This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 3503

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Inhibition, cytochrome oxidase leads to Increase, Cell death

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Inhibition, cytochrome oxidase

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Increase, Cell death

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Point of Contact	Author Status
Cytochrome oxidase inhibition leading to increased nasal lesions	adjacent	High	Katy Goyak (send email)	Under development: Not open for comment. Do not cite
Inhibition, cytochrome oxidase leads to Increased, pulmonary edema	adjacent	High	John Frisch (send email)	Under development: Not open for comment. Do not cite
Inhibition, cytochrome oxidase leads to Loss of olfactory function	adjacent	High	John Frisch (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
rodents	rodents	High	NCBI
human	Homo sapiens	High	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Unspecific	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
All life stages	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Cytochrome oxidase is an enzyme involved in the electron transport chain in generating adenosine triphosphate (ATP) in mitochondria as complex IV (Ricci et al. 2003; Kann and Kovacs 2007). Inhibition of cytochrome oxidase leads to loss of mitochondrial energy production resulting in cell death (Ricci et al. 2003; Liang et al. 2006).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

This Key Event Relationship 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. Goyak and Lewis (2021) focused on identifying Adverse Outcome Pathways that linked hydrogen sulfide exposure to adverse outcomes by using a comparative weight of evidence assessment from selected advisory agency reviews, and provided initial network analysis.

Cited empirical studies are focused on inhibition of cytochrome oxidase and resulting increased cell death in mammals, in support of development of AOP 368 for Goyak and Lewis (2021) content.

Authors of KER 3503 did a further evaluation of published peer-reviewed literature to provide additional evidence in support of the key event relationship.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

Inhibition of cytochrome oxidase and resulting increased cell death have been investigated via addition of toxicants to reduce cytochrome oxidase activity and examine cell death rates in laboratory mammals and human cell lines. Evidence from enzyme assays and histological studies show a consistent response in inhibition of cytochrome oxidase leading to increased cell death.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Species	Duration	Dose	Inhibition cytochrome oxidase?	Increase cell death?	Summary	Citation
Laboratory rats (Rattus norvegicus)	5 days	Neurons from rat visual cortex exposed to 10 uM, 100 uM, 300 uM, 1mM, 10 mM, 100 mM potassium cyanide.	yes	yes	Rat neurons exposed to all concentrations of potassium cyanide for 5 days had statistically significant inhibited cytochrome oxidase activity versus control, leading to increased cell death from 300 uM to 100 mM, with 83.6 percent cell death at 300 uM; effect moderated by preexposure to LED.	Wong-Riley et al. (2005)
Human (Homo sapiens)	24 hours	Human neuroblastoma cells exposed to beta-amyloid from adenovirus exposure.	yes	yes	Human neuroblastoma SH-SY5Y cells exposed to beta-amyloid from adenovirus exposure had statistically significant inhibited cytochrome oxidase activity versus control, leading to statistically significant increased cell death; effect moderated by heat shock proteins.	Veereshwarayya et al. (2006)
Laboratory mice (Mus musculus)	7 days	765 ppm hydrogen sulfate for 40 minutes on first day, 15 minutes on subsequent days	yes	yes	Male and female mice had statistically significant inhibited cytochrome oxidase activity versus control in all brain regions on days 1, 3, 7, leading to statistically significant cell death in brains on day 7.	Anantharam et al. (2017)

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Life Stage: Applies to all life stages.

Sex: Applies to both males and females.

Taxonomic: Primarily studied in humans and laboratory rodents. Plausible for all eukaryotes.

References

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

Anantharam, P., Whitley, E.M., Mahama, B., Kim, D.S., Imerman, P.M., Shao, D., Langley, M.R., Kanthasamy, A., Rumbeiha, W.K. 2017. Characterizing a mouse model for evaluation of countermeasures against hydrogen sulfide-induced neurotoxicity and neurological sequelae. Annals of the New York Academy of Sciences 1400(1): 46-64.

Goyak, K.O. and Lewis, R.J. 2021. Application of adverse outcome pathway networks to integrate mechanistic data informing the choice of a point of departure for hydrogen sulfide exposure limits. Critical Reviews in Toxicology 51(3): 193-208.

Kann, O. and Kovacs R. 2007. Mitochondria and neuronal activity. American Journal of Physiology - Cell Physiology 292(2): C641–C657.

Liang, H.L., Whelan, H.T., Eells, J.T., Meng, H., Buchmann, E., Lerch-Gaggl, A., and Wong-Riley, M. 2006. Photobiomodulation partially rescues visual cortical neurons from cyanide-induced apoptosis. Neuroscience. 139(2): 639–649.

Ricci, J.E., Waterhouse, N., Green, D.R. 2003. Mitochondrial functions during cell death, a complex (I-V) dilemma. Cell Death and Differentiation 10(5): 488–492. Veereshwarayya, V., Kumar, P., Rosen, K.M., Mestril, R., and Querfurth, H.W. 2006. Differential effects of mitochondrial heat shock protein 60 and related molecular chaperones to prevent intracellular beta-amyloid-induced inhibition of complex IV and limit apoptosis. Journal of Biological Chemistry 281(40): 29468–29478.

Wong-Riley, M.T., Liang, H.L., Eells J.T., Chance, B., Henry, M.M., Buchmann, E., Kane, M., and Whelan, H.T. 2005. Photobiomodulation directly benefits primary neurons functionally inactivated by toxins: role of cytochrome c oxidase. Journal of Biological Chemistry 280(6): 4761-4771.