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Relationship: 3168

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

Decreased steroidogenesis, Decreased Activity of Steroidogenic Enzymes leads to Decrease, testosterone levels

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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 Quantitative Understanding Point of Contact Author Status OECD Status
Decreased, Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII) leads to Impaired, Spermatogenesis adjacent High Not Specified Arthur Author (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 Do not cite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
mammals mammals Moderate NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific Moderate

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages Moderate

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

In this key event relationship we are focused on the decrease in activity of steroidogenesis genes involved in the synthesis of steroid compounds and corresponding decrease in testosterone levels.  A large number of genes are involved in regulating steroidogenesis, so here we present evidence from available empirical studies.  Decreased testosterone levels are most often noted as resulting from decreases in expression of genes in the StAR, Cyp11, Cyp17, p450, HSD3β, and SR-B1 gene families.

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.  Palermo et al. (2021) focused on identifying Adverse Outcome Pathways associated with adverse male reproductive outcomes from phthalate exposure through review of existing literature, and provided initial network analysis. 

Authors of KER 3168 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

The biological plausibility linking decreased gene expression associated with steroidogenesis to decreased testosterone levels is strong.   Predominately in laboratory mammal studies, gene expression has been studied via toxicant exposure as well as contrasting wild-type strains to strains with knockout gene function, and consistently shown decreased testosterone levels.

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
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: Most representative studies have been done in mammals (humans, lab mice, lab rats); plausible for all vertebrates.  

References

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

Aherrarhou, R., Kulle, A.E., Alenina, N., Werner, R., Vens-Cappell, S., Bader, M., Schunkert, H., Erdmann, J., and Aherrarhou, Z.  2020.  Nature Scientific Reports 10: 8792.

Barlow, N.J., Phillips, S.L., Wallace, D.G., Sar, M., Gaido, K.W., and Foster, P.M.D.  2003.  Quantitative Changes in Gene Expression in Fetal Rat Testes following Exposure to Di(n-butyl) Phthalate.  Toxicological Sciences 73: 431-451.

Borch, J., Metzdorff, S.B., Vinggard, A.M., Brokken, L., and Dalgaard, M.  2006.  Mechanisms underlying the anti-androgenic effects of diethylhexyl phthalate in fetal rat testis.  Toxicology 223 (2006) 144–155.

Chauvigné, F., Plummer, S., Lesné, L., Cravedi, J.-P., Dejucq-Rainsford, N., Fostier, A., and Jégou, B.  2011.   Mono-(2-ethylhexyl) Phthalate Directly Alters the Expression of Leydig Cell Genes and CYP17 Lyase Activity in Cultured Rat Fetal Testis.  Public Library of Science One 6(11): e27172.

Clark, B.J. and Cochrum, R.K.  2007.  The Steroidogenic Acute Regulatory Protein as a Target of Endocrine Disruption in Male Reproduction. Drug Metabolism Reviews 39(2-3): 353-370.

Drake, A.J., van den Driesche, S., Scott, H.M., Hutchinson, G.R., Seckl, J.R. and Sharpe, R.M.  2009.  Glucocorticoids Amplify Dibutyl Phthalate-Induced Disruption of Testosterone Production and Male Reproductive Development.  Endocrinology 150(11): 5055–5064.

Gray, Jr., L.E., Furr, J., Tatum-Gibbs, K.R., Lambright, C., Sampson, H., Hannas, B.R., Wilson, V.S., Hotchkiss, A., and Foster, P.M.D.  2016.  Establishing the “Biological Relevance” of Dipentyl Phthalate Reductions in Fetal Rat Testosterone Production and Plasma and Testis Testosterone Levels.  Toxicological Sciences 149(1): 178–191.

Hannas, B.R., Lambright, C.S., Furr, J., Evans, N. Foster, P.M.D., Gray, E.L., and Wilson, V.S.  2012.  Genomic Biomarkers of Phthalate-Induced Male Reproductive Developmental Toxicity: A Targeted RT-PCR Array Approach for Defining Relative Potency.  Toxicological Sciences 125(2): 544–557.

Kuhl, A.J., Ross, S.M., and Gaido, K.W.  2007.  CCAAT/Enhancer Binding Protein β, But Not Steroidogenic Factor-1, Modulates the Phthalate-Induced Dysregulation of Rat Fetal Testicular Steroidogenesis.  Endocrinology 148(12): 5851–5864.

Lehmann, K.P., Phillips, S., Sar, M., Foster, P.M.D., and Gaido, K.W.  2004.  Dose-Dependent Alterations in Gene Expression and Testosterone Synthesis in the Fetal Testes of Male Rats Exposed to Di (n-butyl) phthalate.  Toxicological Sciences 81: 60-68.

Mendoza-Villarroel, R.E., Robert, N.M., Martin, L.J., Brousseau, C., and Tremblay, J.J.  2014.  The Nuclear Receptor NR2F2 Activates Star Expression and Steroidogenesis in Mouse MA-10 and MLTC-1 Leydig Cells.  Biology of Reproduction 91(1) Article 26: 1-12.

Palermo, C.M., Foreman, J.E., Wikoff, D.S., and Lea, I.  2021.  Development of a putative adverse outcome pathway network for male rat reproductive tract abnormalities with specific considerations for the androgen sensitive window of development.  Current Research in Toxicology 2: 254–271.

Qin, J., Tsai, M.-J., and Tsai S.Y.  2008.  Essential Roles of COUP-TFII in Leydig Cell Differentiation and Male Fertility.  Public Library of Science One 3(9): e3285.

Thompson, C.J., Ross, S.M., and Gaido, K.W.  2004.  Di(n-Butyl) Phthalate Impairs Cholesterol Transport and Steroidogenesis in the Fetal Rat Testis through a Rapid and Reversible Mechanism.  Endocrinology 145(3):1227–1237.

van den Driesche, S., Walker, M., McKinnel, C., Scott, HM., Eddie, S.L., Mitchell, R.T., Seckl, J.R., Drake, A.J., Smith, L.B., Anderson, R.A., and Sharpe, R.M.  2012.  Proposed Role for COUP-TFII in Regulating Fetal Leydig Cell Steroidogenesis, Perturbation of Which Leads to Masculinization Disorders in Rodents. Public Library of Science One 7(5): e37064.

NOTE: Italics symbolize edits from John Frisch