This AOP is licensed under a Creative Commons Attribution 4.0 International License.
Aop: 263
Title
Uncoupling of oxidative phosphorylation leading to growth inhibition via decreased cell proliferation
Short name
Graphical Representation
Additional AOP Exploration Options
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Point of Contact
Contributors
- You Song
- Dan Villeneuve
Status
| Author status | OECD status | OECD project | SAAOP status |
|---|---|---|---|
| Open for citation & comment | WPHA/WNT Endorsed | 1.92 | Included in OECD Work Plan |
This AOP was last modified on November 02, 2022 06:16
Revision dates for related pages
| Page | Revision Date/Time |
|---|---|
| Decrease, Coupling of oxidative phosphorylation | May 28, 2021 07:59 |
| Decrease, Growth | July 06, 2022 07:36 |
| Decrease, Adenosine triphosphate pool | June 14, 2021 13:40 |
| Decrease, Cell proliferation | December 07, 2020 06:55 |
| Decrease, Coupling of OXPHOS leads to Decrease, ATP pool | July 06, 2022 07:39 |
| Decrease, ATP pool leads to Decrease, Cell proliferation | December 07, 2020 07:43 |
| Decrease, Cell proliferation leads to Decrease, Growth | July 06, 2022 07:43 |
| 2,4-Dinitrophenol | November 29, 2016 18:42 |
| Pentachlorophenol | November 12, 2020 17:59 |
| Carbonyl cyanide-p-trifluoromethoxyphenylhydrazone | November 12, 2020 17:59 |
| Carbonyl cyanide m-chlorophenyl hydrazone | November 12, 2020 17:59 |
| Triclosan | November 12, 2020 18:00 |
| Dinoseb | November 12, 2020 18:00 |
| 3,5-Dichlorophenol | October 10, 2017 07:47 |
| Emodin | November 20, 2020 13:48 |
| Arsenite | March 07, 2019 06:14 |
| Niclosamide ethanolamine | July 06, 2022 07:24 |
| Oxyclozanide | July 06, 2022 07:25 |
Abstract
Uncoupling of oxidative phosphorylation (OXPHOS) is a well-known mechanism of action of many chemicals. Mitochondrial uncoupler-mediated energetic dysfunction is known to affect growth, a critical process in most organisms and a chronic toxicity endpoint included in many OECD test guidelines. This adverse outcome pathway (AOP) causally links uncoupling of OXPHOS to growth inhibition, through ATP depletion and reduced cell proliferation as the intermediate key events (KEs), with strong weight of evidence support. The AOP is generalized to reflect its expected applicability to a broad range of taxa, ranging from microalga to human. Three out of four KEs included can be quantified using high-throughput methods, making this AOP particularly useful for screening, prioritization and hazard assessment of mitochondrial uncouplers as potential growth inhibiting chemicals. This AOP is of high regulatory relevance, as it is considered applicable to both human health and ecological risk assessments. The AOP also forms the core of a larger AOP network addressing uncoupling of OXPHOS mediated growth inhibition (AOP 263-268).
AOP Development Strategy
Context
The mitochondrial OXPHOS machinery is a key physiological process responsible for producing the primary cellular energy, adenosine triphosphate (ATP). During OXPHOS, a series of redox reactions (oxidation) are mediated by protein complexes in an electron transport chain to create a protonmotive force (PMF) across the inner mitochondrial membrane (Liberman 1969). The PMF acts as a driving force of ATP synthesis through phosphorylation of adenosine diphosphate (ADP). Mitochondrial oxidation and phosphorylation are coupled to ensure continuous ATP supply for various physiological processes. A number of chemicals can bind to the inner mitochondrial membrane and dissipate the PMF, thus leading to uncoupling of OXPHOS and reduction in ATP synthetic efficiency. Classical “uncouplers” are normally protonophores with major characteristics of bulky hydrophobic moiety, an acid dissociable group and a strong electron-withdrawing group (Terada 1990). With the rapid development of in silico (Russom 1997; Schultz 1997; Naven 2012; Dreier 2019; Troger 2020) and in vitro (Escher 2002; Attene-Ramos 2013; Attene-Ramos 2015; Xia 2018) approaches, more and more uncouplers have been identified. However, their hazards to biota remain to be assessed. Uncoupling of OXPHOS can affect many ATP-dependent biological functions. In particular, cell proliferation as a major process to achieve organismal growth is positively correlated with the cellular ATP level and highly susceptible to energy depletion (Ramaiah 1964; Bonora 2012). Therefore, a link between uncoupling of OXPHOS and growth inhibition can be established with ATP depletion and reduced cell proliferation as the intermediate steps.
Strategy
Summary of the AOP
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
| Type | Event ID | Title | Short name |
|---|
| MIE | 1446 | Decrease, Coupling of oxidative phosphorylation | Decrease, Coupling of OXPHOS |
| KE | 1771 | Decrease, Adenosine triphosphate pool | Decrease, ATP pool |
| KE | 1821 | Decrease, Cell proliferation | Decrease, Cell proliferation |
| AO | 1521 | Decrease, Growth | Decrease, Growth |
Relationships Between Two Key Events (Including MIEs and AOs)
| Title | Adjacency | Evidence | Quantitative Understanding |
|---|
| Decrease, Coupling of OXPHOS leads to Decrease, ATP pool | adjacent | High | High |
| Decrease, ATP pool leads to Decrease, Cell proliferation | adjacent | Moderate | Moderate |
| Decrease, Cell proliferation leads to Decrease, Growth | adjacent | Moderate | Moderate |
Network View
Prototypical Stressors
Life Stage Applicability
| Life stage | Evidence |
|---|---|
| Embryo | High |
| Juvenile | High |
| Adult | High |
Taxonomic Applicability
Sex Applicability
| Sex | Evidence |
|---|---|
| Unspecific | High |
Overall Assessment of the AOP
The weight of evidence (WoE) assessment of the AOP was conducted based on the evolved Bradford-Hill considerations (Becker 2015) and according to the criteria in OECD’s Guidance Document for Developing and Assessing AOPs (OECD 2018). In terms of evidence for the essentiality of the key events, the MIE (Event 1446) and KE1 (Event 1771) were scored as high, whereas KE2 (Event 1821) was scored as moderate due to a lack of solid evidence to support its essentiality. The overall WoE of KER1 (Relationship 2203) is considered high, as strong biological plausibility, empirical evidence and fairly good quantitative understanding were evidenced from multiple studies. The overall WoE of KER2 (Relationship 2204) is considered moderate, due to high biological plausibility, acceptable empirical concordance and some biological understanding. The overall WoE of KER3 (Relationship 2205) is scored as moderate, mainly due to biological plausibility, but there is presently a lack of empirical evidence and quantitative understanding to further support causality. The AOP is considered applicable to a wide range of species as well as a broad domain of chemicals. The rationales for making these judgements will be discussed in detail in the following sections.
Domain of Applicability
The taxonomic application domain of the AOP potential covers all animals, plants and some microorganisms such as fungus and protists, as mitochondrial OXPHOS is highly conserved in eukaryotes (Roger 2017).
The life stage applicability domain of the AOP mainly contains embryos and juveniles, as growth is more relevant to developing organisms. It should be noted that fully grown adults are also susceptible to uncouplers, as tissue/organ (e.g., adipose tissue) growth and regeneration still occur in adults (Yun 2015; Demine 2019). Classical uncouplers such as 2,4-DNP have been reported to cause weight loss in adult humans (Grundlingh 2011). In fact, 2,4-DNP was sold for weight loss until its legal sale was banned over toxicity and abuse concerns (Baker 2020). These suggest that adults are in the applicability domain of this AOP.
The sex applicability domain of the AOP is unspecific, as the AOP is mainly targeting growth effects in sexually immature organisms and the KEs are therefore harmonized between male and females. However, male and females may have different sensitivities to OXPHOS uncoupling, as strategies for allocating energy for developmental processes may be gender specific (Demarest 2015).
The chemical applicability domain of the AOP mainly includes weak acids, such as phenols, benzimidazoles, N-phenylanthranilates, salicylanilides, phenylhydrazones, salicylic acids, acyldithiocarbazates, cumarines, and aromatic amines, which are well-known protonophoric uncouplers. Uncouplers typically have properties as both weak acids and hydrophobic substances. As weak acids, they are capable of gaining and losing an electron. As hydrophobic substances, they are capable of distributing a negative charge over a number of atoms (often by π-orbitals which delocalize a proton's charge when it attaches to the molecule), so that they can diffuse back and forth across the inner mitochondrial membrane in either the charged or uncharged state, thus moving protons back across the concentration gradient generated by the electron transport chain. Classical uncouplers, such as 2,4-dinitrophenol (2,4-DNP), carbonyl cyanide-p-trifluoromethoxyphenyl hydrazone (FCCP), carbonyl cyanide m-chlorophenyl hydrazone (CCCP), pentachlorophenol (PCP), 3,5-dichlorophenol (3,5-DCP), 6-sec-butyl-2,4-dinitrophenol (dinoseb), SF 6847 (3,5-di-t-butyl-4-hydroxybenzylidinemalononitrile) have been widely used as positive controls in (eco)toxicological tests, whereas the hazards of “new” uncouplers, such as triclosan, emodin and metabolites of polybrominated diphenyl ethers (PBDEs) are also under extensive assessments. Other types of uncouplers that are SH-reactive chemicals or hydrophobic ions may also be in the applicability domain of this AOP. A number of potential uncouplers have been identified by in silico (Russom 1997; Schultz 1997; Naven 2012; Dreier 2019; Troger 2020) and in vitro (Escher 2002; Attene-Ramos 2013; Attene-Ramos 2015; Xia 2018) approaches, and are considered in the chemical applicability domain of the AOP.
Essentiality of the Key Events
|
Support for Essentiality of KEs |
Defining Question |
What is the impact on downstream KEs and/or the AO if an upstream KE is modified or prevented? |
|
High |
Direct evidence from specifically designed experimental studies illustrating prevention or impact on downstream KEs and/or the AO if upstream KEs are blocked or modified. |
|
|
Moderate |
Indirect evidence that modification of one or more upstream KEs is associated with a corresponding (increase or decrease) in the magnitude or frequency of downstream KEs. |
|
|
Low |
No or contradictory experimental evidence of the essentiality of any of the KEs. |
|
|
Event 1446: (Decrease, Coupling of OXPHOS) |
Essentiality of Event 1446 is high. Rationale: There is direct evidence from several specifically designed studies showing that removal of an uncoupler from exposure, or addition of a “recoupler” can lead to recovery of the mitochondrial membrane potential (MMP) and total ATP caused by the uncoupler. Evidence:
|
|
|
Event 1771: (Decrease, ATP pool) |
Essentiality of Event 1771 is moderate. Rationale: There is limited direct evidence from specifically designed studies. However, multiple lines of indirect evidence show that modulation of ATP levels by uncouplers can also lead to corresponding changes in cell proliferation. Evidence:
|
|
|
Event 1821: (Decrease, Cell proliferation) |
Essentiality of Event 1821 is moderate. Rationale: There is no direct evidence from specifically designed studies to support this KE. However, there are multiple lines of indirect evidence showing positive relationships between cell proliferation and growth. Evidence:
|
|
|
Inconsistencies & uncertainties |
There is an uncertainty related to KE1446 that mild uncoupling of OXPHOS may also increase the ATP pool in some cases (Desquiret 2006), possibly as a compensatory response. The underlying mechanism remains to be further elucidated. |
|
Evidence Assessment
Biological plausibility
|
Support for Biological Plausibility of KERs |
Defining Question |
Is there a mechanistic (i.e., structural or functional) relationship between KEup and KEdown consistent with established biological knowledge? |
|
High |
Extensive understanding based on extensive previous documentation and broad acceptance -Established mechanistic basis. |
|
|
Moderate |
The KER is plausible based on analogy to accepted biological relationships but scientific understanding is not completely established. |
|
|
Low |
There is empirical support for a statistical association between KEs, but the structural or functional relationship between them is not understood. |
|
|
Relationship 2203: (Decrease, Coupling of OXPHOS leads to Decrease, ATP pool) |
Biological Plausibility of Relationship 2203 is high. Rationale: In eukaryotic cells, the major metabolic pathways responsible for ATP production are OXPHOS, citric acid (TCA) cycle, glycolysis and photosynthesis. Oxidative phosphorylation is much (theoretically 15-18 times) more efficient than the rest due to high energy derived from oxygen during aerobic respiration (Schmidt-Rohr 2020). As the ATP level is relatively balanced between production and consumption (Bonora 2012), ATP depletion is a plausible consequence of reduced ATP synthetic efficiency following uncoupling of OXPHOS. |
|
|
Relationship 2204: (Decrease, ATP pool leads to Decrease, Cell proliferation) |
Biological Plausibility of Relationship 2204 is high. Rationale: Cell proliferation is a well-known ATP-dependent process. Cell division processes, such as the mitotic cell cycle uses ATP for chromosome movements and DNA replication (Kingston 1999). The synthetic processes of major cellular components that are necessary for cell structure and growth, such as proteins and lipids, also require sufficient ATP supply (Bonora 2012). Depletion of ATP therefore has a negative impact on these processes. |
|
|
Relationship 2205: (Decrease, Cell proliferation leads to Decrease, Growth) |
Biological Plausibility of Relationship 2205 is high. Rationale: The biological causality between cell proliferation and growth has also been well established. It is commonly accepted that the size of an organism, organ or tissue is dependent on the total number and volume of the cells it contains, and the amount of extracellular matrix and fluids (Conlon 1999). Impairment to cell proliferation can logically affect tissue and organismal growth. |
|
|
Inconsistencies & uncertainties |
There are currently no inconsistencies and uncertainties identified by the authors. |
|
Empirical support
|
Empirical Support for KERs |
Defining Question |
Does KEup occur at lower doses and earlier time points than KE down and at the same dose of stressor, is the incidence of KEup >than that for KEdown? Are there inconsistencies in empirical support across taxa, species and stressors that don’t align with expected pattern for hypothesized AOP? |
|
High |
Multiple studies showing dependent change in both events following exposure to a wide range of specific stressors. (Extensive evidence for temporal, dose- response and incidence concordance) and no or few critical data gaps or conflicting data. |
|
|
Moderate |
Demonstrated dependent change in both events following exposure to a small number of specific stressors and some evidence inconsistent with expected pattern that can be explained by factors such as experimental design, technical considerations, differences among laboratories, etc. |
|
|
Low |
Limited or no studies reporting dependent change in both events following exposure to a specific stressor (i.e., endpoints never measured in the same study or not at all); and/or significant inconsistencies in empirical support across taxa and species that don’t align with expected pattern for hypothesised AOP. |
|
|
Relationship 2203: (Decrease, Coupling of OXPHOS leads to Decrease, ATP pool) |
Empirical support of Relationship 2203 is high. Rationale: The majority of relevant studies show good incidence, temporal and/or dose concordance in different organisms and cell types after exposure to known uncouplers, with relatively few exceptions (see the Relationship 2203 page and concordance table for detailed evidence). |
|
|
Relationship 2204: (Decrease, ATP pool leads to Decrease, Cell proliferation) |
Empirical support of Relationship 2204 is moderate. Rationale: Although only a few studies were found to be relevant, incidence concordance was found for mammalian cells (see the Relationship 2204 page and concordance table for detailed evidence). |
|
|
Relationship 2205: (Decrease, Cell proliferation leads to Decrease, Growth) |
Empirical support of Relationship 2205 is low. Rationale: This KER was included in a very limited number of studies, as it addresses effects occurring at the apical level that in vitro studies cannot cover. There is one zebrafish study reporting concordant relationship between reduced cell proliferation and embryo growth with some inconsistencies (see the Relationship 2205 page and concordance table for detailed evidence). |
|
|
Inconsistencies & uncertainties |
There are some inconsistencies regarding temporal and dose concordance:
|
|
Known Modulating Factors
Quantitative Understanding
|
Quantitative understanding of the KERs |
High |
Change in KEdownstream can be precisely predicted based on a relevant measure of KEupstream. Uncertainty in the quantitative prediction can be precisely estimated from the variability in the relevant measure of KEupstream. Known modulating factors and feedback/feedforward mechanisms are accounted for in the quantitative description. There is evidence that the quantitative relationship between the KEs generalises across the relevant applicability domain of the KER. |
|
Moderate |
Change in KEdownstream can be precisely predicted based on a relevant measure of KEupstream. Uncertainty in the quantitative prediction is influenced by factors other than the variability in the relevant measure of KEupstream. Quantitative description does not account for all known modulating factors and/or known feedback/feedforward mechanisms. The quantitative relationship has only been demonstrated for a subset of the overall applicability domain of the KER (e.g., based on a single species). |
|
|
Low |
Only a qualitative or semi-quantitative prediction of the change in KEdownstream can be determined from a measure of KEupstream. Known modulating factors and/or known feedback/feedforward mechanisms are not accounted for. The quantitative relationship has only been demonstrated for a narrow subset of the overall applicability domain of the KER (e.g., based on a single species). |
|
|
Relationship 2203: (Decrease, Coupling of OXPHOS leads to Decrease, ATP pool) |
Quantitative understanding of Relationship 2203 is high. Rationale: The theoretical quantitative relationship between OXPHOS and ATP yield has been well established. There are also published computational/mathematical models in which modulating factors known to affect OXPHOS and ATP synthesis are considered. Evidence:
|
|
|
Relationship 2204: (Decrease, ATP pool leads to Decrease, Cell proliferation) |
Quantitative understanding of Relationship 2204 is moderate. Rationale: The total ATP level has been used as an indicator of cell proliferation. Several studies have reported the quantitative relationships between the two events, as well as a threshold value for KE1 to trigger KE2. However, not all modulating factors have been accounted and no well-established computational/mathematical models are found. Evidence:
|
|
|
Relationship 2205: (Decrease, Cell proliferation leads to Decrease, Growth) |
Quantitative understanding of Relationship 2205 is moderate. Rationale: Multiple mathematical models describing the quantitative relationships between cell proliferation and tissue growth exist for both animals (Binder 2008) and plants (Mosca 2018). There are also numerous models that are specifically developed for predicting tumor growth based on the proliferation rate (Jarrett 2018). However, there is currently a lack of quantitative model to link cell proliferation and individual growth in the presence of uncouplers. Evidence:
|
|
Considerations for Potential Applications of the AOP (optional)
The present AOP has several potential applications. First, the AOP anchors a recognized endpoint of regulatory concern (i.e., growth), at least in OECD member countries, and is directly relevant for a number of OECD test guidelines (e.g., TG206, 208, 201, 210, 211, 212, 215, 221, 228, 241, 407, 408, 416, 422, 443 and 453). These guidelines cover a diversity of taxonomic groups including mammals, birds, fish, amphibians, terrestrial plants, aquatic plants and algae, and various invertebrates. Second, the AOP anchors an important molecular initiating event (e.g., uncoupling of oxidative phosphorylation) and can be used to support several initiatives (e.g., Tox21 and ToxCast) for identification of mitochondrial toxicants. The present AOP helps establish the utility of such assays for identifying chemicals with potential to cause growth impacts. Third, three out of four key events in this AOP can be measured using high-throughput in vitro assays, hence offering a tiered testing strategy (i.e., in silico→in vitro→in vivo) or integrated approaches to testing and assessment (IATA) for efficient screening, classification and assessment of potential mitochondrial uncouplers and growth-regulating chemicals. The key events can be considered as useful biomarkers in (eco)toxicological studies. However, it is not recommended to use a single key event (e.g., ATP level alone) as a biomarker for classification and hazard assessment of chemicals, as key events such as decreased ATP pool and cell proliferation can also be the consequences of other biological processes. A combined measurement of 2-3 key events can normally yield more reliable results. Finally, the quantitative relationships of the key events in this AOP have been relatively well defined, allowing it to be further developed into quantitative prediction models for higher tier assessments. This is a range of potential applications that were conceived during the development of the present AOP. However, it is neither an exhaustive list of potential applications, nor can explicit examples of these applications in practice be cited at this time.
We invite users of this AOP to share their applications of this AOP via the Discussion so that practical examples of use can be added.
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