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AOP: 619

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

Androgen receptor antagonism leads to delayed preputial separation via reduced fibroblast growth factor in genital-tubercle tissues

Short name

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AR agonism leads to delayed PPS via reduced FGF expression

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Handbook Version v2.7

Graphical Representation

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Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

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Travis Karschnik (General Dynamics Information Technology, Duluth, MN, USA.)

Point of Contact

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Travis Karschnik (email point of contact)

Contributors

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Travis Karschnik

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 July 08, 2026 15:53

Revision dates for related pages

Page	Revision Date/Time
Antagonism, Androgen receptor	March 20, 2026 11:42
Androgen receptor nuclear transcriptional activity in genital-tubercle tissues, reduced	December 18, 2025 11:35
Fibroblast growth factor 10, fibroblast growth factor receptor 2 isoform IIIb signaling in genital tissue, reduced	December 18, 2025 11:43
Preputial epithelial morphogenesis, disrupted	December 18, 2025 15:33
Male preputial separation, failed/delayed	February 06, 2026 16:55
Antagonism, Androgen receptor leads to AR transcriptional activity in GT tissues, reduced	April 08, 2026 13:13
AR transcriptional activity in GT tissues, reduced leads to FGF10/FGFR2-IIIb signaling in genital tissue, reduced	May 07, 2026 15:54
FGF10/FGFR2-IIIb signaling in genital tissue, reduced leads to Preputial epithelial morphogenesis, disrupted	June 04, 2026 15:18
Preputial epithelial morphogenesis, disrupted leads to Male PPS, failed/delayed	July 07, 2026 17:16
Dibutyl phthalate	November 29, 2016 18:42
Flutamide	August 14, 2025 05:22
Vinclozolin	May 14, 2020 11:28
Procymidone	May 18, 2020 12:55
Linuron	May 18, 2020 12:53

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 describes how antagonism of the androgen receptor (AR) during genital tubercle (GT) development reduces AR-dependent nuclear transcriptional activity, thereby suppressing FGF10/FGFR2-IIIb signaling in genital tissues, disrupting preputial epithelial morphogenesis, and ultimately causing failed or delayed male preputial separation (PPS). The pathway is built on strong developmental genetics and toxicology evidence from rodent systems, particularly ex vivo mouse GT culture and in vivo rat anti-androgen studies. In mouse GT culture, flutamide caused dose-dependent downregulation of Fgfr2-IIIb and Fgf10, and DHT rescued the Fgfr2-IIIb and morphologic effects, indicating that the upstream AR event is causally linked to downstream FGF signaling in GT tissues (Petiot et al., 2005). Genetic evidence shows that Fgfr2-IIIb and Fgf10 are required for normal urethral epithelium maintenance and ventral prepuce development; loss of this signaling causes severe hypospadias-like malformations and failure of epithelial maturation (Petiot et al., 2005; Revest et al., 2001). Rodent developmental anti-androgen studies demonstrate that disruption of androgen signaling during the masculinization programming window delays PPS and induces persistent genital malformations, supporting the biological and regulatory relevance of the terminal adverse outcome (Mylchreest et al., 1999; Welsh et al., 2008; Sinclair et al., 2017). Gaps remain in the direct chromatin-level demonstration of AR regulation of Fgfr2 in GT tissue and in fully quantifying how specific morphogenetic lesions translate to PPS delay. Overall, the AOP has moderate-to-high confidence and is well suited for developmental hazard identification, prioritization, and mechanistic interpretation of anti-androgenic chemicals.

Master prompt

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 was as part of an Environmental Protection Agency effort to develop AOPs that establish scientifically supported causal linkages between alternative endpoints measured using new approach methodologies (NAMs) and guideline apical endpoints measured in Tier 1 and Tier 2 test guidelines (U.S. EPA, 2024) employed by the Endocrine Disruptor Screening Program (EDSP). A series of key events that represent significant, measurable, milestones connecting molecular initiation to apical endpoints indicative of adversity were identified based on scientific review articles and empirical studies. Additionally, scientific evidence supporting the causal relationships between each pair of key events was assembled through a combination of expert knowledge and AI-assisted literature search and synthesis. Specifically, a combination of Claude (Anthropic) using Sonnet 4.6, and EPA AI, using GPT5, was used to identify, retrieve, and summarize relevant primary and secondary literature, and to draft the initial content of this AOP page. Users of this AOP are advised that AI-assisted evidence assembly may introduce selection bias or gaps in coverage that differ from a fully systematic human-conducted review, and independent verification of the evidence base is encouraged. A copy of the initial prompt is attached at the bottom of the Abstract section of this AOP.

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 scope of the aforementioned EPA project was to develop AOP(s) relevant to apical endpoints observed in the test guidelines, based on mechanisms consistent with empirical studies. The literature used to support this AOP and its constituent pages began with the test guidelines and followed to primary, secondary, and/or tertiary works concerning the relevant underlying biology. KE and KER page creation and re-use was determined using Handbook principles where page re-use was preferred.

Summary of the AOP

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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

Antagonism, Androgen receptor

KE	2393	Androgen receptor nuclear transcriptional activity in genital-tubercle tissues, reduced	AR transcriptional activity in GT tissues, reduced
KE	2399	Fibroblast growth factor 10, fibroblast growth factor receptor 2 isoform IIIb signaling in genital tissue, reduced	FGF10/FGFR2-IIIb signaling in genital tissue, reduced
KE	2400	Preputial epithelial morphogenesis, disrupted	Preputial epithelial morphogenesis, disrupted

2401

Male preputial separation, failed/delayed

Male PPS, failed/delayed

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

Antagonism, Androgen receptor leads to AR transcriptional activity in GT tissues, reduced	adjacent	High	High
AR transcriptional activity in GT tissues, reduced leads to FGF10/FGFR2-IIIb signaling in genital tissue, reduced	adjacent	High	Moderate
FGF10/FGFR2-IIIb signaling in genital tissue, reduced leads to Preputial epithelial morphogenesis, disrupted	adjacent	High	Moderate
Preputial epithelial morphogenesis, disrupted leads to Male PPS, failed/delayed	adjacent	High	Low

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
Flutamide
Vinclozolin
Procymidone
Linuron

Life Stage Applicability

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

Life stage	Evidence
Embryo	High
Foetal	High
Fetal to Parturition	High
Development	High
Juvenile	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
Mus musculus	Mus musculus	High	NCBI
Rattus norvegicus	Rattus norvegicus	High	NCBI
Homo sapiens	Homo sapiens	Moderate	NCBI
rodentia	rodentia	High	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

Overall confidence in this AOP is moderate to high. Biological plausibility is high across all KERs, because the pathway follows well-established steroid receptor biology and canonical epithelial-mesenchymal FGF signaling during genital development (Gelmann, 2002; Itoh & Ornitz, 2011; Ohuchi et al., 2000; Quigley et al., 1995). Empirical support is also strong: the AR→FGF10/FGFR2-IIIb link is directly supported by flutamide/DHT rescue data in GT culture, the FGF signaling→morphogenesis link is strongly supported by loss-of-function mouse studies, and the final morphogenesis→PPS link is supported by rat developmental anti-androgen studies and histologic analyses of preputial fusion defects (Petiot et al., 2005; Revest et al., 2001; Gredler et al., 2015; Mylchreest et al., 1999; Sinclair et al., 2017).

The primary uncertainties are: (1) direct AR binding to the Fgfr2 regulatory region in GT tissue has not been experimentally confirmed; (2) Fgf10 regulation by AR may be indirect in GT tissue; and (3) some PPS studies do not measure preputial histology in the same animals, making the morphogenesis-to-PPS bridge partly inferential rather than directly observed (Petiot et al., 2005; Sinclair et al., 2017). These gaps do not undermine the overall pathway, but they do limit the precision of quantitative prediction.

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

Taxonomic Applicability

The AOP is best supported in rodents, especially mouse and rat. Mouse ex vivo and genetic studies provide the strongest mechanistic support for the AR→FGF10/FGFR2-IIIb→preputial morphogenesis sequence, while rat developmental toxicology provides the clearest evidence for delayed PPS as the adverse outcome (Petiot et al., 2005; Harada et al., 2015; Gredler et al., 2015; Mylchreest et al., 1999; Sinclair et al., 2017). Human developmental and histologic studies support translational relevance but do not yet provide direct evidence for the full pathway (Kim et al., 2002; Beleza-Meireles et al., 2007; Carmichael et al., 2013; Haid et al., 2020).

Lifestage Applicability

The pathway is operative during embryonic and fetal external genital development, with the adverse outcome manifesting postnatally in juvenile males as delayed PPS. The critical androgen-sensitive window precedes or overlaps external genital morphogenesis and is distinct from the later postnatal timing of PPS scoring in rat toxicology studies (Mylchreest et al., 1999; Welsh et al., 2008; Seifert et al., 2008; Sinclair et al., 2017).

Sex Applicability

The molecular events can be detected in both sexes in organ culture, but the adverse outcome is male-specific because PPS is a male external genital endpoint. Accordingly, the AOP is most directly applicable to males, with upstream mechanistic relevance in mixed-sex developmental contexts (Petiot et al., 2005; Seifert et al., 2008).

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	Direct Evidence	Indirect Evidence	No experimental evidence	Contradictory experimental evidence
MIE: Antagonism, Androgen receptor	***	**
KE1: Androgen receptor nuclear transcriptional activity in genital-tubercle tissues, reduced	***	*
KE2: Fibroblast growth factor 10, fibroblast growth factor receptor 2 isoform IIIb signaling in genital tissue, reduced	****
KE3: Preputial epithelial morphogenesis, disrupted	***	**
AO: Male preputial separation, failed/delayed	****

MIE: Antagonism, Androgen receptor

Direct evidence is strong because pharmacological AR antagonism with flutamide in GT organ culture suppresses downstream Fgfr2-IIIb/Fgf10 expression and can be rescued by DHT, demonstrating that antagonism of AR initiates the pathway (Petiot et al., 2005; Furutani et al., 2002). Indirect evidence also comes from developmental anti-androgen studies that reproduce the downstream phenotype in vivo (Mylchreest et al., 1999; Welsh et al., 2008; Sinclair et al., 2017).

KE1: Androgen receptor nuclear transcriptional activity in genital-tubercle tissues, reduced

Direct evidence is strong from flutamide-induced suppression of AR-dependent transcript expression in GT organ culture and DHT rescue of the response (Petiot et al., 2005). Indirect evidence includes in vivo anti-androgen studies that are consistent with reduced AR-driven developmental programs in the GT and downstream genital morphogenesis defects (Seifert et al., 2008; Mylchreest et al., 1999).

KE2: FGF10/FGFR2-IIIb signaling in genital tissue, reduced

Direct evidence is strong because Fgfr2-IIIb and Fgf10 are downregulated by flutamide in GT culture in a dose-dependent manner, and genetic loss of Fgfr2-IIIb or Fgf10 causes severe external genital defects and failure of urethral epithelial maturation (Petiot et al., 2005; Revest et al., 2001; Gredler et al., 2015).

KE3: Preputial epithelial morphogenesis, disrupted

Direct evidence is strong from mouse loss-of-function and tissue-specific FGF signaling studies showing abnormal urethral/preputial epithelial maturation and ventral prepuce closure defects when this pathway is impaired (Petiot et al., 2005; Gredler et al., 2015; Harada et al., 2015). Indirect evidence also comes from anti-androgen developmental studies in rats, which produce preputial/genital malformations consistent with disrupted morphogenesis before PPS is delayed (Yoshimura et al., 2004, 2005; Mylchreest et al., 1999).

AO: Male preputial separation, failed/delayed

Direct evidence is strong because developmental anti-androgen exposure delays PPS in rats and, in some cases, ventral defects prevent complete separation altogether (Mylchreest et al., 1999; Welsh et al., 2008; Sinclair et al., 2017; Yoshimura et al., 2004, 2005).

Evidence Assessment

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

KER 1: Antagonism, Androgen receptor → Androgen receptor nuclear transcriptional activity in genital-tubule tissues, reduced

Biological plausibility: High. AR is a ligand-activated nuclear steroid receptor, and antagonists block its transactivation function (Gelmann, 2002; Quigley et al., 1995).

Empirical support: High. Flutamide reduced downstream AR-responsive transcriptional output in GT culture, and DHT reversed the effect (Petiot et al., 2005).

Quantitative understanding: Moderate. The antagonist-dependent suppression is dose-responsive in GT tissue, but the quantitative relationship is not fully parameterized for in vivo extrapolation (Petiot et al., 2005).

KER 2: Androgen receptor nuclear transcriptional activity in genital-tubule tissues, reduced → Fibroblast growth factor 10, fibroblast growth factor receptor 2 isoform IIIb signaling in genital tissue, reduced

Biological plausibility: High. AR-dependent transcription can regulate developmental growth factor signaling, and FGF10/FGFR2-IIIb is a canonical epithelial-mesenchymal signaling pair in genital development (Itoh & Ornitz, 2011; Ohuchi et al., 2000; Petiot et al., 2005).

Empirical support: High. Flutamide caused dose-dependent reduction of Fgfr2-IIIb and Fgf10, and DHT rescued Fgfr2-IIIb expression and normal morphology; an in silico ARE was identified in the Fgfr2 promoter, though direct AR chromatin binding was not shown (Petiot et al., 2005).

Quantitative understanding: Moderate. Dose-response relationships were demonstrated in organ culture, but the quantitative mechanistic threshold between AR activity and FGF pathway output is not fully resolved (Petiot et al., 2005).

KER 3: Fibroblast growth factor 10, fibroblast growth factor receptor 2 isoform IIIb signaling in genital tissue, reduced → Preputial epithelial morphogenesis, disrupted

Biological plausibility: High. FGF10/FGFR2-IIIb controls epithelial proliferation, differentiation, and morphogenesis in multiple organs, including the GT (Harada et al., 2015; Itoh & Ornitz, 2011; Ohuchi et al., 2000).

Empirical support: High. Fgfr2-IIIb-null mice exhibit severe urethral developmental defects, premature arrest of epithelial proliferation, and failed preputial morphogenesis; similar phenotypes occur when Fgf10 signaling is disrupted (Petiot et al., 2005; Revest et al., 2001; Gredler et al., 2015).

Quantitative understanding: Moderate. The genotype-phenotype relationship is strong, but a formal quantitative model linking signaling intensity to morphogenetic severity is not available.

KER 4: Preputial epithelial morphogenesis, disrupted → Male preputial separation, failed/delayed

Biological plausibility: High. PPS requires normal preputial epithelial fusion/canalization and subsequent separation; therefore, disruption of morphogenesis is a direct precursor to delayed or failed PPS (Gairdner, 1949; Sinclair et al., 2017; Yoshimura et al., 2004, 2005).

Empirical support: High. Developmental anti-androgen exposure and morphologic disruption of the preputial region are consistently associated with delayed or failed PPS in rats (Mylchreest et al., 1999; Welsh et al., 2008; Sinclair et al., 2017).

Quantitative understanding: Moderate. PPS timing is readily measured, but the exact quantitative mapping from specific epithelial lesions to day-of-separation shifts remains incompletely defined.

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Modulating Factor (MF)	Influence or Outcome	KER(s) involved	Quantitative Understanding
Developmental timing of exposure	Exposure during the masculinization programming window has the greatest impact on genital morphogenesis and PPS	3705, 3706, 3707, 3708	Moderate
Dose of AR antagonist	Higher antagonist doses produce greater suppression of AR-dependent transcription and downstream FGF signaling	3705, 3706	Moderate
Sex / androgen milieu	Male fetuses/juveniles are more susceptible to the adverse outcome because PPS is androgen-dependent	3705, 3706, 3707, 3708	Moderate
Genetic background / strain	Severity of genital malformations and PPS delay varies among rodent strains	3707, 3708	Low to moderate
General growth delay / body weight	Non-specific developmental delay can shift PPS timing and confound interpretation	3708	Moderate

The main modulating factors are developmental timing, sex-specific androgen milieu, antagonist dose, genetic background, and general growth delay. These factors are most relevant to the AR→FGF signaling and morphogenesis→PPS segments of the pathway, where they influence the magnitude and timing of the downstream phenotype (Mylchreest et al., 1999; Welsh et al., 2008; Sinclair et al., 2017).

Quantitative Understanding

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

Quantitative understanding is moderate for the early KERs and the AO, and lower for the integrated pathway as a whole. There is clear dose-dependent suppression of Fgfr2-IIIb and Fgf10 by flutamide in GT culture and a clear phenotypic association between developmental anti-androgen exposure and delayed PPS in rats, but a fully parameterized quantitative model linking AR antagonism to PPS timing is not yet available (Petiot et al., 2005; Mylchreest et al., 1999; Welsh et al., 2008). The pathway is therefore more suitable for screening and prioritization than for stand-alone quantitative risk prediction.

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

This AOP is well suited for regulatory screening, hazard prioritization, and weight-of-evidence evaluation of anti-androgenic chemicals. It can support grouping and read-across for substances with AR antagonism, assist in interpreting developmental toxicity studies, and help connect in vitro AR assays to in vivo male reproductive developmental outcomes. The pathway is also useful for identifying data gaps when a chemical perturbs AR signaling but has not yet been tested for GT or PPS endpoints. Application to human risk assessment should remain cautious because the strongest evidence derives from rodent systems and because human external genital development differs in timing and anatomy (Kim et al., 2002; Beleza-Meireles et al., 2007; Carmichael et al., 2013; Sharpe, 2020).

References

List of the literature that was cited for this AOP. More help

Beleza-Meireles, A., Lundberg, F., Lagerstedt, K., & others. (2007). FGFR2, FGF8, FGF10 and BMP7 as candidate genes for hypospadias. European Journal of Human Genetics, 15(4), 405–410. https://doi.org/10.1038/sj.ejhg.5201777

Carmichael, S. L., Ma, C., Choudhry, S., Lammer, E. J., Witte, J. S., & Shaw, G. M. (2013). Hypospadias and genes related to genital tubercle and early urethral development. Journal of Urology, 190(5), 1884–1892. https://doi.org/10.1016/j.juro.2013.05.061

Furutani, T., Watanabe, T., Tanimoto, K., Hashimoto, T., Koutoku, H., Kudoh, M., Shimizu, Y., Kato, S., & Shikama, H. (2002). Stabilization of androgen receptor protein is induced by agonist, not by antagonists. Biochemical and Biophysical Research Communications, 294, 779–784.

Gelmann, E. P. (2002). Molecular biology of the androgen receptor. Journal of Clinical Oncology, 20(13), 3001–3015. https://doi.org/10.1200/JCO.2002.10.018

Gredler, M. L., Seifert, A. W., & Cohn, M. J. (2015). Tissue-specific roles of Fgfr2 in development of the external genitalia. Development, 142(12), 2203–2212. https://doi.org/10.1242/dev.119891

Haid, B., Pechriggl, E., Nägele, F., et al. (2020). FGF8, FGF10 and FGF receptor 2 in foreskin of children with hypospadias: An analysis of immunohistochemical expression patterns and gene transcription. Journal of Pediatric Urology, 16(1), 41.e1–41.e10. https://doi.org/10.1016/j.jpurol.2019.10.007

Harada, M., Omori, A., Nakahara, C., Nakagata, N., Akita, K., & Yamada, G. (2015). Tissue-specific roles of FGF signaling in external genitalia development. Developmental Dynamics, 244(6), 759–773. https://doi.org/10.1002/dvdy.24277

Itoh, N., & Ornitz, D. M. (2011). Fibroblast growth factors: From molecular evolution to roles in development, metabolism and disease. Journal of Biochemistry, 149(2), 121–130.

Kim, K. S., Liu, W., Cunha, G. R., Russell, D. W., Huang, H., Shapiro, E., & Baskin, L. S. (2002). Expression of the androgen receptor and 5α-reductase type 2 in the developing human fetal penis and urethra. Cell and Tissue Research, 307(2), 145–153.

Mylchreest, E., Sar, M., Wallace, D. G., & Foster, P. M. D. (1999). Fetal testosterone insufficiency causes reproductive tract abnormalities in male rats. Toxicological Sciences, 52(1), 116–127.

Ohuchi, H., Hori, Y., Yamasaki, M., Harada, H., Sekine, K., Kato, S., & Itoh, N. (2000). FGF10 acts as a major ligand for FGF receptor 2 IIIb in mouse multi-organ development. Biochemical and Biophysical Research Communications, 277(3), 643–649. https://doi.org/10.1006/bbrc.2000.3721

Petiot, A., Perriton, C. L., Dickson, C., & Cohn, M. J. (2005). Development of the mammalian urethra is controlled by Fgfr2-IIIb. Development, 132(10), 2441–2450. https://doi.org/10.1242/dev.01778

Quigley, C. A., De Bellis, A., Marschke, K. B., el-Awady, M. K., Wilson, E. M., & French, F. S. (1995). Androgen receptor defects: Historical, clinical, and molecular perspectives. Endocrine Reviews, 16(3), 271–321. https://doi.org/10.1210/edrv-16-3-271

Revest, J. M., Spencer-Dene, B., Kerr, K., De Moerlooze, L., Rosewell, I., & Dickson, C. (2001). Fibroblast growth factor receptor 2-IIIb acts upstream of Shh and Fgf4 and is required for limb bud maintenance but not for the induction of Fgf8, Fgf10, Msx1, or Bmp4. Developmental Biology, 231(1), 47–62. https://doi.org/10.1006/dbio.2000.0144

Seifert, A. W., Harfe, B. D., & Cohn, M. J. (2008). Cell lineage analysis demonstrates an endodermal origin of the distal urethra and perineum. Developmental Biology, 318(1), 143–152. https://doi.org/10.1016/j.ydbio.2008.03.017

Sharpe, R. M. (2020). Androgens and the masculinization programming window: Human-rodent differences. Biochemical Society Transactions, 48(4), 1725–1735. https://doi.org/10.1042/BST20200200

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

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. The Journal of Clinical Investigation, 118(4), 1479–1490. https://doi.org/10.1172/JCI34241