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AOP: 571

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

5α-reductase inhibition leading to hypospadias in male (mammalian) offspring

Short name

A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help

5α-reductase inhibition leading to hypospadias

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 v2.7

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

Emilie Elmelund; National Food Institute, Technical University of Denmark, Lyngby, DK-2800, Denmark

Monica K. Draskau; National Food Institute, Technical University of Denmark, Lyngby, DK-2800, Denmark

Henrik Holbech; Department of Biology, University of Southern Denmark, DK-5230, Odense M, Denmark

Terje Svingen; National Food Institute, Technical University of Denmark, Lyngby, DK-2800, Denmark

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

Terje Svingen (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

Terje Svingen

Coaches

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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 September 18, 2025 07:28

Revision dates for related pages

Page	Revision Date/Time
Inhibition, 5α-reductase	February 04, 2026 09:16
Decrease, dihydrotestosterone (DHT) levels	August 13, 2025 09:04
Decrease, androgen receptor activation	February 04, 2026 16:01
Altered, Transcription of genes by the androgen receptor	April 05, 2024 09:28
Hypospadias, increased	September 18, 2025 03:48
Inhibition, 5α-reductase leads to Decrease, DHT level	April 05, 2024 08:40
Decrease, AR activation leads to Hypospadias	September 18, 2025 05:48
Decrease, DHT level leads to Decrease, AR activation	April 05, 2024 08:48
Decrease, AR activation leads to Altered, Transcription of genes by the AR	April 05, 2024 08:50
Finasteride	November 29, 2016 18:42

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

This AOP links in utero inhibition of 5α-reductase with hypospadias in male offspring. Hypospadias is a common reproductive disorder with a prevalence of up to ~1/125 newborn boys (Leunbach et al., 2025; Paulozzi, 1999). Developmental exposure to endocrine disrupting chemicals is suspected to contribute to some cases of hypospadias (Mattiske & Pask, 2021). Hypospadias can be indicative of fetal disruptions to male reproductive development, and is associated with short anogenital distance and cryptorchidism (Skakkebaek et al., 2016). Thus, hypospadias is included as an endpoint in OECD test guidelines (TG) for developmental and reproductive toxicity (TG 414, 416, 421/422, and 443; (OECD, 2016b, 2016a, 2018a, 2018b, 2021)), as both a measurement of adverse reproductive effects and a direct clinical adverse outcome.

5α-reductase is an enzyme that converts testosterone to dihydrotestosterone (DHT). In normal male reproductive development, DHT activates the androgen receptor (AR) in peripheral reproductive tissues to drive differentiation of the male phenotype, including development of the penis. While testosterone also acts directly at the AR, DHT is 5-10 times more potent and in peripheral tissues conversion to DHT is necessary for proper masculinization (Amato et al., 2022; Davey & Grossmann, 2016). This AOP delineates the evidence that inhibition of 5α-reductase reduces DHT levels and consequently AR activation, thereby disrupting penis development and causing hypospadias. The AOP is supported by in vitro experiments upstream of AR activation and by in vivo and human case studies downstream of AR activation. Downstream of a reduction in AR activation, the molecular mechanisms of hypospadias development are not fully delineated, highlighting a knowledge gap in this AOP. Thus, the AOP has potential for inclusion of additional KEs and elaboration of molecular causality links, once these are established. Given that hypospadias is both a clinical and toxicological endpoint, this AOP is considered highly relevant in a regulatory context.

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 AOP is a part of an AOP network for reduced androgen receptor activation causing hypospadias in male offspring. The other AOPs in this network are AOP-477 (‘Androgen receptor antagonism leading to hypospadias in male (mammalian) offspring’), and AOP-570 (‘Decreased testosterone synthesis leading to hypospadias in male (mammalian) offspring’). The purpose of the AOP network is to organize the well-established evidence for anti-androgenic mechanisms-of-action leading to hypospadias, thus informing predictive toxicology and identifying knowledge gaps for investigation and method development.

This work received funding from the European Food and Safety Authority (EFSA) under Grant agreement no. GP/EFSA/PREV/2022/01 and from the Danish Environmental Protection Agency under the Danish Center for Endocrine Disrupters (CeHoS).

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 OECD AOP Developer’s Handbook was followed alongside pragmatic approaches (Svingen et al., 2021).

KEs and upstream KER1880 (‘Inhibition, 5α-reductase leads to decrease, DHT levels’), KER-1935 (‘Decrease, DHT levels leads to decrease, AR activation’), and KER-2124 (‘Decrease, AR activation leads to altered, transcription of genes by AR’) were considered canonical knowledge and part of an upstream anti-androgenic network developed using mainly key review articles (Draskau et al., 2024). The non-adjacent KER-2828 linking reduced AR activation with hypospadias was developed using a systematic weight-of-evidence approach, following methodology outlined in (Holmer et al., 2024). Articles were retrieved by literature searches in PubMed and Web of Science and extensive screening using pre-defined inclusion and exclusion criteria. Evaluation of methodological reliability of in vivo animal studies was performed using the Science in Risk Assessment and Policy (SciRAP) online tool. As there are currently no in vivo methods to measure AR activation in mammals, six chemicals with known anti-androgenic mechanisms-of-action were chosen for the empirical evidence for this KER. To supplement the in vivo toxicity studies, human case studies and epidemiologic studies were included in the KER. These studies were not systematically evaluated for reliability but served as supporting evidence.

Regarding the inclusion of KEs and KERs, the rationale for the upstream anti-androgenic network is detailed in (Draskau et al., 2024). The link between the upstream network, more specifically KE-286 (‘altered, transcription of genes by AR’), and AO-2082 (‘hypospadias’) likely contains a tissue-specific KE that has not been developed, as sufficient evidence is not yet available. Thus currently, the strongest evidence linking the upstream anti-androgenic network to hypospadias is captured by KER-2828.

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

MIE

1617

Inhibition, 5α-reductase

KE	1613	Decrease, dihydrotestosterone (DHT) levels	Decrease, DHT level
KE	1614	Decrease, androgen receptor activation	Decrease, AR activation
KE	286	Altered, Transcription of genes by the androgen receptor	Altered, Transcription of genes by the AR

2082

Hypospadias, increased

Hypospadias

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

Title	Adjacency	Evidence	Quantitative Understanding

Inhibition, 5α-reductase leads to Decrease, DHT level	adjacent	High
Decrease, DHT level leads to Decrease, AR activation	adjacent	High
Decrease, AR activation leads to Altered, Transcription of genes by the AR	adjacent	High

Decrease, AR activation leads to Hypospadias

non-adjacent

High

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

Name
Finasteride

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Life stage	Evidence
Foetal	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
human	Homo sapiens	High	NCBI
rat	Rattus norvegicus	High	NCBI
mouse	Mus musculus	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

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

Although the upstream part of the AOPN has a broad applicability domain, the overall AOPN is considered only applicable to male mammals during fetal life, restricted by the applicability of KER-2828 (‘Decrease, AR activation leads to hypospadias’). The term hypospadias is mainly used for describing malformation of the male, and not female, external genitalia. Some studies refer to hypospadias in females, but these have not been reported to be caused by exposure to 5α-reductase inhibitors, and the mechanisms behind these malformations are likely different from the mechanisms in males (Greene, 1937; Stewart et al., 2018). The genital tubercle is programmed by androgens to differentiate into a penis in fetal life in the masculinization programming window, followed by the morphologic differentiation (Welsh et al., 2008). In humans, hypospadias is diagnosed at birth and can also often be observed in rats and mice at this time point, although the rodent penis does not finish developing until a few weeks after birth (Baskin & Ebbers, 2006; Sinclair et al., 2017). The disruption to androgen programming leading to hypospadias thus take place during fetal life, but the AO is best detected postnatally. Regarding taxonomic applicability, hypospadias has mainly been identified in rodents and humans, and the evidence in this AOP is almost exclusively from these species. It is, however, biologically plausible that the AOP is applicable to other mammals as well, given the conserved role of androgens in mammalian reproductive development, and hypospadias has been observed in many domestic animal and wildlife species, albeit not coupled to 5α-reductase inhibition.

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

Event

Evidence

Uncertainties and inconsistencies

MIE-1617

Inhibition, 5α-reductase (high)

Biological plausibility provides strong support for the essentiality of this event, as DHT (produced by 5α-reductase) is one of the primary drivers of penis development.

In utero exposure to the 5α-reductase inhibitor finasteride can cause hypospadias in male rats (Clark et al., 1993)

Human case studies of 5α-reductase deficiency support the essentiality of this KE, as mutations in 5α-reductase can cause low DHT levels and associated hypospadias in males (Robitaille & Langlois, 2020). See also table 4 in KER-2828 listing disruptions of AR activity associated with hypospadias in humans.

In the human case studies, DHT is only measured postnatally and not in fetal life.

KE-1613

Decrease, DHT levels (moderate)

Biological plausibility provides strong support for the essentiality of this event, as DHT is a ligand of the AR and one of the primary drivers of penis development.

In patients with 5α-reductase deficiency, DHT levels are reduced and hypospadias are frequently observed, as listed in table 4 in KER-2828.

In the human case studies, DHT is only measured postnatally and not in fetal life, As hypospadias is a congenital malformation, it cannot be “reversed” by postnatal DHT treatment.

KE-1614

Decrease, AR activation (moderate)

Biological plausibility provides strong support for the essentiality of this event, as AR activation is critical for normal penis development.

Conditional or full knockout of Ar in mice results in partly or full sex-reversal of males, including a female-like urethral opening (Willingham et al., 2006; Yucel et al., 2004; Zheng et al., 2015). Human subjects with AR mutations may also have associated hypospadias (as listed in table 4 in KER-2828).

KE-286

Altered, transcription of genes by AR (low)

Biological plausibility provides support for the essentiality of this event. AR is a nuclear receptor and transcription factor regulating transcription of genes, and androgens, acting through AR, are essential for normal male penis development.

Known AR-responsive genes active in normal penis development have been thoroughly reviewed (Amato et al., 2022).

There are currently no AR-responsive genes proved to be causally involved in hypospadias, and it is known that the AR can also signal through non-genomic actions (Leung & Sadar, 2017).

Event	Direct evidence	Indirect evidence	Contradictory evidence	Overall essentiality assessment
MIE 1617	***			High
KE 1613	*	*		Moderate
KE 1614	**			Moderate
KE 286		*		Low

Evidence Assessment

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

The confidence in each of the KERs comprising the AOP are judged as high, with both high biological plausibility and high confidence in the empirical evidence. The mechanistic link between KE-286 (‘altered, transcription of genes by AR’) and AO-2082 (‘hypospadias’) is not established, but given the high confidence in the KERs including the non-adjacent KER-2828 linking to the AO, the overall confidence in the AOP is judged as high.

KER	Biological Plausibility	Empirical Evidence	Rationale
KER-1880 Inhibition, 5α-reductase leads to decrease, DHT levels	High	High (canonical)	It is well established that 5α-reductase converts testosterone to DHT. In vitro, in vivo and human studies with 5α-reductase inhibitors have shown dose-dependent decreases in formation of DHT (Draskau et al., 2024).
KER-1935 Decrease, DHT levels leads to decrease, AR activation	High	High (canonical)	It is well established that DHT activates the AR. Direct evidence for this KER is not possible since KE-1614 can currently not be measured and is considered an in vivo effect. Indirect evidence using proxy read-outs of AR activation, either in vitro or in vivo strongly supports the relationship (Draskau et al., 2024).
KER-2124 Decrease, AR activation leads to altered, transcription of genes by AR	High	High (canonical)	It is well established that the AR regulates gene transcription. In vivo animal studies and human genomic profiling show tissue-specific changes to gene expression upon disruption of AR (Draskau et al., 2024).
KER-2828 Decrease, AR activation leads to hypospadias	High	High	It is well established that AR drives penis differentiation. Numerous in vivo toxicity studies and human case studies indirectly show that decreased AR activation leads to hypospadias, with few inconsistencies. The empirical evidence moderately supports dose, temporal, and incidence concordance for the KER.

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
Genotype	Extended CAG repeat length in AR is associated with reduced AR activity (Chamberlain et al., 1994; Tut et al., 1997). This MF could initiate the AOP at lower stressor doses.	KER-1935, KER-2124, KER-2828
Androgen deficiency syndrome	Low circulating testosterone levels due to hypogonadism (Bhasin et al., 2010). This MF could lower availability of testosterone for conversion by 5α-reductase and thus initiate the AOP at lower stressor doses.	KER-1935

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors. More help

The quantitative understanding of this AOP is judged as low.

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

Amato, C. M., Yao, H. H.-C., & Zhao, F. (2022). One Tool for Many Jobs: Divergent and Conserved Actions of Androgen Signaling in Male Internal Reproductive Tract and External Genitalia. Frontiers in Endocrinology, 13, 910964. https://doi.org/10.3389/fendo.2022.910964

Baskin, L., & Ebbers, M. (2006). Hypospadias: Anatomy, etiology, and technique. Journal of Pediatric Surgery, 41(3), 463–472. https://doi.org/10.1016/j.jpedsurg.2005.11.059

Bhasin, S., Cunningham, G. R., Hayes, F. J., Matsumoto, A. M., Snyder, P. J., Swerdloff, R. S., & Montori, V. M. (2010). Testosterone Therapy in Men with Androgen Deficiency Syndromes: An Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology & Metabolism, 95(6), 2536–2559. https://doi.org/10.1210/jc.2009-2354

Chamberlain, N. L., Driver, E. D., & Miesfeld, R. L. (1994). The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Research, 22(15), 3181–3186. https://doi.org/10.1093/nar/22.15.3181

Clark, R. L., Anderson, C. A., Prahalada, S., Robertson, R. T., Lochry, E. A., Leonard, Y. M., Stevens, J. L., & Hoberman, A. M. (1993). Critical Developmental Periods for Effects on Male Rat Genitalia Induced by Finasteride, a 5α-Reductase Inhibitor. Toxicology and Applied Pharmacology, 119(1), 34–40. https://doi.org/10.1006/taap.1993.1041

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

Draskau, M., Rosenmai, A., Bouftas, N., Johansson, H., Panagiotou, E., Holmer, M., Elmelund, E., Zilliacus, J., Beronius, A., Damdimopoulou, P., van Duursen, M., & Svingen, T. (2024). Aop Report: An Upstream Network for Reduced Androgen Signalling Leading to Altered Gene Expression of Ar Responsive Genes in Target Tissues. Environ Toxicol Chem, In Press.

Greene, R. R. (1937). Production of Experimental Hypospadias in the Female Rat. Proceedings of the Society for Experimental Biology and Medicine, 36(4), 503–506. https://doi.org/10.3181/00379727-36-9287P

Holmer, M. L., Zilliacus, J., Draskau, M. K., Hlisníková, H., Beronius, A., & Svingen, T. (2024). Methodology for developing data-rich Key Event Relationships for Adverse Outcome Pathways exemplified by linking decreased androgen receptor activity with decreased anogenital distance. Reproductive Toxicology, 128, 108662. https://doi.org/10.1016/j.reprotox.2024.108662

Leunbach, T. L., Berglund, A., Ernst, A., Hvistendahl, G. M., Rawashdeh, Y. F., & Gravholt, C. H. (2025). Prevalence, Incidence, and Age at Diagnosis of Boys With Hypospadias: A Nationwide Population-Based Epidemiological Study. Journal of Urology, 213(3), 350–360. https://doi.org/10.1097/JU.0000000000004319

Leung, J. K., & Sadar, M. D. (2017). Non-Genomic Actions of the Androgen Receptor in Prostate Cancer. Frontiers in Endocrinology, 8. https://doi.org/10.3389/fendo.2017.00002

Mattiske, D. M., & Pask, A. J. (2021). Endocrine disrupting chemicals in the pathogenesis of hypospadias; developmental and toxicological perspectives. Current Research in Toxicology, 2, 179–191. https://doi.org/10.1016/j.crtox.2021.03.004

OECD. (2016a). Test No. 421: Reproduction/Developmental Toxicity Screening Test. OECD. https://doi.org/10.1787/9789264264380-en

OECD. (2016b). Test No. 422: Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test. OECD. https://doi.org/10.1787/9789264264403-en

OECD. (2018a). Test No. 414: Prenatal Developmental Toxicity Study. OECD. https://doi.org/10.1787/9789264070820-en

OECD. (2018b). Test No. 443: Extended One-Generation Reproductive Toxicity Study. OECD. https://doi.org/10.1787/9789264185371-en

OECD. (2021). Test No. 416: Two-Generation Reproduction Toxicity (Section 4).

Paulozzi, L. J. (1999). International trends in rates of hypospadias and cryptorchidism.

Robitaille, J., & Langlois, V. S. (2020). Consequences of steroid-5α-reductase deficiency and inhibition in vertebrates. General and Comparative Endocrinology, 290, 113400. https://doi.org/10.1016/j.ygcen.2020.113400

Sinclair, A., Cao, M., Pask, A., Baskin, L., & Cunha, G. (2017). Flutamide-induced hypospadias in rats: A critical assessment. Differentiation; Research in Biological Diversity, 94, 37–57. https://doi.org/10.1016/j.diff.2016.12.001

Skakkebaek, N. E., Rajpert-De Meyts, E., Louis, G. M. B., Toppari, J., Andersson, A.-M., Eisenberg, M. L., Jensen, T. K., Jorgensen, N., Swan, S. H., Sapra, K. J., Ziebe, S., Priskorn, L., & Juul, A. (2016). Male Reproductive Disorders And Fertility Trends: Influences Of Environement And Genetic susceptibility. PHYSIOLOGICAL REVIEWS, 96(1), 55–97. https://doi.org/10.1152/physrev.00017.2015

Stewart, M. K., Mattiske, D. M., & Pask, A. J. (2018). In utero exposure to both high- and low-dose diethylstilbestrol disrupts mouse genital tubercle development†. Biology of Reproduction, 99(6), 1184–1193. https://doi.org/10.1093/biolre/ioy142

Svingen, T., Villeneuve, D. L., Knapen, D., Panagiotou, E. M., Draskau, M. K., Damdimopoulou, P., & O’Brien, J. M. (2021). A Pragmatic Approach to Adverse Outcome Pathway Development and Evaluation. Toxicological Sciences, 184(2), 183–190. https://doi.org/10.1093/toxsci/kfab113

Tut, T. G., Ghadessy, F. J., Trifiro, M. A., Pinsky, L., & Yong, E. L. (1997). Long Polyglutamine Tracts in the Androgen Receptor Are Associated with Reduced Trans -Activation, Impaired Sperm Production, and Male Infertility ¹. The Journal of Clinical Endocrinology & Metabolism, 82(11), 3777–3782. https://doi.org/10.1210/jcem.82.11.4385

Welsh, M., Saunders, P. T. K., Fisken, M., Scott, H. M., Hutchison, G. R., Smith, L. B., & Sharpe, R. M. (2008). Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. Journal of Clinical Investigation, 118(4), 1479–1490. https://doi.org/10.1172/JCI34241

Willingham, E., Agras, K., Souza, A. J. de, Konijeti, R., Yucel, S., Rickie, W., Cunha, G., & Baskin, L. (2006). Steroid receptors and mammalian penile development: An unexpected role for progesterone receptor? The Journal of Urology, 176(2), 728–733. https://doi.org/10.1016/j.juro.2006.03.078

Yucel, S., Liu, W., Cordero, D., Donjacour, A., Cunha, G., & Baskin, L. (2004). Anatomical studies of the fibroblast growth factor-10 mutant, Sonic Hedge Hog mutant and androgen receptor mutant mouse genital tubercle. Advances in Experimental Medicine and Biology, 545, 123–148. https://doi.org/10.1007/978-1-4419-8995-6_8

Zheng, Z., Armfield, B., & Cohn, M. (2015). Timing of androgen receptor disruption and estrogen exposure underlies a spectrum of congenital penile anomalies. Proceedings of the National Academy of Sciences of the United States of America, 112(52), E7194-203. https://doi.org/10.1073/pnas.1515981112