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AOP: 570

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 testosterone synthesis 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

Decreased testosterone synthesis 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
Emilie Elmelund

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 September 18, 2025 07:14

Revision dates for related pages

Page	Revision Date/Time
Decrease, intratesticular testosterone levels	January 27, 2025 11:33
Decrease, circulating testosterone levels	January 27, 2025 03:37
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
Decrease, intratesticular testosterone leads to Decrease, circulating testosterone levels	May 07, 2025 04:19
Decrease, intratesticular testosterone leads to Hypospadias	September 18, 2025 06:38
Decrease, circulating testosterone levels leads to Decrease, AR activation	February 04, 2026 16:03
Decrease, circulating testosterone levels leads to Hypospadias	September 18, 2025 06:53
Decrease, AR activation leads to Altered, Transcription of genes by the AR	April 05, 2024 08:50
Decrease, AR activation leads to Hypospadias	September 18, 2025 05:48
Dibutyl phthalate	November 29, 2016 18:42
Di(2-ethylhexyl) phthalate	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 decreased intratesticular testosterone levels 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, 2001, 2016b, 2016a, 2018a, 2018b)), as both a measurement of adverse reproductive effects and a direct clinical adverse outcome.

Testosterone is one of the two main steroid sex hormones essential for male reproductive development. Testosterone is primarily, but not exclusively, produced in the testes and then secreted into the circulation. In peripheral reproductive tissues, testosterone is either converted to dihydrotestosterone (DHT) or directly activates the androgen receptor (AR). DHT is more potent than testosterone in activating the AR, and activation of AR by either androgen initiates differentiation of the male phenotype, including development of the penis (Amato et al., 2022; Davey & Grossmann, 2016). This AOP delineates the evidence that decreasing testicular testosterone production lowers circulating testosterone levels and consequently AR activation, thereby disrupting penis development and causing hypospadias. In this AOP, the first KE is not considered an MIE, as testicular testosterone production can be obstructed by various routes. The AOP does not discriminate whether the reduction in AR activation is due to direct lack of testosterone at the AR or due to decreased conversion of testosterone to DHT, as there is not sufficient information on this. 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-571 (‘5α-reductase inhibition 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 KER-3448 (‘Decrease, intratesticular testosterone levels leads to decrease, circulation testosterone levels’), KER-2131 (‘Decrease, circulating testosterone 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; Svingen et al., 2025). The non-adjacent KER-3488, KER-3350, and KER-2828 linking decreased intratesticular testosterone, circulating testosterone, and AR activation, respectively, with hypospadias were 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. For KER-3488 and KER-3350 regarding testosterone levels, articles were included if there was a decrease in fetal testosterone levels and hypospadias was assessed in male offspring. For KER-2828, there are currently no in vivo methods to measure AR activation in mammals, and instead 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 KERs. 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). KE-2298 (‘Decrease, intratesticular testosterone levels’) was added to discriminate between the large difference in testosterone levels between testes and circulation (Coviello et al., 2004; McLachlan et al., 2002; Turner et al., 1984). 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, for now, the most evidence for the link of the anti-androgenic network on 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

KE	2298	Decrease, intratesticular testosterone levels	Decrease, intratesticular testosterone
KE	1690	Decrease, circulating testosterone levels	Decrease, circulating testosterone levels
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

Decrease, intratesticular testosterone leads to Decrease, circulating testosterone levels	adjacent	High
Decrease, circulating testosterone levels leads to Decrease, AR activation	adjacent	High
Decrease, AR activation leads to Altered, Transcription of genes by the AR	adjacent	High

Decrease, intratesticular testosterone leads to Hypospadias	non-adjacent	Moderate
Decrease, circulating testosterone levels leads to Hypospadias	non-adjacent	Low
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
Dibutyl phthalate
Di(2-ethylhexyl) phthalate

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 KE-2298 (‘Decrease, intratesticular testosterone levels’) and KER-3488 (‘Decrease, intratesticular testosterone levels leads to hypospadias’), KER-3350 (‘Decrease, circulating testosterone levels leads to hypospadias’), and KER-2828 (‘Decrease AR activation leads to hypospadias’). By definition, testes are the primary sex organs in males, and the term hypospadias is mainly used for describing malformation of the male and not female external genitalia. The genital tubercle is programmed by androgens to differentiate into a penis in fetal life in the masculinization programming window, followed by the morphological differentiation (Welsh et al., 2008). In humans, hypospadias is diagnosed at birth and can also often be observed in rodents 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 happens in the fetal life stage, but the AO is best detected postnatally. Regarding taxonomic applicability, hypospadias has mainly been identified in rodents (rats and mice) 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 reduced testosterone levels.

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

KE-2298

Decrease, intratesticular testosterone levels (moderate)

Biological plausibility provides strong support for the essentiality of this event as the testes are the main sites of testosterone production in male mammals, and testosterone is a ligand for the AR and one of the primary drivers of penis development.

Experimental evidence with phthalates lowering intratesticular testosterone supports the essentiality (see KE 3488)

Human case studies indirectly support the essentiality as mutations in steroidogenesis enzymes and gonadal dysgenesis are associated with low circulating testosterone levels and hypospadias (as listed in table 4, KER 2828)

In the human studies, testosterone levels were only measured postnatally and not in fetal life.

KE-1690

Decrease, circulating testosterone levels (moderate)

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

Human case studies support the essentiality as low circulating testosterone levels have been associated with hypospadias (as listed in table 4 in KER-2828).

In human case studies, testosterone levels were only measured postnatally and not in fetal life.

As hypospadias is a congenital malformation, it cannot be “reversed” by testosterone 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 presented 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
KE-2298		**	*	Moderate
KE-1690		***	*	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-3448 Decrease, intratesticular testosterone levels leads to decrease, circulating testosterone levels	High	High (canonical)	It is well established that testes are the primary testosterone-producing organs in male mammals. In vivo studies have shown that exposure to substances that lowers intratesticular testosterone also lowers circulating testosterone levels (Svingen et al., 2025).
KER-2131 Decrease, circulating testosterone levels leads to decrease, AR activation	High	High (canonical)	It is well established that testosterone 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-3488 Decrease, intratesticular testosterone leads to hypospadias	High	Moderate	It is well established that testicular testosterone is one of the primary drivers of penis development. In vivo animal studies support that reductions in fetal testicular testosterone can cause hypospadias in male offspring. One study supports dose concordance, where diisocytol caused reduced ex vivo testosterone production in rats at a dose of 0.1 mg/kg bw/day, while hypospadias was observed in male offspring at 1 mg/kg bw/day (Saillenfait et al., 2013).
KER-3350 Decrease, circulating testosterone levels leads to hypospadias	High	Low	It is well established that testosterone is one of the primary drivers of penis development. In vivo evidence for this KER is sparse, but human case studies of subjects with low testosterone levels (postnatally) and associated hypospadias support the KER.
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-2131, KER-2124, KER-2828
Androgen deficiency syndrome	Low circulating testosterone levels due to hypogonadism (Bhasin et al., 2010). This MF lowers general testicular testosterone production and thus initiates the AOP at lower stressor doses.	KER-2131

Quantitative Understanding

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

The quantitative understanding of this AOP is judged as low.

A model for phthalate-induced malformations has been developed which aims to predict the frequency of hypospadias related to a phthalate’s reduction in ex vivo testosterone production. The model predicted that a 60% reduction in testosterone levels would induce hypospadias, although the predictivity of this model was not good when tested for one phthalate (Earl Gray et al., 2024).

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

Coviello, A. D., Bremner, W. J., Matsumoto, A. M., Herbst, K. L., Amory, J. K., Anawalt, B. D., Yan, X., Brown, T. R., Wright, W. W., Zirkin, B. R., & Jarow, J. P. (2004). Intratesticular Testosterone Concentrations Comparable With Serum Levels Are Not Sufficient to Maintain Normal Sperm Production in Men Receiving a Hormonal Contraceptive Regimen. Journal of Andrology, 25(6), 931–938. https://doi.org/10.1002/j.1939-4640.2004.tb03164.x

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.

Earl Gray, L. J., Lambright, C. S., Evans, N., Ford, J., & Conley, J. M. (2024). Using targeted fetal rat testis genomic and endocrine alterations to predict the effects of a phthalate mixture on the male reproductive tract. Current Research in Toxicology, 7, 100180–100180. https://doi.org/10.1016/j.crtox.2024.100180

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

McLachlan, R. I., O’Donnell, L., Stanton, P. G., Balourdos, G., Frydenberg, M., de Kretser, D. M., & Robertson, D. M. (2002). Effects of Testosterone Plus Medroxyprogesterone Acetate on Semen Quality, Reproductive Hormones, and Germ Cell Populations in Normal Young Men. The Journal of Clinical Endocrinology & Metabolism, 87(2), 546–556. https://doi.org/10.1210/jcem.87.2.8231

OECD. (2001). Test No. 416: Two-Generation Reproduction Toxicity [OECD Guidelines for the Testing of Chemicals, Section 4]. OECD Publishing. https://doi.org/10.1787/9789264070868-en

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

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

Saillenfait, A., Sabaté, J., Robert, A., Cossec, B., Roudot, A., Denis, F., & Burgart, M. (2013). Adverse effects of diisooctyl phthalate on the male rat reproductive development following prenatal exposure. Reproductive Toxicology (Elmsford, N.Y.), 42, 192–202. https://doi.org/10.1016/j.reprotox.2013.09.004

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

Svingen, T., Elmelund, E., Holmer, M. L., Bindel, A. O., Holbech, H., & Draskau, M. K. (2025). AOP report: Adverse Outcome Pathway Network for Developmental Androgen Signalling-Inhibition Leading to Short Anogenital Distance in Male Offspring. Environmental Toxicology and Chemistry, vgaf221. https://doi.org/10.1093/etojnl/vgaf221

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

Turner, T. T., Jones, C. E., Howards, S. S., Ewing, L. L., Zegeye, B., & Gunsalus, G. L. (1984). On the androgen microenvironment of maturing spermatozoa. Endocrinology, 115(5), 1925–1932. https://doi.org/10.1210/endo-115-5-1925

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