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Relationship: 2124
Title
Decrease, AR activation leads to Altered, Transcription of genes by the AR
Upstream event
Downstream event
Key Event Relationship Overview
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 | adjacent | Moderate | Moderate | Terje Svingen (send email) | Under development: Not open for comment. Do not cite | Under Development |
Androgen receptor (AR) antagonism leading to decreased fertility in females | adjacent | High | Moderate | Terje Svingen (send email) | Under development: Not open for comment. Do not cite | Under Development |
5α-reductase inhibition leading to short anogenital distance (AGD) in male (mammalian) offspring | adjacent | High | Terje Svingen (send email) | Under development: Not open for comment. Do not cite | Under Development | |
Androgen receptor (AR) antagonism leading to short anogenital distance (AGD) in male (mammalian) offspring | adjacent | Moderate | Terje Svingen (send email) | Under development: Not open for comment. Do not cite | Under Development | |
Decreased testosterone synthesis leading to short anogenital distance (AGD) in male (mammalian) offspring | adjacent | Moderate | Low | Terje Svingen (send email) | Under development: Not open for comment. Do not cite | Under Development |
Decreased testosterone synthesis leading to hypospadias in male (mammalian) offspring | adjacent | Terje Svingen (send email) | Under development: Not open for comment. Do not cite | |||
5α-reductase inhibition leading to hypospadias in male (mammalian) offspring | adjacent | Terje Svingen (send email) | Under development: Not open for comment. Do not cite | |||
5α-reductase inhibition leading to increased nipple retention (NR) in male (rodent) offspring | adjacent | Terje Svingen (send email) | Under development: Not open for comment. Do not cite |
Taxonomic Applicability
Term | Scientific Term | Evidence | Link |
---|---|---|---|
mammals | mammals | High | NCBI |
Sex Applicability
Sex | Evidence |
---|---|
Mixed | High |
Life Stage Applicability
Term | Evidence |
---|---|
During development and at adulthood | High |
Key Event Relationship Description
The androgen receptor (AR) is a ligand-dependent nuclear transcription factor that upon activation translocates to the nucleus, dimerizes, and binds androgen response elements (AREs) to modulate transcription of target genes (Lamont and Tindall, 2010, Roy et al. 2001). Decreased activation of the AR affects its transcription factor activity, therefore leading to altered AR-target gene expression. This KER refers to decreased AR activation and altered gene expression occurring in complex systems, such as in vivo and the specific effect on transcription of AR target genes will depend on species, life stage, tissue, cell type etc.
Evidence Collection Strategy
The KER is considered canonical knowledge and supporting literature was mainly sourced from key review articles from the open literature.
Evidence Supporting this KER
Biological Plausibility
The biological plausibility for this KER is considered high
The AR is a ligand-activated transcription factor part of the steroid hormone nuclear receptor family. Non-activated AR is found in the cytoplasm as a multiprotein complex with heat-shock proteins, immunophilins and, other chaperones (Roy et al. 2001). Upon activation through ligand binding, the AR dissociates from the protein complex, translocates to the nucleus and homodimerizes. Facilitated by co-regulators, AR can bind to DNA regions containing AREs and initiate transcription of target genes, that thus will be different in e.g. different tissues, life-stages, species etc.
Through mapping of AREs and ChIP sequencing studies, several AR target genes have been identified, mainly studied in prostate cells (Jin, Kim, and Yu 2013). Different co-regulators and ligands lead to altered expression of different sets of genes (Jin et al. 2013; Kanno et al. 2022). Alternative splicing of the AR can lead to different AR variants that also affects which genes are transcribed (Jin et al. 2013).
Apart from this canonical signaling pathway, the AR can suppress gene expression, indirectly regulate miRNA transcription, and have non-genomic effects by rapid activation of second messenger pathways in either presence or absence of a ligand (Jin et al. 2013).
Empirical Evidence
The empirical evidence for this KER is considered high
In humans, altered gene expression profiling in individuals with androgen insensitivity syndrome (AIS) can provide supporting empirical evidence (Holterhus et al. 2003; Peng et al. 2021). In rodent AR knockout (KO) models, gene expression profiling studies and gene-targeted approaches have provided information on differentially expressed genes in several organ systems including male and female reproductive, endocrine, muscular, cardiovascular and nervous systems (Denolet et al. 2006; Fan et al. 2005; Holterhus et al. 2003; Ikeda et al. 2005; Karlsson et al. 2016; MacLean et al. 2008; Rana et al. 2011; Russell et al. 2012; Shiina et al. 2006; Wang et al. 2006; Welsh et al. 2012; Willems et al. 2010; Yu et al. 2008, 2012; Zhang et al. 2006; Zhou et al. 2011).
Exposure to known antiandrogens has been shown to alter transcriptional profiles, for example of neonatal pig ovaries (Knapczyk-Stwora et al. 2019).
Dose concordance has also been observed for instance in zebrafish embryos; a dose of 50 µg/L of the AR antagonist flutamide resulted in 674 differentially expressed genes at 96 h post fertilization whereas 500 µg/L flutamide resulted in 2871 differentially expressed genes (Ayobahan et al., 2023).
Uncertainties and Inconsistencies
AR action has been reported to occur also without ligand binding. However, not much is known about the extent and biological implications of such non-canonical, ligand-independent AR activation (Bennesch and Picard 2015).
Known modulating factors
Modulating Factor (MF) | MF Specification | Effect(s) on the KER | Reference(s) |
---|---|---|---|
Age | AR expression in aging male rats | Tissue-specific alterations in AR activity with aging | (Supakar et al. 1993; Wu, Lin, and Gore 2009) |
Genotype | Number of CAG repeats in the first exon of AR | Decreased AR activation with increased number of CAGs |
(Tut et al. 1997; Chamberlain et al. 1994) |
Quantitative Understanding of the Linkage
Response-response Relationship
There is not enough data to define a quantitative relationship between AR activation and alteration of AR target gene transcription, and such a relationship will differ between biological systems (species, tissue, cell type, life stage etc).
Time-scale
AR and promoter interactions occur within 15 minutes of ligand binding, RNA polymerase II and coactivator recruitment are proposed to occur transiently with cycles of approximately 90 minutes in LNCaP cells (Kang et al. 2002). RNA polymerase II elongation rates in mammalian cells have been shown to range between 1.3 and 4.3 kb/min (Maiuri et al. 2011). Therefore, depending on the cell type and the half-life of the AR target gene transcripts, changes are to be expected within hours.
Known Feedforward/Feedback loops influencing this KER
AR has been hypothesized to auto-regulate its mRNA and protein levels (Mora and Mahesh 1999).
Domain of Applicability
This KER is applicable for both sexes, across developmental stages into adulthood, in numerous cells and tissues and across mammalian taxa. It is, however, acknowledged that this KER most likely has a much broader domain of applicability extending to non-mammalian vertebrates. AOP developers are encouraged to add additional relevant knowledge to expand on the applicability to also include other vertebrates.
References
Ayobahan, S. U., Alvincz, J., Reinwald, H., Strompen, J., Salinas, G., Schäfers, C., et al. (2023). Comprehensive identification of gene expression fingerprints and biomarkers of sexual endocrine disruption in zebrafish embryo. Ecotoxicol. Environ. Saf. 250, 114514. doi:10.1016/J.ECOENV.2023.114514.
Bennesch, Marcela A., and Didier Picard. 2015. “Minireview: Tipping the Balance: Ligand-Independent Activation of Steroid Receptors.” Molecular Endocrinology 29(3):349–63.
Chamberlain, Nancy L., Erika D. Driverand, and Roger L. Miesfeldi. 1994. The Length and Location of CAG Trinucleotide Repeats in the Androgen Receptor N-Terminal Domain Affect Transactivation Function. Vol. 22.
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