Aop: 288

Title

Each AOP should be given a descriptive title that takes the form “MIE leading to AO”. For example, “Aromatase inhibition [MIE] leading to reproductive dysfunction [AO]” or “Thyroperoxidase inhibition [MIE] leading to decreased cognitive function [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

Inhibition of 17α-hydrolase/C 10,20-lyase (Cyp17A1) activity leads to birth reproductive defects (cryptorchidism) in male (mammals)

Short name
A short name should also be provided that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Cyp17A1 inhibition leads to undescended testes in mammals

Graphical Representation

A graphical summary of the AOP listing all the KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs should be provided. This is easily achieved using the standard box and arrow AOP diagram (see this page for example). The graphical summary is prepared and uploaded by the user (templates are available) and is often included as part of the proposal when AOP development projects are submitted to the OECD AOP Development Workplan. The graphical representation or AOP diagram provides a useful and concise overview of the KEs that are included in the AOP, and the sequence in which they are linked together. This can aid both the process of development, as well as review and use of the AOP (for more information please see page 19 of the Users' Handbook).If you already have a graphical representation of your AOP in electronic format, simple save it in a standard image format (e.g. jpeg, png) then click ‘Choose File’ under the “Graphical Representation” heading, which is part of the Summary of the AOP section, to select the file that you have just edited. Files must be in jpeg, jpg, gif, png, or bmp format. Click ‘Upload’ to upload the file. You should see the AOP page with the image displayed under the “Graphical Representation” heading. To remove a graphical representation file, click 'Remove' and then click 'OK.'  Your graphic should no longer be displayed on the AOP page. If you do not have a graphical representation of your AOP in electronic format, a template is available to assist you.  Under “Summary of the AOP”, under the “Graphical Representation” heading click on the link “Click to download template for graphical representation.” A Powerpoint template file should download via the default download mechanism for your browser. Click to open this file; it contains a Powerpoint template for an AOP diagram and instructions for editing and saving the diagram. Be sure to save the diagram as jpeg, jpg, gif, png, or bmp format. Once the diagram is edited to its final state, upload the image file as described above. More help

Authors

List the name and affiliation information of the individual(s)/organisation(s) that created/developed the AOP. In the context of the OECD AOP Development Workplan, this would typically be the individuals and organisation that submitted an AOP development proposal to the EAGMST. Significant contributors to the AOP should also be listed. A corresponding author with contact information may be provided here. This author does not need an account on the AOP-KB and can be distinct from the point of contact below. The list of authors will be included in any snapshot made from an AOP. More help

Bérénice Collet; Bart van der Burg

BioDetection Systems (Science Park 406,1098 XH Amsterdam - The Netherlands)

Corresponding author: berenice.collet@bds.nl; bart.van.der.burg@bds.nl

Point of Contact

Indicate the point of contact for the AOP-KB entry itself. This person is responsible for managing the AOP entry in the AOP-KB and controls write access to the page by defining the contributors as described below. Clicking on the name will allow any wiki user to correspond with the point of contact via the email address associated with their user profile in the AOP-KB. This person can be the same as the corresponding author listed in the authors section but isn’t required to be. In cases where the individuals are different, the corresponding author would be the appropriate person to contact for scientific issues whereas the point of contact would be the appropriate person to contact about technical issues with the AOP-KB entry itself. Corresponding authors and the point of contact are encouraged to monitor comments on their AOPs and develop or coordinate responses as appropriate.  More help
Evgeniia Kazymova   (email point of contact)

Contributors

List user names of all  authors contributing to or revising pages in the AOP-KB that are linked to the AOP description. This information is mainly used to control write access to the AOP page and is controlled by the Point of Contact.  More help
  • Bérénice COLLET
  • Bart van der Burg
  • Evgeniia Kazymova

Status

The status section is used to provide AOP-KB users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. “Author Status” is an author defined field that is designated by selecting one of several options from a drop-down menu (Table 3). The “Author Status” field should be changed by the point of contact, as appropriate, as AOP development proceeds. See page 22 of the User Handbook for definitions of selection options. More help
Author status OECD status OECD project SAAOP status
Open for citation & comment
This AOP was last modified on April 05, 2021 18:16
The date the AOP was last modified is automatically tracked by the AOP-KB. The date modified field can be used to evaluate how actively the page is under development and how recently the version within the AOP-Wiki has been updated compared to any snapshots that were generated. More help

Revision dates for related pages

Page Revision Date/Time
Inhibition, Cytochrome P450 enzyme (CYP17A1) activity April 10, 2019 05:13
Reduction, 17-OH-pregnenolone conversion in DHEA April 10, 2019 05:15
Reduction, 17-OH-progesterone conversion in androstenedione April 10, 2019 05:33
Decrease, testosterone synthesis/level April 10, 2019 05:20
Decrease, dihydrotestosterone (DHT) level April 10, 2019 05:22
Decrease, androgen receptors (AR) activation April 10, 2019 05:24
Impaired inguinoscrotal testicular descent phase April 10, 2019 05:25
Malformation, cryptorchidism - maldescended testis April 10, 2019 05:27
Inhibition of Cyp17A1 activity leads to Reduction, DHEA April 10, 2019 05:31
Inhibition of Cyp17A1 activity leads to Reduction, androstenedione April 10, 2019 05:35
Reduction, DHEA leads to Decrease, testosterone level June 03, 2019 08:39
Reduction, androstenedione leads to Decrease, testosterone level June 03, 2019 08:40
Decrease, testosterone level leads to Decrease, DHT level June 03, 2019 08:40
Decrease, DHT level leads to Decrease, AR activation February 02, 2021 05:50
Decrease, testosterone level leads to Decrease, AR activation June 03, 2019 08:41
Decrease, AR activation leads to Impaired inguinoscrotal phase June 03, 2019 08:41
Impaired inguinoscrotal phase leads to Malformation, cryptorchidism June 03, 2019 08:42

Abstract

In the abstract section, authors should provide a concise and informative summation of the AOP under development that can stand-alone from the AOP page. Abstracts should typically be 200-400 words in length (similar to an abstract for a journal article). Suggested content for the abstract includes the following: The background/purpose for initiation of the AOP’s development (if there was a specific intent) A brief description of the MIE, AO, and/or major KEs that define the pathway A short summation of the overall WoE supporting the AOP and identification of major knowledge gaps (if any) If a brief statement about how the AOP may be applied (optional). The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance More help

This Adverse Outcome Pathway describes the linkage between a decrease in 7α-hydroxylase/C17,20-lyase (Cyp17a1) activity and a specific reproductive malformation in male newborns : impaired testicular descent also called cryptorchidism.

Cyp17a1 enzyme is known to mediate 17 alpha-hydroxylase and 17,20-lyase activities, the distinction between the two being functional and not genetic or structural. Mainly expressed in Leydig cells, this steroidogenic enzyme catalyzes the conversion of 17-OH-pregnenolone and 17-OH-progesterone to dehydroepiandrosterone (DHEA) and androstenediol, respectively. In that way, a decrease in Cyp17a1 activity would inevitably lead to a decline in both steroid precursors’ levels. As a result, this succession of key events will affect testosterone (T) and dihydrotestosterone (DHT) synthesis and circulating levels. A direct consequence to such a drop in major androgens levels would be a decline in androgen receptor activation, causing potential disturbances in development and maintenance of the male reproductive system such as cryptorchidism. To understand this AOP, it is important to notice that the second stage of the testicular descent process called “inguinoscrotal“ is an androgen-dependent event that can be dramatically affected by variations in androgenic activity.

The present AOP is linked to EU-ToxRisk Case Study 7: Read across evaluation of reproductive toxicity of conazoles. Conazoles are fungicide used in agriculture and as pharmaceuticals for treatment of human fungal diseases. They are known to act through inhibition of CYP51 which can be related to cross-reactivity with human enzymes involved in steroid metabolism, such as CYP17a1. In that respect, the proposed AOP and associated methods can be used as a basis to assess the effects of conazoles on steroidogenesis and reproductive development.

Background (optional)

This optional subsection should be 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. Examples of potential uses of the optional background section are listed on pages 24-25 of the User Handbook. More help

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 stressor and the biological system) of an AOP. More help
Key Events (KE)
This table summarises all of the KEs of the AOP. This table is populated in the AOP-Wiki as KEs are added to the AOP. Each table entry acts as a link to the individual KE description page.  More help
Adverse Outcomes (AO)
An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP.  More help
Sequence Type Event ID Title Short name
1 MIE 1609 Inhibition, Cytochrome P450 enzyme (CYP17A1) activity Inhibition of Cyp17A1 activity
2 KE 1610 Reduction, 17-OH-pregnenolone conversion in DHEA Reduction, DHEA
3 KE 1611 Reduction, 17-OH-progesterone conversion in androstenedione Reduction, androstenedione
4 KE 1612 Decrease, testosterone synthesis/level Decrease, testosterone level
5 KE 1613 Decrease, dihydrotestosterone (DHT) level Decrease, DHT level
6 KE 1614 Decrease, androgen receptors (AR) activation Decrease, AR activation
7 KE 1615 Impaired inguinoscrotal testicular descent phase Impaired inguinoscrotal phase
8 AO 1616 Malformation, cryptorchidism - maldescended testis Malformation, cryptorchidism

Relationships Between Two Key Events (Including MIEs and AOs)

TESTINGThis table summarises 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.To add a key event relationship click on either Add relationship: events adjacent in sequence or Add relationship: events non-adjacent in sequence.For example, if the intended sequence of KEs for the AOP is [KE1 > KE2 > KE3 > KE4]; relationships between KE1 and KE2; KE2 and KE3; and KE3 and KE4 would be defined using the add relationship: events adjacent in sequence button.  Relationships between KE1 and KE3; KE2 and KE4; or KE1 and KE4, for example, should be created using the add relationship: events non-adjacent button. This helps to both organize the table with regard to which KERs define the main sequence of KEs and those that provide additional supporting evidence and aids computational analysis of AOP networks, where non-adjacent KERs can result in artifacts (see Villeneuve et al. 2018; DOI: 10.1002/etc.4124).After clicking either option, the user will be brought to a new page entitled ‘Add Relationship to AOP.’ To create a new relationship, select an upstream event and a downstream event from the drop down menus. The KER will automatically be designated as either adjacent or non-adjacent depending on the button selected. The fields “Evidence” and “Quantitative understanding” can be selected from the drop-down options at the time of creation of the relationship, or can be added later. See the Users Handbook, page 52 (Assess Evidence Supporting All KERs for guiding questions, etc.).  Click ‘Create [adjacent/non-adjacent] relationship.’  The new relationship should be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. To edit a key event relationship, click ‘Edit’ next to the name of the relationship you wish to edit. The user will be directed to an Editing Relationship page where they can edit the Evidence, and Quantitative Understanding fields using the drop down menus. Once finished editing, click ‘Update [adjacent/non-adjacent] relationship’ to update these fields and return to the AOP page.To remove a key event relationship to an AOP page, under Summary of the AOP, next to “Relationships Between Two Key Events (Including MIEs and AOs)” click ‘Remove’ The relationship should no longer be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. More help

Network View

The AOP-Wiki automatically generates a network view of the AOP. This network graphic is based on the information provided in the MIE, KEs, AO, KERs and 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

Stressors

The stressor field is a structured data field that can be used to annotate an AOP with standardised terms identifying stressors known to trigger the MIE/AOP. Most often these are chemical names selected from established chemical ontologies. However, depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). It can also include non-chemical stressors such as genetic or environmental factors. Although AOPs themselves are not chemical or stressor-specific, linking to stressor terms known to be relevant to different AOPs can aid users in searching for AOPs that may be relevant to a given stressor. More help

Life Stage Applicability

Identify the life stage for which the KE is known to be applicable. More help
Life stage Evidence
Development 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 in relation to this KE. More help
Term Scientific Term Evidence Link
human Homo sapiens Moderate NCBI
rat Rattus norvegicus Moderate NCBI

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
Sex Evidence
Male High

Overall Assessment of the AOP

This section addresses the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and WoE for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). The goal of the overall assessment is to provide a high level synthesis and overview of the relative confidence in the AOP and where the significant gaps or weaknesses are (if they exist). Users or readers can drill down into the finer details captured in the KE and KER descriptions, and/or associated summary tables, as appropriate to their needs.Assessment of the AOP is organised into a number of steps. Guidance on pages 59-62 of the User Handbook is available to facilitate assignment of categories of high, moderate, or low confidence for each consideration. While it is not necessary to repeat lengthy text that appears elsewhere in the AOP description (or related KE and KER descriptions), a brief explanation or rationale for the selection of high, moderate, or low confidence should be made. More help

Domain of Applicability

The relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context are defined in this section. Biological domain of applicability is informed by the “Description” and “Biological Domain of Applicability” sections of each KE and KER description (see sections 2G and 3E for details). In essence the taxa/life-stage/sex applicability is defined based on the groups of organisms for which the measurements represented by the KEs can feasibly be measured and the functional and regulatory relationships represented by the KERs are operative.The relevant biological domain of applicability of the AOP as a whole will nearly always be defined based on the most narrowly restricted of its KEs and KERs. For example, if most of the KEs apply to either sex, but one is relevant to females only, the biological domain of applicability of the AOP as a whole would be limited to females. While much of the detail defining the domain of applicability may be found in the individual KE and KER descriptions, the rationale for defining the relevant biological domain of applicability of the overall AOP should be briefly summarised on the AOP page. More help

Life Stage Applicability

This AOP is relevant for developing male.

Sex Applicability

This AOP applies to males only.

Essentiality of the Key Events

An important aspect of assessing an AOP is evaluating the essentiality of its KEs. 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.When assembling the support for essentiality of the KEs, authors should organise relevant data in a tabular format. The objective is to summarise briefly the nature and numbers of investigations in which the essentiality of KEs has been experimentally explored either directly or indirectly. See pages 50-51 in the User Handbook for further definitions and clarifications.  More help
  Key Events                      
MIE Inhibition, Cyp17a1 CYP17a1 has a decisive function in steroidogenesis by constituting the initial step in a series of biochemical reactions.
KE1 Reduction, DHEA conversion 17-OH-pregnenolone is the direct precursor of dehydroepiandrosterone (DHEA). (Miller et al., 1988 - 2011)
    DHEA is the precursor of steroid hormones like testosterone and estradiol.
KE2 Reduction, Androstenedione conversion 17-OH-progesterone is the direct precursor of  androstenedione. (Miller et al., 1988; Liu et al., 2005)
    Androstenedione is the precursor of steroid hormones like testosterone and estradiol.
KE3 Decrease, testosterone levels Reduction in testosterone synthesis leads to a reduction in testosterone circulating levels. (Miller et al., 1988; Elder et al., 1985; Shiraishi et al., 2008)
KE4 Decrease, DHT levels Reduction in DHT synthesis leads to a reduction in DHT circulating levels. (Miller et al., 1988 - 2011 1985; Shiraishi et al., 2008)
KE5 Decrease, AR activation Androgen receptor activation is regulated by the binding of androgens. (Davey et al., 2016; Gao et al., 2005)
    AR activity can be decreased by either a lack of steroidal ligands (testosterone, DHT) or the presence of an antagonist.
KE6 Impaired inguinoscrotal phase Second phase of a two-step testis descent: the testis descends into the scrotum. (Hutson et al., 2015)
    Any impairment in testis migration will directly result in the absence of one or both testes from the scrotum.
AOP Malformation, cryptorchidism Insertion of the testis in another position than the scrotum. (Hutson et al., 2015a - 2015b; Boisen et al., 2004; Acerini et al., 2009)
       How to measure                    
MIE   Measurement in CYP17 MA-10 wild-type and CYP17 knock down MA-10 clone can be used to assess the effects of a dysfunction in CYP17a1 activity. (Liu et al., 2005)
     
KE1   17-OH-pregnenolone and DHEA can be fractionated using High Performance Liquid Chromatography. After separation, pregnenolone and DHEA levels can be quantify using immunoassay such as ELISA or Radio Immuno Assay (RIA). For both steroids, LC-MS/MS is also an option.
     
KE2  

Competitive immunoenzymatic colorimetric methods (ELISA) for quantitative determination of 17-OH-progesterone and androstenedione concentration in serum or plasma are available. Progesterone and androstenedione synthesis can be monitored using radiolabeled steroid precursor in association with High Performance Liquid Chromatography (HPLC). During synthesis, steroids will incorporate the radioactive label which can be afterwards, used for quantification. First of all, HPLC combined with internal standards can be used for steroids collection, fractionation and identification. Once separated from the other steroids, progesterone and androstenedione can be finally quantified using liquid scintillation spectrometry.

     
KE3  

ELISA kit can be used for quantitative measurement of testosterone in various samples. Liquid Chromatography- tandem Mass Spectrometry is also an option. (Shiraishi et al., 2008)

Detection of increase and decrease in the production of testosterone after chemical exposure can be measured using the validated H295R Steroidogenesis Assay associated with hormone measurement kits (ELISA) and/or instrumental techniques (LC-MS). (OECD, 2011)

Testosterone (T) levels in a sample can be measured by (High Performance) Liquid Chromatography. After sample fractionation, testosterone can be identified by comparison with internal standards spectrum. Quantification of T levels can be performed using hormones measurements kits (ELISA), instrumental techniques (LC-MS) or liquid scintillation spectrometry (after radiolabeling).

     
KE4   DHT levels in a sample can be measured by (High Performance) Liquid Chromatography. After sample fractionation, DHT can be identify by comparison with internal standards spectrum. Quantification of DHT levels can be performed using hormones measurements kits (ELISA), instrumental techniques (LC-MS) or liquid scintillation spectrometry (after radiolabeling). (Shiraishi et al., 2008)
     
KE5  

Significance of AR signaling in fetal development can be studied through a conditional deletion of the androgen receptor using a Cre/loxP approach. The recommended animal model for reproductive study is the mouse. (Kaftanovskaya et al., 2012)

Also, epidemiological case-studies following mouse or humans expressing a complete androgen insensitivity allow to directly assess the effects of a lack of AR activation on the development. (Hutson 1985)

Enzyme immunoassay (ELISA) kits for in vitro quantitative measurement of AR activity are available. Androgen receptors activity can be measured using bioassay such as the (Anti-)Androgen Receptor CALUX reporter gene assay. (van der Burg et al., 2010)

     
KE6   -
     
AOP   Cryptorchidism is a birth defect that can be highlighted by a clinical examination. The aim of this palpation is to locate the gonad and determine its lowest position without causing painful traction on the spermatic cord. (Hutson et al., 2015)

Evidence Assessment

The biological plausibility, empirical support, and quantitative understanding from each KER in an AOP are assessed together.  Biological plausibility of each of the KERs in the AOP is the most influential consideration in assessing WoE or degree of confidence in an overall hypothesised AOP for potential regulatory application (Meek et al., 2014; 2014a). Empirical support entails consideration of experimental data in terms of the associations between KEs – namely dose-response concordance and temporal relationships between and across multiple KEs. It is examined most often in studies of dose-response/incidence and temporal relationships for stressors that impact the pathway. While less influential than biological plausibility of the KERs and essentiality of the KEs, empirical support can increase confidence in the relationships included in an AOP. For clarification on how to rate the given empirical support for a KER, as well as examples, see pages 53- 55 of the User Handbook.  More help
  Key Event Relations General informations                    
                         
KER1 Inhibition, Cyp17a1 - Reduction, DHEA conversion Cyp17a1 catalyzes the conversion of 17-OH-pregnenolone in DHEA through its 17α-hydroxylase activity. 
KER2 Inhibition, Cyp17a1 - Reduction, Androstenedione conversion Cyp17a1 catalyzes the cleavage of c17,20 bond of 17-OH-progesterone to give androstenedione.
KER3 Reduction, DHEA/Androstenedione - Decrease, testosterone Levels of two main testosterone precursors (DHEA and androstenedione) are decreased (KE1-KE2) 
    Deficiency in these intermediate steroids directly lead to a reduction in testosterone synthesis.
KER4 Decrease, testosterone levels - Decrease, DHT levels Testosterone being the precursor of DHT, a reduction in its synthesis/levels directly affects this metabolite.
KER5 Decrease, testosterone levels - Decrease, AR activation A lack in androgenic hormones (either testosterone or DHEA) results in a diminution of AR activation.
KER6 Decrease, AR activation - Impaired inguinoscrotal phase A dysfunction in androgens synthesis and AR activation leads to a defect in the inguinoscrotal stage.
AOP Impaired inguinoscrotal phase - Malformation, cryptorchidism A defect in the inguinoscrotal stage leads to an impairment in the testis descent to the scrotum. 
  Key Event Relations Biological plausibility
KER1 Inhibition, Cyp17a1 - Reduction, DHEA conversion High Cyp17a1 is known to cleave the c17,20bond of 10-OH-pregnenolone through its 17α-hydroxylase activity.
KER2 Inhibition, Cyp17a1 - Reduction, Androstenedione conversion High Most of androstenedione is synthesized through the 17,20-lyase activity of Cyp17a1.
KER3 Reduction, DHEA/Androstenedione - Decrease, testosterone High This steroid can be synthesized from either  DHEA/Androstenediol or Androstenedione both catalyzed by the 3β-hydroxysteroid dehydrogenase enzyme.
KER4 Decrease, testosterone levels - Decrease, DHT levels High Testosterone is converted to DHT by 5alpha-reductase.
KER5 Decrease, testosterone levels - Decrease, AR activation High AR is a ligand-dependent nuclear transcription factor. Its activation is known to be mediated by Testosterone and DHT.
KER6 Decrease, AR activation - Impaired inguinoscrotal phase Moderate Although causes of cryptorchidism are not well-established, androgens are known to play an important role in the inguinoscrotal testicular descent
KER6 Decrease, AR activation - Impaired inguinoscrotal phase   in both animals and humans. Variation affecting androgens levels and AR activation directly lead to defect in the inguinoscrotal phase of testis descent. 
AOP Impaired inguinoscrotal phase - Malformation, cryptorchidism High Any impairment affecting thie inguinoscrotal phase has direct repercussion on proper testis descent.
     Empirical support
KER1   In 2005, Liu Y., Yao ZX., and Papadopoulos V. showed that MA-10 CYP17 knock down cells synthesize much  less 
    pregnenolone and DHEA compared with MA-10 wild type cells.
    https://doi.org/10.1210/me.2004-0271 
KER2   Using MA-10 CYP17 knock down cells, Liu Y., Yao ZX., and Papadopoulos V. showed that cells without CYP17 enzyme
     tend to synthesize less progesterone than MA-10 wild type cells.
    https://doi.org/10.1210/me.2004-0271 
KER3   -
KER4   An enzyme immunoassay such as ELISA kit can be used for quantitative determination of DHT levels.
    The ratio of serum testosterone to serum DHT shows the general activity of 5-alpha reductase.
KER5   Norris J.D., et al. highlighted that CYP17 inhibition using lyase–selective inhibitor antagonize AR activation.
    https://doi.org/10.1172/JCI87328 
KER6   In 1985, Hutson studied both mice model and humans expressing a complete androgen insensitivity. This particular
    research demonstrated that in such case, the testis remains in the inguinal canal or groin.
    http://dx.doi.org/10.1016/S0140-6736(85)92739-4 
    Kaftanovskaya et al. confirmed the previous statement in 2012 using a Cre-loxP approach study    
    https://doi.org/10.1210/me.2011-1283 
AOP   Kaftanovskaya et al. research are based on conditional deletion of the androgen receptor using a Cre/loxP approach in male mice. 
    Study from 2012 showed that a depletion of the AR in the gubernaculum leads to an impairment in inguinoscrotal phase and induces cryptorchidism. 
    https://doi.org/10.1210/me.2011-1283 

Quantitative Understanding

Some proof of concept examples to address the WoE considerations for AOPs quantitatively have recently been developed, based on the rank ordering of the relevant Bradford Hill considerations (i.e., biological plausibility, essentiality and empirical support) (Becker et al., 2017; Becker et al, 2015; Collier et al., 2016). Suggested quantitation of the various elements is expert derived, without collective consideration currently of appropriate reporting templates or formal expert engagement. Though not essential, developers may wish to assign comparative quantitative values to the extent of the supporting data based on the three critical Bradford Hill considerations for AOPs, as a basis to contribute to collective experience.Specific attention is also given to how precisely and accurately one can potentially predict an impact on KEdownstream based on some measurement of KEupstream. This is captured in the form of quantitative understanding calls for each KER. See pages 55-56 of the User Handbook for a review of quantitative understanding for KER's. More help

Considerations for Potential Applications of the AOP (optional)

At their discretion, the developer may include in this section discussion of the 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. While it is challenging to foresee all potential regulatory application of AOPs and any application will ultimately lie within the purview of regulatory agencies, potential applications may be apparent as the AOP is being developed, particularly if it was initiated with a particular application in mind. This optional section is intended to provide the developer with an opportunity to suggest potential regulatory applications and describe his or her rationale.To edit the “Considerations for Potential Applications of the AOP” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Considerations for Potential Applications of the AOP” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page or 'Update and continue' to continue editing AOP text sections.  The new text should appear under the “Considerations for Potential Applications of the AOP” section on the AOP page. More help

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References

List the bibliographic references to original papers, books or other documents used to support the AOP. More help

Acerini C.L., Miles H.L., Dunger D.B., Ong K.K. and Hughes I.A. (2009) The descriptive epidemiology of congenital and acquired cryptorchidism in a UK infant cohort. Archives of disease in childhood, 94(11):868-72 https://doi.org10.1136/adc.2008.150219 

Anitha B. Alex, Sumanta K. Pal, and Neeraj Agarwal (2016) CYP17 inhibitors in prostate cancer: latest evidence and clinical potential. Therapeutic Advances in Medical Oncology, 8(4):267-75  https://doi.org/10.1177/1758834016642370

Auchus R.J. (2004) Overview of dehydroepiandrosterone biosynthesis. Seminars in Reproductive Medicine, 22(4):281-8.https://doi.org/10.1055/s-2004-861545 

Boisen K.A., Kaleva M., Main K.M., Virtanen H.E., Haavisto A.M., Schmidt I.M., Chellakooty M., Damgaard I.N., Mau C., Reunanen M., Skakkebaek N.E. and Toppari J. (2004) Difference in prevalence of congenital cryptorchidism in infants between two Nordic countries. Lancet, 17;363(9417):1264-9 https://doi.org/10.1016/S0140-6736(04)15998-9 

Brinkmann A.O., Blok L.J., de Ruiter P.E., Doesburg P., Steketee K., Berrevoets C.A. and Trapman J. (1999) Mechanisms of androgen receptor activation and function. The Journal of steroid biochemistry and molecular biology. PMID: 10419007

Davey R.A and Grossmann M. (2016) Androgen Receptor Structure, Function and Biology: From Bench to Bedside. Clinical Biochemist Reviews, 37(1): 3-15. PCM4810760

Elder P.A. and Lewis J.G. (1985) An enzyme-linked immunosorbent assay (ELISA) for plasma testosterone. Journal of steroid biochemistry, 22(5):635-8.

Gao W., Bohl C.E. and Dalton J.T. (2005) Chemistry and Structural Biology of Androgen Receptor. Chemical Reviews 105(9): 3352-3370https://doi.org/10.1021/cr020456u 

Hutson J.M. (1985) A biphasic model for the hormonal control of testicular descent. Lancet, 24;2(8452): 419-21http://dx.doi.org/10.1016/S0140-6736(85)92739-4 

Hutson J.M., et al. (2015) Cryptorchidism and Hypospadias. Endotext https://www.ncbi.nlm.nih.gov/books/NBK279106/ 

Hutson J.M., Li R., Southwell B.R., Newgreen D., and Cousinery M. (2015) Regulation of testicular descent. Pediatric Surgery International, 31(4): 317-325 https://doi.org/10.1007/s00383-015-3673-4 

Kaftanovskaya E.M., Huang Z., Barbara A.M., De Gendt K., Verhoeven G., Ivan P. Gorlov, and Agoulnik A.I. (2012) Cryptorchidism in Mice with an Androgen Receptor Ablation in Gubernaculum Testis. Molecular Endocrinology, 26(4): 598-607.https://doi.org/10.1210/me.2011-1283 

Liu Y., Yao ZX., and Papadopoulos V. (2005) Cytochrome P450 17α Hydroxylase/17,20 Lyase (CYP17) Function in Cholesterol Biosynthesis: Identification of Squalene Monooxygenase (Epoxidase) Activity Associated with CYP17 in Leydig Cells. Molecular Endocrinology, 19(7): 1918-1931 https://doi.org/10.1210/me.2004-0271 

Miller Walter L. (1988) Molecular Biology of Steroid Hormone Synthesis. Endocrine Reviews, 9(3): 295-318. https://doi.org/10.1210/edrv-9-3-295 

Miller W.L. and Auchus R.J. (2011) The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders. Endocrine Reviews, 32(1): 81-151.https://doi.org/10.1210/er.2010-0013 

Norris J.D., Ellison S.J., Baker J.G., Stagg D.B., Wardell S.E., Park S., Alley H.M., Baldi R.M., Yllanes A., Andreano K.J., Stice J.P., Lawrence S.A., Eisner J.R., Price D.K., Moore W.R., Figg W.D. and, McDonnell D.P. (2017) Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer. The journal of clinical investigation, 127(6):2326-2338 https://doi.org/10.1172/JCI87328 

OECD Guideline For the Testing of Chemicals - H295R Steroidogenesis Assay (2011)https://ntp.niehs.nih.gov/iccvam/suppdocs/feddocs/oecd/oecd-tg456-2011-508.pdf 

Petrunak E.M., DeVore N.M., Patrick R. Porubsky PR.., and Scott E.E.(2014) Structures of human steroidogenic cytochrome P450 17A1 with substrates. Journal of Biological Chemistry, 289(47): 32952–32964  https://doi.org/10.1074/jbc.M114.610998 

Roelofs M.J., Piersma A.H., van den Berg M. and van Duursen M.B. (2013) The relevance of chemical interactions with CYP17 enzyme activity: assessment using a novel in vitro assay. Toxicology and Applied Pharmacology 1;268(3):309-17 https://doi.org/10.1016/j.taap.2013.01.033 

Shiraishi S., Lee P.W., Leung A., Goh V.H., Swerdloff R.S. and Wang C. (2008) Simultaneous measurement of serum testosterone and dihydrotestosterone by liquid chromatography-tandem mass spectrometry. Clinical chemistry, 54(11): 1855-63.https://doi.org/10.1373/clinchem.2008.103846 

Storbeck K., Swart P., Africander D., Conradie R., Louw R. and.Swart A.C. (2011) 16α-Hydroxyprogesterone: Origin, biosynthesis and receptor interaction. Molecular and Cellular Endocrinology, 336(1-2): 92-101https://doi.org/10.1016/j.mce.2010.11.016

van der Burg B., Winter R., Man HY., Vangenechten C., Berckmans P., Weimer M., Witters M. and van der Linden S. (2010) Optimization and prevalidation of the in vitro AR CALUX method to test androgenic and antiandrogenic activity of compounds. Reproductive Toxicology, 30(1):18-24 https://doi.org/0.1016/j.reprotox.2010.04.012 

Vinggaard A.M., Christiansen S., Laier P., Poulsen M.E., Breinholt V, Jarfelt K., Jacobsen H., Dalgaard M., Nellemann C. and Hass U. (2005) Perinatal exposure to the fungicide prochloraz feminizes the male rat offspring. Toxicological Sciences, 85:886–897https://doi.org/10.1093/toxsci/kfi150