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AOP: 576

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

5α-reductase inhibition leading to increased nipple retention (NR) in male (rodent) offspring

Short name

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

5α-reductase inhibition leading to nipple retention

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

Marie Holmer; National Food Institute, Technical University of Denmark, Lyngby, DK-2800, Denmark

Johanna Zilliacus; Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden

Anna Beronius; Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden

Sofie Christiansen; National Food Institute, Technical University of Denmark, Lyngby, DK-2800, Denmark

Eleni Bampari; National Food Institute, Technical University of Denmark, Lyngby, DK-2800, 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

Emilie Elmelund
Terje Svingen

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 03:26

Revision dates for related pages

Page	Revision Date/Time
Inhibition, 5α-reductase	February 04, 2026 09:16
Decrease, dihydrotestosterone (DHT) levels	August 13, 2025 09:04
Decrease, androgen receptor activation	February 04, 2026 16:01
Altered, Transcription of genes by the androgen receptor	April 05, 2024 09:28
Nipple retention (NR), increased	January 11, 2023 05:53
Inhibition, 5α-reductase leads to Decrease, DHT level	April 05, 2024 08:40
Decrease, AR activation leads to nipple retention, increased	September 18, 2025 03:29
Decrease, DHT level leads to Decrease, AR activation	April 05, 2024 08:48
Decrease, AR activation leads to Altered, Transcription of genes by the AR	April 05, 2024 08:50
Finasteride	November 29, 2016 18:42

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

This AOP links inhibition of 5α-reductase during fetal life with increased nipple/areola retention (NR) in male rodent offspring. NR, measured around 2 weeks postpartum, is a marker for disrupted masculinization of male rodents (primarily investigated in laboratory rats and mice) and is associated with general feminization of male offspring.

5α-reductase is an enzyme that converts testosterone to dihydrotestosterone (DHT). In normal male reproductive development, DHT activates the androgen receptor (AR) in many peripheral reproductive tissues to drive differentiation of the male phenotype, including regression of nipple anlagen in male rats and mice. While testosterone also acts directly at the AR, DHT is 5-10 times more potent and in tissues peripheral to the testes, conversion to DHT is necessary for proper masculinization (Amato et al., 2022; Davey & Grossmann, 2016).

This AOP delineates the evidence that inhibition of 5α-reductase reduces DHT levels and consequently AR activation, causing retention of nipples in male rodents. The AOP is supported by in vitro experiments upstream of AR activation and by in vivo studies downstream of AR activation. Downstream of a reduction in AR activation, the molecular mechanisms of NR are unclear, highlighting a knowledge gap in this AOP and potential for further development.

The confidence in each of the KERs comprising the AOP is judged as high, with both high biological plausibility and high confidence in empirical evidence. The mechanistic link between KE-286 (‘altered, transcription of genes by AR’) and AO 1786 (‘increase, nipple retention’) is not established, but given the high confidence in the KERs, the overall confidence in the AOP is judged as high.

The AOP supports the regulatory application of NR as a measure of endocrine disruption relevant for human health and the use of NR as an indicator of anti-androgenicity in environmentally relevant species. Even though NR cannot be directly translated to a human endpoint, the AOP is considered human relevant since NR is a clear readout of reduced androgen action and masculinization during development and is considered an ‘adverse outcome’ in OECD test guidelines (TG 443, TG 421, TG 422). The AOP also holds utility for informing on anti-androgenicity more generally, as this modality is highly relevant across mammalian species and vertebrates more broadly due to the conserved nature of the AR and its implication in sexual differentiation across species.

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 AR activation leading to increased NR in male offspring. The other AOPs in this network are AOP 344 (‘Androgen receptor antagonism leading to increased nipple retention in male (rodent) offspring’), and AOP 575 (‘Decreased testosterone synthesis leading to increased nipple retention in male (rodent) offspring’). The purpose of the AOP network is to organize the well-established evidence for anti-androgenic mechanisms-of-action leading to increased NR. It can be used in identification and assessment of endocrine disruptors and to inform predictive toxicology, identification of 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.

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 v2.7 was followed alongside pragmatic approaches (Svingen et al., 2021).

The adverse outcome, AO 1786: Increase, nipple retention, was originally developed in (Pedersen et al., 2022).

Upstream KEs and KERs were developed in Draskau et al., 2024 as part of an anti-androgenic network, using mainly key review publications since it was considered canonical knowledge. This included MIE 1617: Inhibition, 5α-reductase; KE 1613: Decrease, DHT levels; KE 1614: Decrease, AR activation and KE 286: Altered transcription of genes by the AR as well as the connecting KERs, KER 1880: Inhibition, 5α-reductase leads to decrease, DHT levels; KER 1935: Decrease, DHT levels leads to decrease, AR activation and KER 2124: Decrease, AR activation leads to altered, transcription of genes by AR (Draskau et al., 2024).

The non-adjacent KER3348 linking reduced AR activation with NR was developed using a systematic weight-of-evidence approach, following the methodology outlined in (Holmer et al., 2024). Publications were retrieved by literature searches in PubMed and Web of Science and extensive screening using pre-defined inclusion and exclusion criteria. Evaluation of methodological reliability of in vivo animal studies was performed using the Science in Risk Assessment and Policy (SciRAP) online tool. As there are currently no in vivo methods to measure AR activation in mammals, six chemicals with known anti-androgenic mechanisms-of-action were chosen for the empirical evidence for this KER.

The rationale for the inclusion of KEs and KERs in the upstream anti-androgenic network is detailed in (Draskau et al., 2024). The link between the upstream network, more specifically KE 286 (‘altered, transcription of genes by AR’), and AO1786 (‘increase, nipple retention’) 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 between the upstream anti-androgenic network and increased NR is captured by KER 3348.

Summary of the AOP

This section is for information that describes the overall AOP.The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)

An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help

Key Events (KE)

A measurable event within a specific biological level of organisation. More help

Adverse Outcomes (AO)

An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

Type	Event ID	Title	Short name

MIE

1617

Inhibition, 5α-reductase

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

1786

Nipple retention (NR), increased

nipple retention, increased

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Title	Adjacency	Evidence	Quantitative Understanding

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

Decrease, AR activation leads to nipple retention, increased

non-adjacent

High

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Name
Finasteride

Life Stage Applicability

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

Life stage	Evidence
Foetal	High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help

Term	Scientific Term	Evidence	Link
rat	Rattus norvegicus	High	NCBI
mouse	Mus musculus	Low	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

The upstream part of the AOP has a broad applicability domain, but KER 3348 (Decrease, AR activation, leads to increased nipple retention) is considered only directly applicable to male rodent (current evidence primarily from rats and mice) during fetal life, restricting the applicability of the AOP. NR is specific to animals with sexual dimorphism in the number of nipples, a feature most prominently investigated in laboratory rats and mice. It is, however, biologically plausible that the AOP is applicable to other rodent species. The process of retention of nipples by disruption of androgen programming happens in the fetal life stage, but the AO is detected postnatally. In the males of mice and rats, the nipple anlagen are programmed during fetal development by androgens to regress, leading to no visible nipples in males postnatally, while females exhibit nipples. This AOP only contains empirical evidence for the applicability to male rats, but the AOP is considered equally applicable to male mice, as these also normally exhibit nipple regression stimulated by androgens. Moreover, the AOP is relevant for other taxa, including humans, as NR in male rodents indicates a reduction in fetal masculinization. NR is therefore included as a mandatory endpoint in multiple OECD Test Guideline studies for developmental and reproductive toxicity and is considered applicable as an adverse outcome to set NOAELs and LOAELs of substances in human health risk assessments.

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, inconsistencies and contradictory evidence
MIE-1617 Inhibition, 5α-reductase HIGH: This MIE is usually measured in vitro, whereas the downstream events in the AOP are usually measured in vivo. Canonical knowledge of normal male reproductive development provides strong support for essentiality, along with 5α-reductase knockout models and models using exposure to 5α-reductase inhibitors.	Biological plausibility provides strong support for the essentiality of this event, as DHT, produced by 5α-reductase, is a ligand of the AR and a primary driver of normal regression of nipple anlagen in male fetuses (Imperato-McGinley et al., 1986). Indirect evidence of impact of inhibition of 5α-reductase (MIE-1617) in vitro on AR activity in vitro: • Finasteride, a specific inhibitor of 5α-reductase, can decrease proliferation of prostate cancer cells in vitro, a proxy read-out of AR activity (Bologna et al., 1995). Direct evidence of impact of inhibition of 5α-reductase (MIE-1617) in vivo on decreased DHT levels (KE-1613): • Lack of 5α-reductase type 2 activity by e.g. inhibitor or KO decrease DHT levels locally in tissues and blood. This is demonstrated in humans, rats, monkeys, and mice (Robitaille & Langlois, 2020). Indirect evidence of impact of inhibition of 5α-reductase (MIE-1617) in vivo on decreased DHT levels (KE-1613): • Men with androgenic alopecia treated with finasteride or dutasteride presented with decreased DHT levels in serum (Clark et al., 2004; Drake et al., 1999). Direct evidence of impact of inhibition of 5α-reductase (MIE-1617) in vivo on increased nipple retention (AO-1786): • Exposure to the 5α-reductase inhibitors leads to increased retention of nipples in male offspring after in utero exposure (Christiansen et al., 2009; Imperato-McGinley et al., 1986).
KE-1613 Decreased, DHT levels HIGH: Canonical knowledge of normal male reproductive development provides strong support for essentiality, along with rescue studies specifically demonstrating how DHT is essential for normal regression of nipple anlagen in male offspring.	Biological plausibility provides strong support for the essentiality of this event. Androgens are AR ligands and main drivers for the regression of nipple anlagen in male offspring (Goldman et al., 1976), with DHT playing an important role (Imperato-McGinley et al., 1986). Indirect evidence of impact of decreased DHT levels (KE-1613) on AR activity in vivo (KE-1614): • Androgen deprivation is used as treatment for prostate cancer, including 5α-reductase inhibitors, to reduce DHT levels and cancer growth (Aggarwal et al., 2010). Indirect evidence of impact of decreased DHT levels (KE-1613) on AR activity in vitro: • Increasing concentrations of DHT lead to increasing AR activation in vitro in AR reporter gene assays (OECD, 2023; Williams et al., 2017). Indirect evidence of impact of decreased DHT levels (KE-1613) on AR activity in vivo: • 5α-reductase 2 deficiency is an autosomal recessive condition in which 46,XY subjects with bilateral testes and normal testosterone production have impaired virilization during fetal life due to diminished DHT (Mendonca et al., 2016). Direct evidence of impact of decreased DHT levels (KE-1613) on increased nipple retention (AO-1786). • Nipple formation is inhibited in female rat fetuses exposed to DHT during gestation (Goldman et al., 1976). • Exposure to the 5α-reductase inhibitor 390 MSD leads to increased retention of nipples in male rats after in utero exposure, whereas simultaneous exposure to DHT reverses the effects (Imperato-McGinley et al., 1986).
KE-1614 Decreased, AR activation HIGH: There is experimental evidence from mutant mice insensitive to androgens showing that the AR is essential for nipple retention in male offspring. There is also evidence from exposure studies in animals that substances antagonizing AR induce nipple retention in male pups.	Biological plausibility provides strong support for the essentiality of this event, as AR activation is critical for normal regression of nipple anlagen in male embryos. Indirect evidence of the impact of decreased AR activation (KE-1614) on altered gene transcription by AR (KE-286): • Exposure to known anti-androgenic chemicals induces a changed gene expression pattern, e.g. in neonatal pig ovaries (Knapczyk-Stwora et al., 2019). Direct evidence of the impact of decreased AR activation (KE-1614) on altered gene transcription by AR (KE-286): • Male AR KO mice have altered gene expression pattern in a broad range of organs (see KER-2124). Indirect evidence of impact of decreased AR activation (KE-1614) on increased nipple retention (AO-1786): • Rat in vivo exposure to vinclozolin, procymidone and flutamide, which are known AR antagonists, leads to increased nipple retention in offspring (see KER-3348). Direct evidence of impact of decreased AR activation (KE-1614) on increased nipple retention (AO-1786): • Male Tfm mutant mice, which are insensitive to androgens and believed to be so due to a nonfunctional androgen receptor, present with retained nipples (Kratochwil & Schwartz, 1976)
KE-286 Altered, trans. of genes by AR LOW: Strongest support for essentiality comes from biological plausibility. However, exact transcriptional effects and causality remain to be fully characterized.	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 regression of nipple anlagen in male fetuses.	There are currently no AR-responsive genes proved to be causally involved in nipple retention, and it is known that AR can also signal through non-genomic actions (Leung & Sadar, 2017).

Event	Direct evidence	Indirect evidence	Contradictory evidence	Overall essentiality assessment
MIE-1617	***	**		High
KE-1613	***	**		High
KE-1614	***	***		High
KE-286				Low (biological plausibility)

*Low level of evidence (some support for essentiality), ** Intermediate level of evidence (evidence for impact on one or more downstream KEs), ***High level of evidence (evidence for impact on AO).

Evidence Assessment

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

KER	Biological Plausibility	Empirical Evidence	Rationale
KER-1880 Inhibition, 5α-reductase leads to a decrease, DHT levels	High	High (canonical)	It is well established that 5α-reductase converts testosterone to DHT. In vitro, in vivo and human studies with 5α-reductase inhibitors have shown that the stressors dose-dependently decrease formation of DHT.
KER-1935 Decrease, DHT levels leads to a decrease, AR activation	High	High (canonical)	It is well established that DHT activates the AR. Direct evidence for this KER is not possible since KE 1614 can currently not be measured and is considered an in vivo effect. Indirect evidence using proxy read-outs of AR activation, either in vitro or in vivo, strongly supports the relationship.
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.
KER-3348 Decrease, AR activation leads to increase, nipple retention	High	High	It is well established that activation of AR drives regression of nipple anlagen in males. The empirical evidence includes numerous in vivo toxicity studies showing that decreased AR activation leads to increased NR in male offspring, with few inconsistencies. The empirical evidence combined with theoretical considerations provide some support for dose, temporal, and incidence concordance for the KER, although this evidence is weak and indirect.

Known Modulating Factors

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

Modulating factor (MF)	Influence or Outcome	KER(s) involved
Genotype	Extended CAG repeat length in AR is associated with reduced AR activity (Chamberlain et al., 1994; Tut et al., 1997). This MF could initiate the AOP at lower stressor doses.	KER-1935, KER-2124, KER-3348
Rat strain	Long-Evans Hooded rat is less sensitive to NR than the Sprague-Dawley rat (Wolf et al., 1999; You et al., 1998). Thus, the effects on AO at certain stressor doses may vary between strains	KER-3348

Quantitative Understanding

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

The quantitative understanding of the AOP is limited. A key difficulty lies in the challenge of extrapolating from in vitro to in vivo events since these cannot be captured within the same experimental framework. Specifically, MIE-1617 is evaluated in vitro, while both KE-1613 (decrease, DHT levels’), KE-1614 (decrease, AR activation’) and the AO (Increase, NR) are in vivo endpoints. It should be noted that KE-1614 pertains to AR activation in vivo - currently lacking viable methods for direct measurement.

For in vivo to in vivo KERs like KER-1935 (‘Decrease, DHT level leads to Decrease, AR activation’) and KER-2124 (‘Decrease, AR activation leads to Altered, Transcription of genes by the AR’), there is not enough data to define a quantitative relationship, and such a relationship will differ between biological systems (species, tissue, cell type, life stage etc).

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

The AOP supports the regulatory application of NR as a measure of endocrine disruption relevant for human health and the use of NR as an indicator of anti-androgenicity in mammals and other vertebrates in the environment. NR is a mandatory endpoint in multiple OECD test guidelines, including TG 443 (extended one-generation reproductive toxicity study) and TGs 421/422 (reproductive toxicity screening studies) (OECD 2025a; OECD 2025b; OECD 2025c). NR can contribute to establishing a No Observed Adverse Effect Level (NOAEL), as outlined in OECD guidance documents No. 43 and 151 (OECD 2008; OECD 2013). The ability to derive a NOAEL for increased NR in male rodent offspring, which can serve as a point of departure for determining human safety thresholds, underscores the regulatory significance of this AOP. The AOP also holds utility for informing on anti-androgenicity more generally, as this modality is highly relevant across mammalian species (Schwartz et al., 2021) and vertebrates more broadly due to the conserved nature of the AR and its implication in sexual differentiation across species (Ogino et al., 2023).

References

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

Aggarwal, S., Thareja, S., Verma, A., Bhardwaj, T. R., & Kumar, M. (2010). An overview on 5α-reductase inhibitors. Steroids, 75(2), 109–153. https://doi.org/10.1016/j.steroids.2009.10.005

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. https://doi.org/10.3389/fendo.2022.910964

Bologna, M., Muzi, P., Biordi, L., Festuccia, C., & Vicentini, C. (1995). Finasteride dose-dependently reduces the proliferation rate of the LnCap human prostatic cancer cell line in vitro. Urology, 45(2), 282–290. https://doi.org/10.1016/0090-4295(95)80019-0

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

Christiansen S, Scholze M, Dalgaard M, Vinggaard AM, Axelstad M, Kortenkamp A, & Hass U. (2009). Synergistic disruption of external male sex organ development by a mixture of four antiandrogens. Environmental Health Perspectives, 117(12), 1839–1846. https://doi.org/10.1289/ehp.0900689

Clark, R. V., Hermann, D. J., Cunningham, G. R., Wilson, T. H., Morrill, B. B., & Hobbs, S. (2004). Marked Suppression of Dihydrotestosterone in Men with Benign Prostatic Hyperplasia by Dutasteride, a Dual 5α-Reductase Inhibitor. The Journal of Clinical Endocrinology & Metabolism, 89(5), 2179–2184. https://doi.org/10.1210/jc.2003-030330

Davey, R. A., & Grossmann, M. (2016). Androgen Receptor Structure, Function and Biology: From Bench to Bedside. The Clinical Biochemist. Reviews, 36(4), 3–15.

Drake, L., Hordinsky, M., Fiedler, V., Swinehart, J., Unger, W. P., Cotterill, P. C., Thiboutot, D. M., Lowe, N., Jacobson, C., Whiting, D., Stieglitz, S., Kraus, S. J., Griffin, E. I., Weiss, D., Carrington, P., Gencheff, C., Cole, G. W., Pariser, D. M., Epstein, E. S., … Waldstreicher, J. (1999). The effects of finasteride on scalp skin and serum androgen levels in men with androgenetic alopecia. Journal of the American Academy of Dermatology, 41(4), 550–554.

Draskau, M. K., Rosenmai, A. K., Bouftas, N., Johansson, H. K. L., Panagiotou, E. M., Holmer, M. L., Elmelund, E., Zilliacus, J., Beronius, A., Damdimopoulou, P., van Duursen, M., & Svingen, T. (2024). AOP Report: An Upstream Network for Reduced Androgen Signaling Leading to Altered Gene Expression of Androgen Receptor–Responsive Genes in Target Tissues. Environmental Toxicology and Chemistry, 43(11), 2329–2337. https://doi.org/10.1002/etc.5972

Goldman AS, Shapiro B, & Neumann F. (1976). Role of testosterone and its metabolites in the differentiation of the mammary gland in rats. Endocrinology, 99(6), 1490–1495. https://doi.org/10.1210/endo-99-6-1490

Holmer ML, Zilliacus J, Draskau MK, Hlisníková H, Beronius A, Svingen T. Methodology for developing data-rich Key Event Relationships for Adverse Outcome Pathways exemplified by linking decreased androgen receptor activity with decreased anogenital distance. Reprod Toxicol. 2024 Sep;128:108662. doi: 10.1016/j.reprotox.2024.108662 . Epub 2024 Jul 8. PMID: 38986849.

Imperato-McGinley J, Binienda Z, Gedney J, & Vaughan ED Jr. (1986). Nipple differentiation in fetal male rats treated with an inhibitor of the enzyme 5 alpha-reductase: definition of a selective role for dihydrotestosterone. Endocrinology, 118(1), 132–137. https://doi.org/10.1210/endo-118-1-132

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