (PPAR)/lipid metabolism pathway and acetylcholinesterase/mitochondrial energy metabolism pathway) as increases in reactive oxygen species (ROS) disrupt multiple cellular pathways. Additional evidence can be found in experimental designs that manipulate oxygen stress levels via use of strains of organisms with inhibited gene and enzyme function, as well as physical damage to nerves and organs of organisms.

The empirical support of KERs is largely found in toxicological studies derived from reference chemicals with dose-response and temporal concordance assessed. There are a large number of studies that have investigated the effects of increases in reactive oxygen species (ROS), because of researcher interest in the resulting cellular effects. Although there is a bias to publish studies that show an effect, and studies that show no effect are less likely to be published, given the number of dose-concordance studies from a wide variety of taxa, there is strong evidence in favor of the KERs represented in this AOP.

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Life Stage: The life stage applicable to this AOP is all life stages. Older individuals are more likely to manifest this adverse outcome pathway (adults > juveniles > embryos) due to accumulation of reactive oxygen species.

Sex: This AOP applies to both males and females.

Taxonomic: This AOP appears to be present broadly, with representative studies including mammals (humans, lab mice, lab rats), teleost fish, and invertebrates (cladocerans, mussels).

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Support for the essentiality of the key events can be obtained from a wide diversity of taxonomic groups, with mammals (lab ice, lab rats, human cell lines), telost fish, and invertebrates (cladocerans and mussels) particularly well-studied.

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Path	Support
Increased, Reactive oxygen species leads to Oxidative Stress	Biological plausibility is high. Representative studies have been done with mammals (Liu et al. 2015; Deng et al. 2017; Schrinzi et al. 2017; Jeong and Choi 2020); fish (Oliveira et al. 2013; Lu et al. 2016; Alomar et al. 2017; Chen et al. 2017; Veneman et al. 2017; Barboza et al. 2018; Choi et al. 2018; Espinosa et al. 2018); invertebrates (Browne et al. 2013; Avio et al. 2015; Jeong et al. 2016, 2017; Paul-Pont et al. 2016; Imhof et al. 2017; Lei et al. 2018; Yu et al. 2018).
Oxidative Stress leads to Increase, Inflammation	Biological plausibility is high. Representative studies have been done with mammals (Gamo et al. 2008; Jeong and Choi 2020); fish (Lu et al. 2016; Jin et al. 2018); invertebrates (Lei et al. 2018). For review (Wright and Kelly 2017).
Increase, Inflammation leads to General Apoptosis	Biological plausibility is high. Representative studies have been done with mammals (Gamo et al. 2008); fish (Karami et al. 2016; Lu et al. 2016; Jin et al. 2018). For review (Balkwill 2003, Villeneuve et al. 2018).
General Apoptosis leads to Increase, Cancer	Biological plausibility is high. Representative studies have been done with mammals (Pavet et al. 2014; Jeong and Choi 2020). For review (Heinlein and Chang 2004; Vihervaara and Sistonen 2014).

Increased oxidative stress due to increased production of reactive oxygen species (ROS) has been established as plausible in mammals, fish, and invertebrates. Oxidative stress can be detected through changes in gene expression (ex. superoxide dismutase, catalase, glutathione S-transferase), protein content (ex. glutathione), and enzyme activity (ex. superoxide dismutase, catalase, glutathione peroxidase).

Increased inflammation due to increased oxidative stress has been established as plausible in mammals, fish, and invertebrates. Inflammation is generally detected in histopathological examination of organs (ex. liver, intestines) or in changes in gene expression (ex. interleukins).

Increased apoptosis due to increased inflammation has been established as plausible in mammals and fish. Apoptosis is generally detected in histopathological examination of organs (ex. livers, brains) or in changes in gene expression (ex. tumor necrosis factor).

Increased cancer due to increased apoptosis has been established as plausible primarily in mammals, through histopathological examination of organs, uncontrolled cellular proliferation, and associated changes in gene expression.

For overview of the biological mechanisms involved in this AOP, see Liu et al. (2015) and Jeong and Choi (2020); their studies analyzed ToxCast in vitro assays of mammalian acute toxicity data to identify correlations between toxicity pathways and chemical stressors, providing support for the key event relationships represented here.

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Modulating Factor (MF)	Influence or Outcome	KER(s) involved

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors. More help

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

List of the literature that was cited for this AOP. More help

Alomar, C., Sureda, A., Capo, X., Guijarro, B., Tejada, S. and Deudero, S. 2017. Microplastic ingestion by Mullus surmuletus Linnaeus, 1758 fish and its potential for causing oxidative stress. Environmental Research 159: 135-142.

Avio, C.G., Gorbi, S., Milan, M., Benedetti, M., Fattorini, D., D’Errico, G., Pauletto, M., Bargelloni, L., and Regoli, F. 2015. Pollutants bioavailability and toxicological risk from microplastics to marine mussels. Environmental Pollutants 198: 211-222.

Barboza, LG.A., Vieira, L.R., Branco, V., Figueiredo, N., Carvalho, F., Carvalho, C., and Guilhermino, L. 2018. Microplastics cause neurotoxicity, oxidative damage and energy-related changes and interact with the bioaccumulation of mercury in the European seabass, Dicentrachus labrux (Linneaeus, 1758). Aquatic Toxicology 195: 49-57.

Balkwill, F. 2003. Chemokine biology in cancer. Seminars in Immunology 15: 49-55.

Browne, M.A. Niven, S.J., Galloway, T.S., Rowland, S.J., and Thompson, R.C. 2013. Microplastic moves pollutants and additives to worms, reducing functions linked to health and biodiversity. Current Biology 23: 2388-2392.

Chen, Q., Gundlach, M., Yang, S., Jiang, J., Velki, M., Yin, D., and Hollert, H. 2017 Quantitative investigation of the mechanisms of microplastics and nanoplastics toward larvae locomotor activity. Science of the Total Environment 584-585: 1022-1031.

Choi, J.S., Jung, Y.J., Hong, N.H., Hong, S.H., and Park, J.W. 2018. Toxicological effects of irregularly shaped and spherical microplastics in a marine teleost, the sheepshead minnow (Cyprinodon variegatus). Marine Pollution Bulletin 129: 231-240.

Deng, Y., Zhang, Y., Lemos, B., and Ren, H. 2017. Tissue accumulation of microplastics in mice and biomarker responses suggest widespread health risks of exposure. Science Reports 7: 1-10.

Elmore, S. 2007. Apoptosis: A Review of Programmed Cell Death. Toxicologic pathology 35 (4): 495-516.

Espinosa, C., Garcia Beltran, J.M., Esteban, M.A., and Cuesta, A. 2018. In vitro effects of virgin microplastics on fish head-kidney leucocyte activities. Environmental Pollution 235: 30-38.

Gamo, K., Kiryu-Seo, S., Konishi, H., Aoki, S., Matushima, K., Wada, K., and Kiyama, H. 2008. G-protein-coupled receptor screen reveals a role for chemokine recepteor CCR5 in suppressing microglial neurotoxicity. Journal of Neuroscience 28: 11980-11988.

Heinlein, C.A. and Chang, C. 2004. Androgen receptor in prostate cancer. Endocrine Reviews 25: 276-308.

Imhof, H.K., Rusek, J., Thiel, M., Wolinska, J., and Laforsch, C. 2017. Do microplastic particles affect Daphnia magna at the morphological life history and molecular level? Public Library of Science One 12: 1-20.

Jeong, J. and Choi, J. 2019. Adverse outcome pathways potentially related to hazard identification of microplastics based on toxicity mechanisms. Chemosphere 231: 249-255.

Jeong, J. and Choi, J. 2020. Development of AOP relevant to microplastics based on toxicity mechanisms of chemical additives using ToxCast™ and deep learning models combined approach. Environment International 137:105557.

Jeong, C.B., Kang, H.M., Lee, M.C., Kim, D.H., Han, J., Hwang, D.S. Souissi, S., Lee, S.J., Shin, K.H., Park, H.G., and Lee, J.S. 2017. Adverse effects of microplastics and oxidative stress-induced MAPK/NRF2 pathway-mediated defense mechanisms in the marine copepod Paracyclopina nana. Science Reports 7: 1-11.

Jeong, C.B., Wong, E.J., Kang, H.M., Lee, M.C., Hwang, D.S., Hwang, U.K., Zhou, B., Souissi, S., Lee, S.J., and Lee, J.S. 2016. Microplastic size-dependent toxicity, oxidative stress induction, and p-JNK and p-p38 activation in the Monogonout rotifer (Brachionus koreanus). Environmental Science and Technology 50: 8849-8857.

Jin, Y., Xia, J., Pan, Z., Yang, J., Wang, W., and Fu, Z. 2018. Polystyrene microplastics induce microbiota dysbiosis and inflammation in the gut of adult zebrafish. Environmental Pollution 235: 322-329.

Karami, A., Romano, N., Galloway, T. and Hamzah, H. 2016. Virgin microplastics cause toxicity and modulate the impacts of phenanthrene on biomarker responses in African catfish (Clarias gariepinus). Environmental Research 151: 58-70.

Lei, L., Wu, S., Lu, S., Liu, M., Song, Y., Fu, Z., Shi, H., Raley-Susman, K.M., and He, D. 2018. Microplastic particles cause intestinal damage and other adverse effects in zebrafish Danio rerio and nematode Caenorhabditis elegans. Science of the Total Environment 619-620: 1-8.

Liu, J., Mansouri, K., Judson, R.S., Martin, M.T., Hong, H., Chen, M., Xu, X., Thomas, R.S., and Shah, I. 2015. Predicting hepatoxicity using ToxCast in vitro bioactivity and chemical structure. Chemical Research in Toxicology 28: 738-751.

Lu, Y., Zhang, Y., Dengy, Y., Jiang, W., Zhao, Y., Geng, J., Ding, L., Ren, H. 2016. Uptake and accumulation of polystyrene microplastics in zebrafish (Danio rerio) and toxic effects in liver. Environmental Science and Technology 50: 4054-4060.

Oliveira, M., Ribeiro, A., Hylland, K., and Guilhermino, L. 2013. Single and combined effects of microplastics and pyrene on juveniles (0+ group) of the common goby Pomatoschistus microps (Teleostei, Gobiidae). Ecological Indicators 34: 641-647.

Paul-Pont, I., Lacroix, C., Gonzalez Fernandez, D., Hegaret, H., Lambert, C., Le Goic, N., Frere, L., Cassone, A.L., Sussarellu, R. Fabioux, C., Guyomarch, J., Albentosa, M., Huvet, A., and Soudant, P. 2016. Exposure of marine mussels Mytillus spp. to polystyrene microplastics: Toxicity and influence on fluoranthene bioaccumulation. Environmental Pollution 216: 724-737.

Pavet, V., Shlyakhtina, Y., He, T., Ceschin, D.G., Kohonen, P., Perala, M., Kallioniemi, O., and Gronemeyer, H. 2014. Plasminogen activator urokinase expression reveals TRAIL responsiveness and support fractional survival of cancer cells. Cell Death and Disease 5: e1043.

Schrinzi, G.F., Perez-Pomeda, I., Sanchis, J., Rossini, C., Farre, M., and Barcelo, D. 2017. Cytotoxic effects of commonly used nanomaterials and microplastics on cerebral and epithelial human cells. Environmental Research 159: 579-587.

Veneman, W.J., Spaink, H.P., Brun, N.R., Bosker, T., and Vijver, M.G. 2017. Pathway analysis of systemic transcriptome responses to injected polystyrene particles in zebrafish larvae. Aquatic Toxicology 190: 112-120.

Vihervaara, A. and Sistonen, L. 2014. HSF1 at a glance. Journal of Cell Scientce 127: 261-266.

Villeneuve, D.L., Landesmann, B., Allavena, P., Ashley, N., Bal-Price, A., Corsini, E., Halappanavar, S., Hussell, T., Laskin, D., Lawrence, T., Nikolic-Paterson, D., Pallary, M., Paini, A., Pietrs, R., Roth, R., and Tschudi-Monnet, F. 2018. Toxicological Sciences 346:352.

Wright, S.L. and Kelly, F.J. 2017. Plastic and human health: a micro issue? Enviromental Science and Technology 51: 6634-6647.

Yu, P., Liu, Z., Wu, D., Chen, M., Lv, W., and Zhao, Y. 2018. Accumulation of polystyrene microplastics in juvenile Eriocheir sinensis and oxidative stress effects in the liver. Aquatic Toxicology 200: 28-36.