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Relationship: 2133


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

Antagonism, Androgen receptor leads to nipple retention, increased

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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 (AR) antagonism leading to nipple retention (NR) in male (mammalian) offspring non-adjacent Moderate Low Terje Svingen (send email) Under development: Not open for comment. Do not cite Under Development

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
rat Rattus norvegicus High NCBI
mouse Mus musculus High 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
Development 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

Several chemicals can antagonize the androgen receptor (AR) in vitro, resulting in decreased AR activation. Decreased AR activation can lead to incomplete reproductive development in males, which can be expressed in several ways. One endpoint affected is areola/nipple retention (NR), which in vivo studies have shown to be linked to suppressed AR activation. NR in rat and mouse toxicity studies is considered an adverse effect (i.e., an AO).

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

Strategi was described by Pedersen et al (2022): A semi-systematic literature search was conducted during March 2022 in the peer-reviewed databases PubMed and Web of Science, using the search terms “(Nipple) AND (retain* OR retention) AND (androgen)” as well as “(Androgen receptor OR AR) AND (active*) AND (nipple OR areolae) AND (retain* OR retention)”. These searches resulted in 138 papers in total. Upon removal of duplicates, papers were screened according to title, abstract and ultimately full text based on pre-defined inclusion criteria. In vivo studies were included if (i) the study was carried out in mice or rats, (ii) NR in males was investigated as an endpoint, (iii) AR antagonism was the suspected mechanism of action and (iv) anti-androgenic effects of single substance exposures (i.e., not studies on chemical mixtures) were investigated. In vitro studies were included if they contained mechanistic information on AR inhibition by chemical stressors.

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

The biological plausibility of a link between decreased AR activation and increased NR in male rats is high. The relationship is supported by numerous studies showing that several potent AR antagonists in vitro induce NR in vivo. However, in the literature review conducted for this KER, no studies in mice were found to fulfill the inclusion criteria. The present KER is hence exclusively a description of the situation in rats, although it is believed that the link also exists in mice.

The AR is activated through binding of either testosterone or dihydrotestosterone (DHT), the latter having the highest affinity for the AR. Upon binding, the AR translocates to the target cell nucleus where it acts as a transcription factor (Albert, 2018).

NT has been shown to be more dependent on DHT-signaling, which suggests that chemicals inducing increased NR also have a higher affinity for the AR than DHT in order to outcompete DHT for AR binding, although supra-high doses of chemicals with lower AR affinity could be speculated to also outcompete T or DHT. The general principle of higher affinity, however, has been confirmed by in vitro studies (Gray et al., 2019; Hass et al., 2012; McIntyre et al., 2000).

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

A major challenge with NR as a biomarker is the subjectivity of the measure. In juvenile rat pups, nipples are only present as areolae, i.e., dark shadows with or without a nipple bud. This means that the experience of the personnel assessing the presence and number of areolae/nipples can influence the results. Furthermore, the results are likely prone to larger variation if several assessors are used to record NR within the same study. To minimize these sources of uncertainty, assessors must be trained to recognize areolae and not look for fully developed nipples. Moreover, the number of assessors should be limited to one or two, and they should always be blinded to exposure groups.

Another factor that may affect NR results is the age of the rat pups at the time of assessment. OECD guidelines have standardized the time for measuring occurrence of NR to be optimal at PD 12 or 13, when they are visible in female littermates (OECD, 2013). However, assessment of permanent NR is not included in any international guidelines. Hence, if NR is measured in older offspring, the time of measurement is not consistent between studies and varies between PD 20 and PD 100. Thus, conclusions on whether NR is permanent or not may differ based on study design. This distinction between a transient and a permanent effect is important from a regulatory perspective, since only a permanent effect will be categorized as a malformation according to OECD guidance document 43 (OECD, 2008).

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

No response-response relationship has been identified.

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

NR manifest in juvenile male rat pup offspring in response to reduced androgen signaling, e.g. resulting from exposure to an anti-androgenic chemical stressor during fetal development. Developmental sensitivity during fetal development is highest during the so-called male masculinization programming window (MPW) which in rats is between gestational day (GD) 15 and 19 (Welsh et al., 2008).

A study in which pregnant rat dams were exposed to the AR antagonist vinclozolin for two-day periods during gestation showed that GD 16–17 was the most sensitive period for increased NR in male offspring (Wolf et al., 2000). A similar study using di-n-butyl phthalate (reduces testosterone levels) also showed that GD 16–17 was the most sensitive period for increased NR in male rats (Carruthers & Foster, 2005). However, to determine if other chemical stressors also have the highest antagonistic potential towards the AR during GD 16-17, further studies with a similar design would be informative.

NR can only be recorded when pups are old enough to display them, yet before excessive fur has developed. Hence, the most accurate results can be obtained from assessing the number of nipples on PD 12–14 depending on rat strain and the time of female littermates displaying nipples (OECD, 2013).

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

No feedback loops that could influence the KER have been identified.

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


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

Alapi, E. M., & Fischer, J. (2006). Table of Selected Analogue Classes. In Analogue-based Drug Discovery (pp. 441–552). Wiley-VCH Verlag GmbH & Co. KGaA.

Albert, O. (2018). Antiandrogens. In Encyclopedia of Reproduction (Vol. 1, pp. 594–601). Elsevier.

Barlow, N. J., McIntyre, B. S., & Foster, P. M. D. (2004). Male Reproductive Tract Lesions at 6, 12, and 18 Months of Age Following in Utero Exposure to Di(n-butyl) Phthalate. Toxicologic Pathology, 32(1), 79–90.

Bowman, C. J., Barlow, N. J., Turner, K. J., Wallace, D. G., & Foster, P. M. D. (2003). Effects of in utero exposure to finasteride on androgen-dependent reproductive development in the male rat. Toxicological Sciences, 74(2), 393–406.

Carruthers, C. M., & Foster, P. M. D. (2005). Critical window of male reproductive tract development in rats following gestational exposure to di-n-butyl phthalate. Birth Defects Research (Part B) Developmental and Reproductive Research, 74(3), 277–285.

Christiansen, S., Axelstad, M., Scholze, M., Johansson, H.K.L., Hass, U., Mandrup, K., Frandsen, H.L., Frederiksen, H., Isling, L.K., Boberg, J. (2020). Grouping of endocrine disrupting chemicals for mixture risk assessment – Evidence from a rat study. Environ Int, 142, 105870.

Christiansen, S., Boberg, J., Axelstad, M., Dalgaard, M., Vinggaard, A. M., Metzdorff, S. B., & Hass, U. (2010). Low-dose perinatal exposure to di(2-ethylhexyl) phthalate induces anti-androgenic effects in male rats. Reproductive Toxicology, 30(2), 313–321.

Christiansen, S., Scholze, M., Axelstad, M., Boberg, J., Kortenkamp, A., & Hass, U. (2008). Combined exposure to anti-androgens causes markedly increased frequencies of hypospadias in the rat. International Journal of Andrology, 31(2), 241–248.

Christiansen, S., Scholze, M., Dalgaard, M., Vinggaard, A., 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.

Clewell, R. A., Thomas, A., Willson, G., Creasy, D. M., & Andersen, M. E. (2013). A dose response study to assess effects after dietary administration of diisononyl phthalate (DINP) in gestation and lactation on male rat sexual development. Reproductive Toxicology, 35(1), 70–80.

Conley JM, Lambright CS, Evans N, Cardon M, Furr J, Wilson VS, Gray LE Jr (2018). Mixed "Antiandrogenic" Chemicals at Low Individual Doses Produce Reproductive Tract Malformations in the Male Rat. Toxicol Sci. 164(1), 166-178.


Conley JM, Lambright CS, Evans N, Cardon M, Medlock-Kakaley E, Wilson VS, Gray LE Jr. (2021). A mixture of 15 phthalates and pesticides below individual chemical no observed adverse effect levels (NOAELs) produces reproductive tract malformations in the male rat. Environ Int. 156, 106615.

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

Draskau, M. K., Ballegaard, A. S. R., Ramhøj, L., Bowles, J., Svingen, T., & Spiller, C. M. (2022). AOP Key Event Relationship report: Linking decreased retinoic acid levels with disrupted meiosis in developing oocytes. Current Research in Toxicology, 3(100069).

Draskau, M. K., Boberg, J., Taxvig, C., Pedersen, M., Frandsen, H. L., Christiansen, S., & Svingen, T. (2019). In vitro and in vivo endocrine disrupting effects of the azole fungicides triticonazole and flusilazole. Environmental Pollution, 255, 113309.

Foster, P. M. D., & Harris, M. W. (2005). Changes in androgen-mediated reproductive development in male rat offspring following exposure to a single oral dose of flutamide at different gestational ages. Toxicological Sciences, 85(2), 1024–1032.

Fussell, K. C., Schneider, S., Buesen, R., Groeters, S., Strauss, V., Melching-Kollmuss, S., & van Ravenzwaay, B. (2015). Investigations of putative reproductive toxicity of low-dose exposures to flutamide in Wistar rats. Archives of Toxicology, 89(12), 2385–2402.

Gray, L. E., Furr, J. R., Conley, J. M., Lambright, C. S., Evans, N., Cardon, M. C., Wilson, V. S., Foster, P. M., & Hartig, P. C. (2019). A Conflicted Tale of Two Novel AR Antagonists In Vitro and In Vivo: Pyrifluquinazon Versus Bisphenol C. Toxicological Sciences, 168(2), 632–643.

Gray, L. E., Ostby, J., Furr, J., Price, M., Veeramachaneni, D. N. R., & Parks, L. (2000). Perinatal Exposure to the Phtalates DEHP, BBP, and DINP, but Not DEP, DMP, or DOTP, Alters Sexual Differentiation of the Male Rat. Toxicological Sciences, 58, 350–365.

Hass, U., Boberg, J., Christiansen, S., Jacobsen, P. R., Vinggaard, A. M., Taxvig, C., Poulsen, M. E., Herrmann, S. S., Jensen, B. H., Petersen, A., Clemmensen, L. H., & Axelstad, M. (2012). Adverse effects on sexual development in rat offspring after low dose exposure to a mixture of endocrine disrupting pesticides. Reproductive Toxicology, 34(2), 261–274.

Hass, U., Scholze, M., Christiansen, S., Dalgaard, M., Vinggaard, A. M., Axelstad, M., Metzdorff, S. B., & Kortenkamp, A. (2007). Combined exposure to anti-androgens exacerbates disruption of sexual differentiation in the rat. Environmental Health Perspectives, 115(suppl 1), 122–128.

Heemers, H. v., & Tindall, D. J. (2007). Androgen Receptor (AR) Coregulators: A Diversity of Functions Converging on and Regulating the AR Transcriptional Complex. Endocrine Reviews, 28(7), 778–808.

Heinlein, C. A., & Chang, C. (2002). The Roles of Androgen Receptors and Androgen-Binding Proteins in Nongenomic Androgen Actions. Molecular Endocrinology, 16(10), 2181–2187.

Hellwig, J., van Ravenzwaay, B., Mayer, M., & Gembardt, C. (2000). Pre- and postnatal oral toxicity of vinclozolin in Wistar and Long-Evans rats. Regulatory Toxicology and Pharmacology, 32(1), 42–50.

Hotchkiss, A. K., Parks-Saldutti, L. G., Ostby, J. S., Lambright, C., Furr, J., Vandenbergh, J. G., & Gray, L. E. (2004). A mixture of the “antiandrogens” linuron and butyl benzyl phthalate alters sexual differentiation of the male rat in a cumulative fashion. Biology of Reproduction, 71(6), 1852–1861.

Howdeshell KL, Hotchkiss AK, Gray LE Jr (2017). Cumulative effects of antiandrogenic chemical mixtures and their relevance to human health risk assessment. Int J Hyg Environ Health. 220(2 Pt A), 179-188.

Huliganga, E., Marchetti, F., O’Brien, J. M., Chauhan, V., & Yauk, C. L. (2022). A Case Study on Integrating a New Key Event Into an Existing Adverse Outcome Pathway on Oxidative DNA Damage: Challenges and Approaches in a Data-Rich Area. Frontiers in Toxicology, 4(827328).

Imperato-McGinley, J., Binienda, Z., Gedney, J., & Vaughan, E. D. (1986). Nipple Differentiation in Fetal Male Rats Treated with an Inhibitor of the Enzyme 5α-Reductase: Definition of a Selective Role for Dihydrotestosterone. Endocrinology, 118(1), 132–137.

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Kjærstad, M. B., Taxvig, C., Nellemann, C., Vinggaard, A. M., & Andersen, H. R. (2010). Endocrine disrupting effects in vitro of conazole antifungals used as pesticides and pharmaceuticals. Reproductive Toxicology, 30(4), 573–582.

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McIntyre, B. S., Barlow, N. J., Wallace, D. G., Maness, S. C., Gaido, K. W., & Foster, P. M. D. (2000). Effects of in utero exposure to linuron on androgen-dependent reproductive development in the male Crl:CD(SD)BR rat. Toxicology and Applied Pharmacology, 167(2), 87–99.

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Panagiotou, E. M., Draskau, M. K., Li, T., Hirschberg, A., Svingen, T., & Damdimopoulou, P. (2022). AOP key event relationship report: Linking decreased androgen receptor activation with decreased granulosa cell proliferation of gonadotropin-independent follicles. Reproductive Toxicology, 112, 136-147.

Pedersen, E. B., Christiansen, S., & Svingen, T. (2022). AOP key event relationship report: Linking androgen receptor antagonism with nipple retention. Current Research in Toxicology, 3, 100085.   

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Saillenfait, A. M., Sabaté, J. P., & Gallissot, F. (2008). Diisobutyl phthalate impairs the androgen-dependent reproductive development of the male rat. Reproductive Toxicology, 26(2), 107–115.

Saillenfait, A. M., Sabaté, J. P., & Gallissot, F. (2009). Effects of in utero exposure to di-n-hexyl phthalate on the reproductive development of the male rat. Reproductive Toxicology, 28(4), 468–476.

Satoh, K., Ohyama, K., Aoki, N., Iida, M., & Nagai, F. (2004). Study on anti-androgenic effects of bisphenol a diglycidyl ether (BADGE), bisphenol F diglycidyl ether (BFDGE) and their derivatives using cells stably transfected with human androgen receptor, AR-EcoScreen. Food and Chemical Toxicology, 42(6), 983–993.

Schneider, S., Kaufmann, W., Strauss, V., & van Ravenzwaay, B. (2011). Vinclozolin: A feasibility and sensitivity study of the ILSI-HESI F1-extended one-generation rat reproduction protocol. Regulatory Toxicology and Pharmacology, 59(1), 91–100.

Schreiber, E., Garcia, T., González, N., Esplugas, R., Sharma, R. P., Torrente, M., Kumar, V., Bovee, T., Katsanou, E. S., Machera, K., Domingo, J. L., & Gómez, M. (2020). Maternal exposure to mixtures of dienestrol, linuron and flutamide. Part I: Feminization effects on male rat offspring. Food and Chemical Toxicology, 139(1), 1–13.

Schwartz, C. L., Christiansen, S., Hass, U., Ramhøj, L., Axelstad, M., Löbl, N. M., & Svingen, T. (2021). On the Use and Interpretation of Areola/Nipple Retention as a Biomarker for Anti-androgenic Effects in Rat Toxicity Studies. Frontiers in Toxicology, 3.

Schwartz, C. L., Christiansen, S., Vinggaard, A. M., Axelstad, M., Hass, U., & Svingen, T. (2019). Anogenital distance as a toxicological or clinical marker for fetal androgen action and risk for reproductive disorders. Archives of Toxicology, 93(2), 253–272.

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