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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, steroidogenic protein expression leads to Decrease, testosterone levels

Upstream event

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

Decreased, steroidogenic protein expression

Downstream event

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

Decrease, testosterone levels

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	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 Do not cite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
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. Steroidogenesis is the process of generating biological hormones starting from cholesterol as precursor to create a variety of steroid structures via enzyme catalyzed reactions. 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 activities of enzymes in the StAR, Cyp11, Cyp17, p450, HSD3β, and SR-B1 gene families within the steroid biosynthesis pathway, resulting in decreased precursor steroid compounds.

Decreased steroidogenesis rates of androgens has been linked to malformation of reproductive organs and decreased reproduction function through decreased testosterone levels (see Palermo et al. 2021 for review with focus on exposure to phthalates).

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

Predominantly in laboratory mammal studies, enzyme activity 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. Decreases in levels of steroid precursors lead to decreased testosterone levels.

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	Decreased Steroidogenic Enzymes?	Decreased Testosterone?	Summary	Citation
Mouse (Mus musculus)	4-6 months	Gene knockout study	yes	yes	Wild-type and Cyp17a1 knock out-mice, decreased Cyp17a1 gene expression (involved in steroid biosynthesis) and decreased testosterone levels in XY mice.	Aherrarhou et al. (2020)
Rat (Rattus norvegicus)	7 days	500 mg/kg/day DBP in utero	yes	yes	Crl:CD(SD)BR rats, decreased steroidogenic acute regulatory (STAR) gene expression, hormone levels of p450scc, 3B-HSD, P450c17 involved in steroid biosynthesis and resulting decreased testosterone levels.	Barlow et al. (2003)
Rat (Rattus norvegicus)	15 days	10,30,100,300 mg/kg/day DEHP in utero	yes	yes	Wistar rats, dose-dependent decrease in gene and protein expression of StAR, PBR, P450scc, decreased SR-B1 and P450c17 gene expression (involved in steroid biosynthesis) and resulting decreased testosterone levels	Borch et al. (2006)
Rat (Rattus norvegicus)	3 days	1,10,100 uM explanted fetal testes	yes	yes	Sprague-Dawley rats, dose-dependent effect on Cyp17a1 gene expression and protein levels, decreased gene expression of FDX1 (involved in steroid biosynthesis) and corresponding decreases in testosterone levels.	Chauvigné et al. (2011)
Mouse (Mus musculus)	50 days	NR dose, sodium arsenite exposure in utero	yes	yes	CD-1 mice, decreased Star gene expression involved in steroid biosynthesis, resulting decrease in testosterone levels	Clark et al. (2007)
Rat (Rattus norvegicus)	5 days	100,500 mg/kg DBP, 100 ug/kg dexamethasone and mixture of DBP and dexamethasone in utero	yes	yes	Wistar rats, dose-dependent decrease in gene expression of StAR, CYP11A1 (involved in steroid biosynthesis) and resulting decrease in testosterone levels.	Drake et al. (2009)
Rat (Rattus norvegicus)	5 days in utero; juvenile - adulthood	0,11,33,300 mg/kg/d DPeP in utero and juvenile-adulthood	yes	yes	Harlan Sprague-Dawley rats, dose-dependent decrease in gene expression of Cyp11b1, StAR, Cyp17a1, Cyp11a1, Hsd3b, other genes involved in steroid biosynthesis and resulting decrease in testosterone levels.	Gray et al. (2016)
Rat (Rattus norvegicus)	5 days	100,300,600,900 mg/kg/d DHeP, DHP in utero	yes	yes	Sprague-Dawley rats, dose-dependent decrease in gene expression of Star, Cyp11a1, Hsd3b, Cyp17a1, Cyp11b1 (involved in steroid biosynthesis) and resulting decrease in testosterone levels.	Hannas et al. (2012)
Rat (Rattus norvegicus)	24 hours	100, 500 mg/kg DEP in utero	yes	yes	Sprague-Dawley rats, dose-dependent decrease in gene expression of SR-B1, StAR, CYP17A1, CYP11A1 (involved in steroid biosynthesis) and resulting decrease in testosterone levels.	Kuhl et al. (2007)
Rat (Rattus norvegicus)	6 days	0.01,0.1,1,10,100,1000 mg/kg/day DPT in utero	Yes	Yes	Sprague-Dawley rats, dose-dependent decrease in gene expression of SR-B1, StAR, P450scc, CYP17, 3βHSD involved in steroid biosynthesis, dose-dependent decrease in protein of SR-B1, STAR, P450scc, CYP17 and resulting decreased testosterone levels.	Lehman et al. (2004)
Mouse (Mus musculus)	40 days	Knock-out gene study	yes	yes	CD1-mice, various cell lines with wild-type and knock-out gene expression, decreased steroidogenic acute regulatory (STAR) gene expression and resulting decreased testosterone levels.	Mendoza-Villarroel et al. (2014)
Mouse (Mus musculus)	3 months	1 mg/50 g bw tamoxifen for 5 consecutive days in utero, knock-out gene study, juvenile exposure.	yes	yes	COUP-TFII flox/flox mice and CAGG-Cre-ERTM mice, tamoxifen exposure, decreased 3β-HSD, 450Scc, and CYP17 gene expression, genes related to steroid biosynthesis and resulting decreased testosterone levels.	Qin et al. (2008)
Rat (Rattus norvegicus)	6 days	500 mg/kg/day DBP in utero	yes	yes	Sprague-Dawley rats, decreased gene and protein expression SR-B1, StAR, SCC, CYP17 (related to steroid biosynthesis) and resulting decreased testosterone levels, additional experiment showed restoration of SR-B1, StAR, SCC, CYP17 protein levels after 48 hours withdrawal of DBP	Thompson et al. (2004)
Rat (Rattus norvegicus)	8 days	20, 100, 500 mg/kg/day DBP, 100 ug/kg/day dexamethasone, 100 ug/kg diethylstilbestrol every other day, mixture 500 mg/kg/day DBP plus 100 ug/kg day dexamethasone in utero	yes	yes	Wistar rats, dose-dependent response decreased STAR, CYP17, CYP11 gene expression, genes related to steroid biosynthesis and resulting decreased testosterone levels.	van den Driesche et al. (2012)

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: 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 indicate edits from John Frisch