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AOP: 526

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

Decreased, Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII) leads to Impaired, Spermatogenesis

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Decreased COUP-TFII in Leydig cells leads to Impaired, Spermatogenesis
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 v2.6

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: Christine M. Palermo and Jennifer E. Foreman, ExxonMobile; Daniele S. Wikoff, Isabel Lea, ToxStrategies.

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

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
John Frisch   (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

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

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
This AOP was last modified on May 23, 2024 14:26

Revision dates for related pages

Page Revision Date/Time
Decreased, Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII) May 29, 2024 09:50
Decreased, steroidogenic protein expression May 29, 2024 16:31
Decrease, testosterone levels May 24, 2024 12:27
Epididymal agenesis April 16, 2024 11:52
Impaired, Spermatogenesis April 10, 2024 17:41
Decreased COUP-TFII in Leydig cells leads to Decreased, steroidogenic protein expression April 16, 2024 09:39
Decreased, steroidogenic protein expression leads to Decrease, testosterone levels May 29, 2024 16:03
Decrease, testosterone levels leads to Epididymal agenesis April 08, 2024 15:40
Epididymal agenesis leads to Impaired, Spermatogenesis April 08, 2024 16:19

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

Impaired spermatogenesis is an adverse outcome often observed among a group of male reproductive abnormalities caused by organ malformation (epididymis, vas deferens, seminal vesicles, prostate, external genitalia) during development (Drake et al. 2009; Palermo et al. 2021).  These reproductive abnormalities have been observed in studies of laboratory mice and rats exposed to phthalates during in utero development, in attempts to understand the gene expression/inhibition, hormone levels, and other factors leading to the observed adverse outcomes.  Studies in laboratory mammals have allowed researchers to target the role of individual genes by knockout gene studies, and target critical developmental windows by timed exposure to toxicants, to explore the mechanisms leading to reproductive defects similar to human birth defects observed in clinical studies (Review in Foster 2006).  Although a molecular initiating event isn’t well established, decreased Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII)) gene expression has been linked to decreased expression of genes coding for enzymes involved in steroidogenesis and decreased testosterone levels in mammals (Qin et al. 2008; van den Driesche et al. 2012; Mendoza-Villarroel et al. 2014).  One adverse outcome of decreased testosterone, and the focus of this adverse outcome pathway, is epididymal agenesis, and resulting impaired spermatogenesis (Mahood et al. 2007; Qin et al. 2008; Kim et al. 2010).  Impaired spermatogenesis results in decreased sperm counts, as well as decreases in the number of sperm capable of fertilization (Barlow and Foster 2003).

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) 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.  The originating work for this AOP was: 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.  This publication, and the work cited within, were used create and support this AOP and its respective KE and KER pages. 

Phthalates are of increasing human health concern because of increased use and accumulating evidence of disruption of reproductive development in vertebrates.  First detected in laboratory mammals, exposure to phthalates and other toxicants in utero when male sexual differentiation is occurring have resulted in increased malformation of reproductive organs, failure of male characteristics to develop, and failure of proper positioning of organs (ex. hypospadias and cryptorchidism).  Clinical studies in humans have used laboratory mammal data to help understand and treat conditions exhibited by individual people.   This AOP focuses on the pathway leading to impaired to spermatogenesis, via abnormal formation of the epididymis, decreased testosterone levels, and initiated by decreased Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII) gene expression and subsequent disrupted signaling for steroidogenesis.

The focus of the originating work was to use an AOP framework to integrate lines of evidence from multiple disciplines based on evolving guidance developed by the Organization for Economic Cooperation and Development (OECD).  Palermo et al. (2021) provided network analysis based on two literature searches: 1. rodent male reproductive development abnormalities using key terms; 2. effects of low molecular weight phthalates (LMWPs) during the rodent male programming window (MPW) of development.  Relevant key events and key event relationships were narrowed by focusing on empirical studies related to ‘rat phthalate syndrome’ which resulted in 3 recommended Adverse Outcome Pathways: 1. INSL expression to cryptorchidism (see AOP 528 for related content); 2. COUP-TFII expression to hypospadias (see AOP 527 for related content); 3. COUP-TFII expression to altered sperm maturation (see this AOP 526 for related content).  

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

The originating authors conducted a literature search to develop a database of publications categorized by discipline or field of study: toxicology, epidemiology, exposure, and gene-environment interaction. The literature search relied on standard search engines such as Web of Science and Google Scholar, and the search strategy focused on toxicants known to disrupt lipid pathways in organisms, and diet studies with elevated levels of lipids. The originating authors reviewed references from individual citations to identify additional studies not captured through the literature search itself. They then included all relevant publications through 2023. Only studies focused primarily on developmental or neurotoxic endpoints were included; those focused on carcinogenesis or other systemic effects were not included unless there was a particular relevance to a neurotoxic or developmental outcome.

The scope of the aforementioned EPA project was limited to re-representing the AOP(s) as presented in the originating publication. The literature used to support this AOP and its constituent pages began with the originating publication and followed to the primary, secondary, and tertiary works cited therein. KE and KER page creation and re-use was determined using Handbook principles where page re-use was preferred.  

The authors of AOP 526 also referred to existing AOP-wiki content on disruption of steroidogenesis pathways, especially work by Gary Klinefelter (ex. AOP 70, 71).  We found existing Adverse Outcome Pathway content documented different series of key events then the pathways provided by Palermo et al. (2021), and therefore initiated AOP 526 and updated existing AOP-wiki key events when available.  

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
KE 656 Decreased, Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII) Decreased COUP-TFII in Leydig cells
KE 647 Decreased, steroidogenic protein expression Decreased, steroidogenic protein expression
KE 1690 Decrease, testosterone levels Decrease, testosterone levels
KE 2212 Epididymal agenesis Epididymal agenesis
AO 1758 Impaired, Spermatogenesis Impaired, Spermatogenesis

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

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

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
During development and at adulthood 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
mammals mammals Moderate NCBI

Sex Applicability

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

1. Support for Biological Plausibility of Key Event Relationships: Is there a mechanistic relationship  between KEup and KEdown consistent with established biological knowledge?

Key Event Relationship (KER)

Level of Support  

Strong = Extensive understanding of the KER based on extensive previous documentation and broad acceptance.

Relationship 3167: Decreased COUP-TFII in Leydig cells, leads to Decreased steroidogenesis, Decreased Activity of Steroidogenic Enzymes in Adult Leydig cells

Strong support.  The relationship between decrease in COUP-TFII expression and decreased steroidogenic enzymes (ex. CYP11, CYP17, P450scc, SR-B1, StAR) is broadly accepted and consistently supported across lab mice, lab rats, and clinical human studies.

Relationship 3168: Decreased steroidogenesis, Decreased Activity of Steroidogenic Enzymes in Adult Leydig cells leads to Decrease, testosterone levels

Strong support.  The relationship between decreased steroidogenic enzymes and decreased testosterone is broadly accepted and consistently supported across lab mice, lab rats, and clinical human studies.

Relationship 3169: Decrease, testosterone levels leads to Epididymal Agenesis

Strong support. Decreased testosterone levels have consistently been linked to epididymal agenesis and consistently supported across lab mice, lab rats, and clinical human studies.

Relationship 3170: Epididymal Agenesis leads to Impaired, Spermatogenesis

Strong support.  Epididymal agenesis and improper formation of the epididymis has been shown to results in impaired spermatogenesis (decreased sperm counts and function) across lab mice, lab rats, and clinical human studies.

Overall

Strong support.  Extensive understanding of the relationships between events from empirical studies from a variety of taxa, including frequent testing in lab mammals.

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: Problems first can be observed during development, with adverse outcome manifesting in mature individuals.

Sex: Applies to males.

Taxonomic: Appears to be present broadly in mammals, with most representative studies in mammals (humans, lab mice, lab rats).  

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

2. Essentiality of Key Events: Are downstream KEs and/or the AO prevented if an upstream KE is blocked?

Key Event (KE)

Level of Support

Strong = Direct evidence from specifically designed experimental studies illustrating essentiality and direct relationship between key events.

Moderate = Indirect evidence from experimental studies inferring essentiality of relationship between key events due to difficulty in directly measuring at least one of key events.

KE 656: Decreased COUP-TFII in Leydig cells

Moderate support.  Decrease in COUP-TFII expression has been linked to decreased steroidogenic enzymes (ex. CYP11, CYP17, P450scc, SR-B1, StAR).  Evidence is available from toxicant, gene-knockout, and protein studies.

KE 647 Decreased steroidogenesis, Decreased Activity of Steroidogenic Enzymes in Adult Leydig cells

Strong support.  Decreased expression of steroidogenic enzymes (ex. CYP11, CYP17, P450scc, SR-B1, StAR is linked to decreased testosterone levels.   Evidence is available from toxicant, gene-knockout, and protein studies.

KE 1690 Decrease, testosterone levels

Moderate support.  Decreases in testosterone have been correlated with epididymal agenesis and abnormal development of epididymides.  Evidence is available from toxicant and histology studies.

KE 2212 Epididymal Agenesis

Strong support. Malformed epididymides and epididymal agenesis is linked to impaired spermatogenesis.  Evidence is available from toxicant and histology studies.

AO 1758 Impaired, Spermatogenesis

Strong support. Impaired spermatogenesis is often caused by development issues in formation of reproductive tissues including epididymides.  Evidence is available from toxicant and histology studies.

Overall

Moderate to strong support.  Direct evidence from empirical studies from laboratory mammals for most key events, with more inferential evidence for gene expression and protein studies.

Evidence Assessment

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

3. Empirical Support for Key Event Relationship: Does empirical evidence support that a  change in KEup leads to an appropriate change in KEdown?

Key Event Relationship (KER)

Level of Support 

Strong =  Experimental evidence from exposure to toxicant shows consistent change in both events across taxa and study conditions. 

Relationship 3167: Decreased COUP-TFII in Leydig cells, leads to Decreased steroidogenesis, Decreased Activity of Steroidogenic Enzymes in Adult Leydig cells

Strong support.  Decreases in COUP-TFII expression lead to decreased steroidogenic enzymes (ex. CYP11, CYP17, P450scc, SR-B1, StAR, primarily from studies examining COUP-TFII knock-out genes, as well as changes in gene expression/protein levels after exposure to chemical stressors.

Relationship 3168: Decreased steroidogenesis, Decreased Activity of Steroidogenic Enzymes in Adult Leydig cells leads to Decrease, testosterone levels

Strong support. Decreases in steroidogenesis enzymes lead to decreases in testosterone levels, primarily from studies measuring gene expression and correlation to protein and hormone levels.

Relationship 3169: Decrease, testosterone levels leads to Epididymal Agenesis

Strong support. Decreases in testosterone have been correlated with malformation and agenesis of epididymides through measurement of hormone levels, and resulting issues in reproductive tissue formation.

Relationship 3170: Epididymal Agenesis leads to Impaired, Spermatogenesis

Strong support. Malformation of epididymides directly impacts ability of the organ to develop normal numbers of functional sperm.

Overall

Strong support. Exposure from empirical studies shows consistent change in both events from a variety of taxa, including frequent testing in lab mammals.

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

Barlow, N.J. and Foster, P.M.D.  2003.  Pathogenesis of Male Reproductive Tract Lesions from Gestation Through Adulthood Following in Utero Exposure to Di(n-butyl) Phthalate.  Toxicologic Pathology 31:397–410.

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.

Foster, P.M.D.  2006. Disruption of reproductive development in male rat offspring following in utero exposure to phthalate esters.  International Journal of Andrology 29: 140–147.

Kim, T.S., Jung, K.K., Kim, S.S., Kang, I.H., Baek, J.H., Nam, H.-S., Hong, S.-K., Lee, B.M., Hong, J.T., Oh, K.W., Kim, H.S., Han, S.Y., and Kang, T.S.  2010.  Effects of in Utero Exposure to DI(n-Butyl) Phthalate on Development of Male Reproductive Tracts in Sprague-Dawley Rats.  Journal of Toxicology and Environmental Health, Part A 73(21-22): 1544-1559.

Mahood, I.K., Scott, H.M., Brown, R., Hallmark, N., Walker, M., and Sharpe, R.M.  2007.  In Utero Exposure to Di(n-butyl) Phthalate and Testicular Dysgenesis: Comparison of Fetal and Adult End Points and Their Dose Sensitivity.  Environmental Health Perspectives 115 (supplement 1): 55-61.

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.

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.