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Aop: 289

AOP Title

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Inhibition of 5α-reductase leading to impaired fertility in female fish

Short name:

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5α-reductase,female fish

Graphical Representation

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Click to download graphical representation template

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Authors

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Chang Seon Ryu, KIST Europe, Germany

Baeckkyoung Sung, KIST Europe, Germany

Seungyun Baik, KIST Europe, Germany 

Young Jun Kim, KIST Europe. Germany

Point of Contact

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Young Jun Kim   (email point of contact)

Contributors

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  • Young Jun Kim

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite


This AOP was last modified on April 22, 2019 13:35

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Revision dates for related pages

Page Revision Date/Time
5α-reductase, inhibition April 18, 2019 19:48
Decrease, dihydrotestosterone (DHT) level April 10, 2019 05:22
Reduction, Plasma 17beta-estradiol concentrations September 26, 2017 11:30
Reduction, Plasma vitellogenin concentrations September 16, 2017 10:14
Reduction, Cumulative fecundity and spawning March 20, 2017 17:52
5α-reductase, inhibition leads to Decrease, DHT level April 18, 2019 19:54
Decrease, DHT level leads to Reduction, Plasma 17beta-estradiol concentrations April 18, 2019 19:55
Reduction, Plasma 17beta-estradiol concentrations leads to Reduction, Plasma vitellogenin concentrations October 18, 2018 11:02
Reduction, Plasma vitellogenin concentrations leads to Reduction, Cumulative fecundity and spawning September 18, 2018 20:55
finasteride, dutasteride, epristeride April 18, 2019 19:56

Abstract

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This AOP is designed to detect changes in cumulative fecundity and spawning resulted from the inhibition of 5α-reductases by 5α-reductase inhibitors. 5α-reductase catalyzes a 3-oxo-5α-steroid to a 3-oxo-Δ4-steroid.  Major reaction is the conversion of testosterone to 5α-dihydrotestosterone (DHT) which is a strong endogenous androgen receptor agonist.  Inhibition of 5α-reductase can be caused by chemical inhibitors such as finasteride, dutasteride, epristeride, and etc. 5α-reductase inhibition (KE 790), the MIE for this AOP, results in decreasing levels of DHT and possibly 3β-androstanediol (3β-diol, agonist of estrogen receptor β), metabolite of DHT, followed by increasing of the level of testosterone in female fish (L.Mariotta-Calsaluci et al., 2013 Aquatic Toxicol). Whereas inhibition of 5α-reductase leads to decrease in the level of 17β-estradiol (E2) (KE 219) in a female by the unknown mechanism, which corresponds to decreased egg production and spawning.

 


Background (optional)

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Summary of the AOP

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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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Sequence Type Event ID Title Short name
1 MIE 1617 5α-reductase, inhibition 5α-reductase, inhibition
2 KE 1613 Decrease, dihydrotestosterone (DHT) level Decrease, DHT level
3 KE 219 Reduction, Plasma 17beta-estradiol concentrations Reduction, Plasma 17beta-estradiol concentrations
4 KE 221 Reduction, Plasma vitellogenin concentrations Reduction, Plasma vitellogenin concentrations
5 AO 78 Reduction, Cumulative fecundity and spawning Reduction, Cumulative fecundity and spawning

Relationships Between Two Key Events
(Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
5α-reductase, inhibition leads to Decrease, DHT level adjacent High High
Decrease, DHT level leads to Reduction, Plasma 17beta-estradiol concentrations adjacent Low Low
Reduction, Plasma 17beta-estradiol concentrations leads to Reduction, Plasma vitellogenin concentrations adjacent High High
Reduction, Plasma vitellogenin concentrations leads to Reduction, Cumulative fecundity and spawning adjacent High High

Network View

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Stressors

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Name Evidence Term
finasteride, dutasteride, epristeride High

Life Stage Applicability

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Life stage Evidence
3 to < 6 months Moderate

Taxonomic Applicability

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Sex Applicability

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Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

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Evidence Assessment

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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This AOP is designed to detect changes in cumulative fecundity and spawning resulted from the inhibition of 5α-reductases by 5α-reductase inhibitors. Alteration of fecundity and spawning in fish is the critical endpoint for reproductive toxicity caused by endocrine disruption. This endpoint is essential and useful for screening of the potential endocrine disrupting chemicals and/or risk assessment for the possible contaminated sites by these chemicals. Therefore, this AOP can be applied to the prediction of reproductive toxicity caused by the inhibition of 5α-reductase .


References

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This AOP describes an adverse outcome that results from the inhibition of 5α-reductase (3-Oxo-5α-steroid 4-dehydrogenase) in female fish. 5α-reductase catalyzes a 3-oxo-5α-steroid to a 3-oxo-Δ4-steroid.  Major reaction is the conversion of testosterone to 5α-dihydrotestosterone (DHT) which is a strong endogenous androgen receptor agonist.  Inhibition of 5α-reductase can be caused by chemical inhibitors such as finasteride, dutasteride, epristeride, and etc. 5α-reductase inhibition (KE 790), the MIE for this AOP, results in decreasing levels of DHT and possibly 3β-androstanediol (3β-diol, agonist of estrogen receptor β), metabolite of DHT, followed by increasing of the level of testosterone in female fish (L.Mariotta-Calsaluci et al., 2013 Aquatic Toxicol). Whereas inhibition of 5α-reductase leads to decrease in the level of 17β-estradiol (E2) (KE 219) in a female by the unknown mechanism, which corresponds to decreased egg production and spawning. There have been a few studies on the evaluation of the inhibition of 5α-reductase in fish (L.Mariotta-Calsaluci et al., 2013 Aquatic Toxicol.;García-García et al. 2017  J Steroid Biochem Mol Biol) and these studies did not clarify the mechanism of the inhibition of 5α-reductase to decrease 17β-estradiol (E2) in female fish. Ornostay et al. (2016) reported DHT increased the level of E2 and steroidogenesis gene expression in fathead minnow ovary. The level of E2 is highly correlated with the synthesis of vitellogenin (VTG), having significant roles in reproduction. Reduced VTG (KE 221) in fish has been used as an endpoint for adverse effects on fertility and reproduction (Toxicol Sci, 2013. 132(2):284-297; Environ Toxicol Chem, 2016. 35(8): 2117-2224; Environ Toxicol, 2017. 32(7):1869-1877; Aquat Toxicol, 2018. 200:206-216). Additionally, possible KE is the inhibition of 5α-reductase affects the level of the other endogenous substrate steroids such as androstenedione, progesterone, cortisol, and aldosterone. The physiological responses of the reduction of these steroids and the inhibition of 5α-reductase are not fully understood (Azzouni et al. 2012). Furthermore, key event relationship (KER) to the levels of reduced aromatase (expression/activity) or reduced VTG by the inhibition of 5α-reductase was not well defined. Cumulative fertility is the major endpoint for the evaluation of reproductive toxicity caused by endocrine disruption with the exposure to endocrine disrupting chemicals (Ecotoxicol Environ Saf, 2018. 162:438-445; Environ Pollut, 2018. 240:403-411; J Appl Toxicol, 2018.38(4):544-551).