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Relationship: 3708

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Preputial epithelial morphogenesis, disrupted leads to Male PPS, failed/delayed

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Preputial epithelial morphogenesis, disrupted

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Male PPS, failed/delayed

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Androgen receptor antagonism leads to delayed preputial separation via reduced fibroblast growth factor in genital-tubercle tissues	adjacent	High	Low	Travis Karschnik (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
Rattus norvegicus	Rattus norvegicus	High	NCBI
Mus musculus	Mus musculus	High	NCBI
Homo sapiens	Homo sapiens	Moderate	NCBI
rodentia	rodentia	Moderate	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Male	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
Juvenile	High
3 to < 6 years	High
6 to < 11 years	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Preputial separation (PPS) is the postnatal detachment of the prepuce from the glans penis that enables foreskin retraction and is routinely scored as a pubertal endpoint in rats (U.S. EPA, 2011). Proper PPS depends on androgen‑regulated preputial epithelial morphogenesis, specifically, terminal keratinocyte differentiation and cornification of the preputial lamina, and formation of a cleavage plane that canalizes the lamina into two epithelial surfaces (inner preputial lining and glans epithelium) (Yoshimura et al., 2004; Yoshimura et al., 2005; Mahawong et al., 2014; Cunha et al., 2021). The upstream KE (preputial epithelial morphogenesis, disrupted) encompasses failures in keratinocyte differentiation/cornification and cleavage/canalization; in mice, reduced expression of cornification markers such as keratin 10 and loricrin is observed when canalization is abnormal and penile–preputial tethers persist (Cunha et al., 2021; Mahawong et al., 2014). The downstream KE is failed or delayed PPS, operationalized in rats as a postponement of the age at complete separation or persistence of epithelial attachments (U.S. EPA, 2011; Monosson et al., 1999; Blystone et al., 2009).

Mechanistically, insufficient androgen receptor signaling or impaired 5α‑reductase–dependent androgen activation during the period of preputial morphogenesis reduces epithelial cornification and canalization, compromising the formation of the physical cleavage plane required for timely separation (Wilson, 1993; Clark et al., 1993; Kelce & Wilson, 1997). Prenatal/perinatal disruptions that alter glans/prepuce epithelial patterning (e.g., ventral clefting/hypospadias) can preclude complete separation later in development, resulting in permanent failure of PPS (Yoshimura et al., 2004; Yoshimura et al., 2005). Thus, disruption of preputial epithelial morphogenesis causally leads to delayed or failed PPS through loss of the cornified, canalized lamina that is prerequisite for separation (Yoshimura et al., 2004; Yoshimura et al., 2005; Mahawong et al., 2014; Cunha et al., 2021; U.S. EPA, 2011).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence for this KER 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 KER page. All citations generated through this process were subsequently reviewed and verified by the KER author against primary sources and DOI resolution checks, prior to inclusion. Users of this KER 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 to AOP619.

A review of primary experimental literature using the following databases and search strategies was employed:

PubMed and Google Scholar using the following terms and combinations: "preputial separation," "preputial lamina," "balano-preputial separation," "cornification prepuce," "androgen receptor penile development," "preputial morphogenesis," "flutamide preputial separation rat," "vinclozolin preputial separation," "preputial separation puberty male rat," "keratin 10 loricrin preputial lamina."

Searches were conducted in June 2026 with no formal date restriction. The OECD TG 443 and associated guidance documents were consulted for regulatory context. Study screening prioritized original experimental studies in rodents (rat and mouse) with defined endpoint measurements of PPS timing or histopathological characterization of the preputial lamina. Reviews were used to contextualize findings but claims are traced to primary data.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

Structure and timing

The preputial lamina is a stratified ectodermal epithelial sheet linking the glans to the prepuce at birth. Around puberty, terminal differentiation/cornification and formation of a cleavage plane canalize this lamina into two epithelial surfaces (inner preputial lining and glans/penile surface), creating the preputial space and enabling detachment/retraction. In rats, histology shows progressive postnatal cornification from tip-to-base and dorsal-to-ventral across the glans; once cornification reaches the base, the double-layered epithelium separates and sexual maturity is achieved (Yoshimura et al., 2004). In mice, the external preputial lamina canalizes at about PND 25–30 (CD‑1; slightly later in C57BL/6) through an androgen-regulated cornification program, and abnormal canalization yields persistent penile–preputial tethers (Mahawong et al., 2014; Cunha et al., 2021).

Mechanistic chain

Reduced AR signaling (e.g., AR antagonism or reduced DHT from 5α‑reductase inhibition) diminishes epithelial cornification and compromises cleavage-plane formation/canalization, leaving the prepuce–glans adhesion intact; PPS is thereby delayed until morphogenesis proceeds or fails if prenatal/perinatal malformations remove the epithelial substrate needed for separation (Clark et al., 1993; Yoshimura et al., 2004). In rats exposed in utero to antiandrogens, ventral defects (e.g., cleft phallus/hypospadias) are associated with lack of a ventral epithelial layer; separation proceeds dorsally, but ventral separation fails and the day of PPS cannot be determined (Yoshimura et al., 2004).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Species/Model	Perturbation	Upstream KE: disrupted preputial epithelial morphogenesis	Downstream KE: PPS failed/delayed	Notes/Citations
Rat (Sprague–Dawley)	Prenatal flutamide GD14–17 or GD18–21	Ventral epithelial deficit/cleft phallus; lack of ventral epithelial layer; cornification proceeds dorsally but ventrally absent epithelium prevents cleavage/canalization	Complete separation not observed; day of puberty undetermined in affected males (ventral part does not separate)	Histology shows cornification from tip to base and dorsal to ventral in controls; prenatal antiandrogen creates ventral epithelial absence so PPS cannot complete (Yoshimura et al., 2004)
Rat (Sprague–Dawley)	Prenatal flutamide or vinclozolin; postnatal flutamide/vinclozolin/estrogens	Structural malformations (cleft phallus; hypoplastic prepuce) after prenatal antiandrogen; neonatal estrogens perturb epithelial development	Prenatal antiandrogen: complete separation does not occur, so PPS cannot be assigned; postnatal antiandrogen/estrogen: significant PPS delay; some neonatal estrogen groups show incomplete PPS at PND 56	Integrates developmental histology and PPS outcomes: prenatal malformations preclude PPS; postnatal exposures delay PPS without gross malformation (Yoshimura et al., 2005)
Mouse (CD‑1; AR pathway genetics)	AR pathway manipulation (AR‑C vs AR‑C/NC vs AR‑NC)	Canalization requires cornification; AR‑C sufficient; AR‑C/NC males show reduced keratin‑10 and absent loricrin in penile epithelium; partial canalization; persistent epithelial tethers	Functional failure of separation evidenced by penile–preputial tethering; restricted penile extrusion	Direct upstream–downstream linkage in mice: abnormal canalization and reduced cornification markers associate with tethering that functionally prevents separation (Cunha et al., 2021)
Mouse (CD‑1, C57BL/6)	Neonatal diethylstilbestrol (DES)	Persistence of ventral gap in the preputial lamina (failure of ventral epithelial fusion/delamination) leading to persistent mesenchymal confluence between penis and prepuce	Ventral penile–preputial tether in adulthood (failure of separation ventrally)	Developmental description links ventral gap persistence to adult tethering; DES perturbs normal closure/canalization of the lamina (Mahawong et al., 2014)
Rat (Sprague–Dawley; mechanistic synthesis)	Prenatal flutamide	Impaired ventral epithelial–epithelial fusion of the external preputial lamina (U‑shaped lamina; broad stromal confluence)	Extensive ventral tethering of the penis in adulthood (functional failure of separation)	Developmental fusion defect described as the morphogenetic basis for tethering after prenatal antiandrogen exposure in rats (Sinclair et al., 2016).
Rat (Sprague–Dawley)	Finasteride (5α‑reductase inhibitor), GD15 to PD21; and window studies	Inference: delay in cornification of the balano‑preputial membrane proposed as basis for delayed separation; prenatal windows cause malformations (hypospadias, cleft prepuce)	Five‑day delay in PPS in non‑hypospadiac males at 3 mg/kg/day; prenatal GD16–17 window produces cleft prepuce/hypospadias that preclude PPS	Provides dose/time windows and explicitly links delayed PPS to delayed cornification as a prerequisite and shows permanent failure when prenatal morphogenesis is disrupted (Clark et al., 1993)

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Confounding by growth/weight

Body weight and general developmental delay can shift PPS timing independently of androgen-specific mechanisms; analyses that adjust for age–weight and concurrent evaluation of other androgen-dependent endpoints (e.g., accessory sex organ weights, AGD) are needed to strengthen causal inference (Melching‑Kollmuss et al., 2017; U.S. EPA, 2011).

Histology gaps

Many PPS delay studies do not co-measure preputial lamina histology or cornification markers. As a result, the upstream KE (disrupted epithelial morphogenesis) is often inferred from the downstream endpoint (age at PPS) rather than demonstrated directly in the same animals (U.S. EPA, 2011; Monosson et al., 1999; Blystone et al., 2009).

Failure versus delay

Prenatal organogenesis‑window exposures can yield permanent PPS failure due to structural epithelial deficits (e.g., ventral clefting/hypospadias), whereas peripubertal exposures more commonly cause delay without gross malformation (Yoshimura et al., 2004; Yoshimura et al., 2005; Gray et al., 1994; McIntyre et al., 2001).

Quantitative threshold

The degree of impairment in upstream cornification/canalization required to produce a defined magnitude of PPS delay or permanent failure has not been quantified with histomorphometric or biomarker-based response–response data in rats; most mechanistic quantification to date is qualitative or based on mouse models (Yoshimura et al., 2004; Yoshimura et al., 2005; Mahawong et al., 2014; Cunha et al., 2021).

Species and strain differences

Anatomy and timing differ between rats and mice (e.g., mouse external preputial lamina canalizes ~PND 25–30 in CD‑1 and later in C57BL/6; rat PPS typically occurs later), and rodent PPS is not directly comparable to gradual human foreskin retractability. Translation is plausible based on shared epithelial remodeling but is not isomorphic across species (Mahawong et al., 2014; Yoshimura et al., 2005; Gairdner, 1949; Oster, 1968).

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Modulating Factor (MF)	MF Specification	Effect(s) on the KER	Reference(s)
Gestational vs. postnatal timing of exposure	Sensitivity is greatest during the organogenesis/programming window; peripubertal exposures primarily affect maturation of existing structures.	Gestational antiandrogen exposure produces structural deficits (e.g., ventral clefting/hypospadias) that preclude complete separation (permanent failure), whereas peripubertal antiandrogen exposure more commonly causes a delay without gross malformation.	(Gray et al., 1994; McIntyre et al., 2001; Yoshimura et al., 2004; Yoshimura et al., 2005; Wolf et al., 2000)
Growth and nutritional/metabolic status	Body weight and general growth retardation can shift PPS timing independently of androgen-specific mechanisms; guidance recommends age–weight analyses with concurrent androgen-dependent organ endpoints.	May delay PPS through nonspecific developmental slowing; interpretation of PPS delays should adjust for body weight/growth to distinguish endocrine-specific effects.	(U.S. EPA, 2011; Melching‑Kollmuss et al., 2017)
Estrogen/androgen receptor signaling balance	In mice, the AR–ER balance modulates epithelial canalization of the external preputial lamina; aromatase/ERα perturbations alter delamination timing. Direct rat PPS data are limited.	Estrogenic signaling can shift the timing/extent of canalization (upstream KE), thereby modulating risk of delayed/failed PPS; species differences apply.	(Cunha et al., 2021; Cripps et al., 2019; Blaschko et al., 2013)
Genetic background (strain)	Baseline timing of preputial canalization/PPS varies by strain (e.g., CD‑1 vs. C57BL/6 in mice), and guideline materials note variability.	Shifts the sensitive window for detecting PPS delay/failure and may influence magnitude of effects.	(Mahawong et al., 2014; U.S. EPA, 2011)

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Although dose and mixture based relationships robustly quantify changes in the downstream KE (age at PPS), there is currently no validated histomorphometric model in rats that maps the magnitude of upstream epithelial changes (e.g., keratin 10/loricrin expression or canalization indices) to the number of days of PPS delay. Simlalry, mechanistic mouse studies link reduced cornification markers and partial canalization to persistent penile–preputial tethers, but these have not yet been translated into quantitative predictors of PPS timing in rats (Mahawong et al., 2014; Cunha et al., 2021).

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Normal timing (rat)

In regulatory assays, PPS is scored daily starting around PND 30, with complete separation typically occurring during the PND 40–50 window depending on strain and laboratory conditions (U.S. EPA, 2011). Upstream epithelial cornification in rats spreads across the glans postnatally before PPS, progressing from tip to base and dorsal to ventral during approximately PND 22–42 (Yoshimura et al., 2004). Normal timing (mouse)

Canalization of the external preputial lamina occurs around PND 25–30 in CD‑1 males (slightly later in C57BL/6); disruption manifests as persistent penile–preputial tethers (Mahawong et al., 2014; Cunha et al., 2021). Developmental logic

The downstream KE (PPS) lags the upstream epithelial events by design: laminar cornification and cleavage/canalization must proceed to completion to form the preputial space before separation can occur (Yoshimura et al., 2004; Mahawong et al., 2014).

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Taxonomic Applicability

In rats, the downstream KE (age at preputial separation, PPS) is a well-established, routinely measured pubertal endpoint in standardized regulatory assays, providing strong empirical support for applicability in this species (U.S. EPA, 2011). In mice, the upstream KE (preputial epithelial morphogenesis) is well supported by developmental histology and genetics showing androgen‑dependent cornification and canalization of the external preputial lamina around puberty; disruption yields persistent penile–preputial tethers and failed separation (Mahawong et al., 2014; Cunha et al., 2021). Extension to other prepuce‑bearing rodents is plausable as the key morphogenetic mechanism, epithelial cornification/desquamation leading to canalization of the preputial lamina and formation of the preputial space, is a conserved epithelial process across rodents with a prepuce. Although PPS as a toxicology endpoint is not scored in humans, the underlying biology is consistent, newborn boys have fused prepuce–glans epithelia that separate postnatally via desquamation/keratinization, with retractability increasing through childhood (Gairdner, 1949; Oster, 1968).

Sex Applicability

Preputial development is a male-specific process with no female analog in this context. The upstream KE (preputial epithelial morphogenesis leading to canalization of the male external preputial lamina) and downstream KE (PPS) are male‑specific developmental processes

Lifestage Applicability

The KER is most applicable during the peripubertal/juvenile window when preputial epithelial canalization and PPS normally occur and are measured. In rats, the OCSPP 890.1500 male pubertal assay scores PPS by daily examination beginning around PND 30, with age at complete PPS as the endpoint (U.S. EPA, 2011). In mice, canalization of the external preputial lamina occurs around puberty (e.g., CD‑1 ~PND 25–30; slightly later in C57BL/6), and disrupted epithelial morphogenesis at this time yields persistent penile–preputial tethers and failed separation (Mahawong et al., 2014; Cunha et al., 2021). Human prepuce–glans separation progresses postnatally through childhood via desquamation/keratinization, with retractability increasing from infancy into school age; therefore, this lifestage was reflected in the controlled vocabulary terms, “3 to < 6 years” and “6 to < 11 years” (Gairdner, 1949; Oster, 1968).

References

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

Blaschko, S. D., Mahawong, P., Ferretti, M., Cunha, T. J., Sinclair, A., Wang, H., Schlomer, B. J., Risbridger, G., Baskin, L. S., & Cunha, G. R. (2013). Analysis of the effect of estrogen/androgen perturbation on penile development in transgenic and diethylstilbestrol-treated mice. The Anatomical Record, 296(7), 1127–1141.

Blystone, C. R., Lambright, C. S., Cardon, M. C., Furr, J., Rider, C. V., Hartig, P. C., Wilson, V. S., & Gray, L. E., Jr. (2009). Cumulative and antagonistic effects of a mixture of the antiandrogens vinclozolin and iprodione in the pubertal male rat. Toxicological Sciences, 111(1), 179–188. https://doi.org/10.1093/toxsci/kfp137

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.

Cripps, S. M., Mattiske, D. M., Black, J., Risbridger, G., Govers, L., Phillips, T., & Pask, A. J. (2019). A loss of estrogen signaling in the aromatase‑deficient mouse penis results in mild hypospadias. Differentiation, 109, 42–52.

Cunha, G. R., Cao, M., Derpinghaus, A., Baskin, L. S., Cooke, P., & Walker, W. (2021). Cornification and classical versus nonclassical androgen receptor signaling in mouse penile/preputial development. Differentiation, 121, 1–12. https://doi.org/10.1016/j.diff.2021.08.002

Gairdner, D. (1949). The fate of the foreskin: A study of circumcision. British Medical Journal, 2(4642), 1433–1437. https://doi.org/10.1136/bmj.2.4642.1433

Gray, L. E., Jr., Ostby, J. S., & Kelce, W. R. (1994). Developmental effects of an environmental antiandrogen: The fungicide vinclozolin alters sex differentiation of the male rat. Toxicology and Applied Pharmacology, 129(1), 46–52.

Hughes, I. A., & Acerini, C. L. (2008). Factors controlling testis descent. European Journal of Endocrinology, 159(Suppl 1), S75–S82.

Kelce, W. R., & Wilson, E. M. (1997). Environmental antiandrogens: Developmental effects, molecular mechanisms, and clinical implications. Journal of Molecular Medicine, 75(3), 198–207. https://doi.org/10.1007/s001090050104

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.

Mahawong, P., Li, M., & Baskin, L. S. (2014). Canalization of the external preputial lamina during mouse penile development. Differentiation, 87(5), 181–190.

McIntyre, B. S., Barlow, N. J., & Foster, P. M. D. (2001). Androgen‑mediated development in male rat offspring exposed to flutamide in utero: Permanence and correlation of early postnatal changes in anogenital distance and nipple retention with malformations in androgen‑dependent tissues. Toxicological Sciences, 62(2), 236–249. https://doi.org/10.1093/toxsci/62.2.236

Melching‑Kollmuss, S., Fussell, K. C., Schneider, S., Buesen, R., Groeters, S., Strauss, V., & van Ravenzwaay, B. (2016). Comparing effect levels of regulatory studies with endpoints derived in targeted anti‑androgenic studies: Example prochloraz. Archives of Toxicology, 90(12), 3051–3073. https://doi.org/10.1007/s00204-016-1678-y

Monosson, E., Kelce, W. R., Lambright, C., Ostby, J., & Gray, L. E., Jr. (1999). Peripubertal exposure to the antiandrogenic fungicide, vinclozolin, delays puberty, inhibits the development of androgen‑dependent tissues, and alters androgen receptor function in the male rat. Toxicology and Industrial Health, 15(1–2), 65–79.

OECD. (2012). Test No. 443: Extended One‑Generation Reproductive Toxicity Study. OECD Guidelines for the Testing of Chemicals, Section 4. Paris: OECD Publishing.

Oster, J. (1968). Further fate of the foreskin: Incidence of preputial adhesions, phimosis, and smegma among Danish schoolboys. Archives of Disease in Childhood, 43(228), 200–203. https://doi.org/10.1136/adc.43.228.200

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

Schneider, S., Fussell, K. C., Melching‑Kollmuss, S., Buesen, R., Gröters, S., Strauss, V., Jiang, X., & van Ravenzwaay, B. (2017). Investigations on the dose–response relationship of combined exposure to low doses of three anti‑androgens in Wistar rats. Archives of Toxicology, 91(8), 3961–3989. https://doi.org/10.1007/s00204-017-2053-3

U.S. Environmental Protection Agency (U.S. EPA). (2011). OCSPP 890.1500: Pubertal development and thyroid function in intact juvenile/peripubertal male rats (Standard Evaluation Procedure). Endocrine Disruptor Screening Program, Office of Chemical Safety and Pollution Prevention.

Wilson, J. D., Griffin, J. E., & Russell, D. W. (1993). Steroid 5α‑reductase 2 deficiency. Endocrine Reviews, 14(5), 577–593. https://doi.org/10.1210/edrv-14-5-577

Wilson, V. S., Lambright, C., Furr, J., Ostby, J., Wood, C., Held, G., & Gray, L. E., Jr. (2004). Phthalate ester‑induced gubernacular lesions are associated with reduced Insl3 gene expression in the fetal rat testis. Toxicology Letters, 146(3), 207–215.

Wolf, C. J., LeBlanc, G. A., Ostby, J. S., & Gray, L. E., Jr. (2000). Characterization of the period of sensitivity of fetal male sexual development to vinclozolin. Toxicological Sciences, 55(1), 152–161. https://doi.org/10.1093/toxsci/55.1.152

Yoshimura, S., Yamaguchi, H., Konno, K., Ohsawa, N., Noguchi, S., & Chisaka, A. (2004). Hypospadias and incomplete preputial separation in male rats induced by prenatal exposure to an anti‑androgen, flutamide. Journal of Toxicologic Pathology, 17(2), 113–118.

Yoshimura, S., Yamaguchi, H., Konno, K., Ohsawa, N., Noguchi, S., & Chisaka, A. (2005). Observation of preputial separation is a useful tool for evaluating endocrine active chemicals. Journal of Toxicologic Pathology, 18(3), 141–157.