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Aop: 348

AOP Title

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Inhibition of 11β-HSD leading to impaired spermatogenesis in fish

Short name:

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11βHSD inhibition, impaired spermatogenesis

Graphical Representation

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Authors

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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 Do not cite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 July 21, 2020 09:51

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Revision dates for related pages

Page Revision Date/Time
Inhibition of 11β-HSD July 13, 2020 09:23
Decreased, 11-ketotestosterone May 19, 2020 12:29
Impaired, Spermatogenesis May 19, 2020 12:25
Decrease, Fertility June 29, 2017 08:09
Inhibition of 11β-HSD leads to Decreased, 11KT July 13, 2020 09:31
Decreased, 11KT leads to Impaired, Spermatogenesis May 19, 2020 12:43
Impaired, Spermatogenesis leads to Decrease, Fertility July 13, 2020 09:32
N-(5-Hydroxytricyclo[3.3.1.13,7]dec-2-yl)-α,α-dimethyl-4-[5-(trifluoromethyl)-2-pyridinyl]-1-piperazineacetamide July 05, 2020 11:13
Carbenoxolone March 30, 2020 15:25
Glycyrrhizin July 13, 2020 10:41
PF915275 July 13, 2020 10:42

Abstract

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This AOP links inhibition of 11βHSD to reproductive toxicity in fish. This AOP describes impaired spermatogenesis that may result from the inhibition of 11βHSD. Chemical inhibition of 11βHSD, the molecular-initiating event (MIE), results in decreased 11-KT and cortisone synthesis. The reduction of 11-KT induces the cumulative cortisol by enzymatic conversion insufficiency of cortisone, which leads to decreased spermatogonial proliferation. Impaired fertility is a significant endpoint for evaluation of reproductive toxicity caused by endocrine disruption. It can be used as an endpoint for endocrine disruptor screening. Therefore, this AOP would be useful to identify chemicals with known potential to affect male fish fertility.

 


Background (optional)

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In fish spermatogenesis,11-KT is the main androgen in teleosts, where it has functions in spermatogenesis and their main action of 11-beta dehydrogenase(11βHSD Type 2)  is generally regarded as the induction of sperm maturation. it has also its role is to protect these tissues from an excess of cortisol. Stress conditions or inhibition of 11bHSD dehydrogenase activities result in a cortisol excess in the Leydig cells. A surplus of glucocorticoids causes delayed genomic repression of 11KT production through GR or a rapid nongenomic decrease in 11 KT production. The rapid depression has been hypothesized to occur via the putative plasma membrane corticosteroid receptor11βHSD2 is unidirectional with NAD+ as a cofactor. It is expressed not only in mineralocorticoid sensitive tissues such as testis.11βHSD has enzyme activities, metabolizing cortisol to cortisone, and 11 beta -hydroxytestosterone to 11-ketotestosterone (11-KT) which is the main androgen functions spermatogenesis. Especially, spermatogenesis can induce by 11-ketotestosterone(11-KT), a significant androgen in teleost. However, excess circulating cortisol, which is produced by 11β-hydroxylase and decline of 11KT by 11βHSD inhibition, leads to inhibition of the DNA replication in spermatogonial mitosis, gonadal function, and spermatogonial proliferation in male fish.


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
MIE 1799 Inhibition of 11β-HSD Inhibition of 11β-HSD
KE 1756 Decreased, 11-ketotestosterone Decreased, 11KT
KE 1758 Impaired, Spermatogenesis Impaired, Spermatogenesis
AO 330 Decrease, Fertility Decrease, Fertility

Relationships Between Two Key Events
(Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
Inhibition of 11β-HSD leads to Decreased, 11KT adjacent High Moderate
Decreased, 11KT leads to Impaired, Spermatogenesis adjacent High Moderate
Impaired, Spermatogenesis leads to Decrease, Fertility adjacent High Low

Network View

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Stressors

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Life Stage Applicability

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Life stage Evidence
Adult, reproductively mature Moderate

Taxonomic Applicability

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Term Scientific Term Evidence Link
fish fish High NCBI

Sex Applicability

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Sex Evidence
Male High

Overall Assessment of the AOP

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This AOP will start with reviews about inhibitors of 11βHSD2 as MIE. Stressors for inhibiton were found in table and 11βHSD1 inhibitors were also denoted in previous studies (Jana Vitku et al 2016) . We will further find KERs with Androgen antagonisms and their impact on male fish.

Inhibitors of 11bHSD2 Testing system IC50(μM)
(1E,4E)-1,5-Bis(3-methylthiophen-2-yl)penta-1,4-dien-3-one Human microsomes 19.58
Abietic acid HEK 293 cells 12
Zearalenone HEK 293 cells 107
Fusidic acid  HEK 293 cells 134
Euphane-3b,20-dihydroxy-24-ene HEK 293 cells  8.18
Kansuinone HEK 293 cells  2.63
Euphol HEK 293 cells  0.4
Kansenone HEK 293 cells  0.11
(24R)-Eupha-8,25-diene-3b,24-diol HEK 293 cells  1.69
(20R,23E)-Eupha-8,23-diene-3b,25-diol HEK 293 cells  0.67
Carbenoxolone CHO cells 0.02
Endosulfan HEK 293 cells 61
BPA HEK 293 cells 50
Disulfiram HEK 293 cells 0.13
Thiram HEK 293 cells 0.13
Diethyldithiocarbamate (DEDTC) HEK 293 cells 1.7
HEK 293 cells 6.3
Pyrrolidine dithiocarbamate (PDTC) HEK 293 cells 6.3
Maneb HEK 293 cells 0.75
Zineb HEK 293 cells 1.42
Diphenyltin HEK 293 cells 2.89
Human microsomes 3.3
HEK 293 cells  3.19
Triphenyltin HEK 293 cells  0.99
Human microsomes 16.5
HEK 293 cells 1.9
Tributyltin HEK 293 cells 1.52
HEK 293 cells 1.95
Dibutyltin HEK 293 cells 5.03
Human microsomes 8.9
4-t-Octylphenol HEK 293 cells 30
Human microsomes 20.3
4-Nonylphenol HEK 293 cells 79
4-n-Octylphenol Human microsomes 23.5
4-n-Nonylphenol Human microsomes 26.2
Dicyclohexyl phtalate Human microsomes 46.5
Rat microsomes 32.64
Dipropyl phthalate Rat microsomes 85.59
Di-n-butyl phthlate Rat microsomes 13.69
Mono(2-ethylhexyl)phthalate Rat microsomes 121.8
Mono(2-ethylhexyl)phthalate Human microsomes 110.8
Perfluorooctyl sulphonate Human microsomes 0.05
Rat microsomes 0.29
Perfluorooctanoic acid Human microsomes 24.41
Rat microsomes 3.8
Perfluorohexanesulfonate Human microsomes 18.97
Rat microsomes 62.87
2-Bis(p-hydroxyphenyl)-1,1,1-trichloroethane Human microsomes 55.57
Rat microsomes 12.96
Source: Journal of Steroid Biochemistry & Molecular Biology 2016 Jan;155(Pt B):207-16  

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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A decrease in 11keto levels leads afterward to adverse changes in spermatogenesis. Therefore, it seems that 11βHSD  could be a target for EDs and this could be one of the possible mechanisms of endocrine disruption in the testis that leads to impaired spermatogenesis.


References

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  1. Roles of 11β-Hydroxysteroid Dehydrogenase in Fish Spermatogenesis. Endocrinology 147(11):5139–5146
  2. Hormonal induction of all stages of spermatogenesis in vitro in the male Japanese eel (Anguilla japonica). Proc Natl Acad Sci USA 88:5774–5778
  3. 17α,20 β Dihydroxy-4-pregnen-3-one: plasma levels during sexual maturation and in vitro production by the testes of amago salmon (Oncorhynchus rhodurus) and rainbow trout (Salmo gairdneri). Gen Comp Endocrinol 51:106–11
  4. Steroid profiles during spawning in male common carp. Gen Comp Endocrinol 80:223–231
  5. 11 β-Hydroxysteroid dehydrogenase complementary deoxyribonucleic acid in rainbow trout: cloning, sites of expression, and seasonal changes in gonads. Endocrinology 144:2534–2545
  6. 11 β –Hydroxysteroid dehydrogenase is a predominant reductase in intact Leydig cells. J Endocrinol 159:233–238
  7. Large-scale transcriptome sequencing reveals novel expression patterns for key sex-related genes in a sex-changing fish.  Biology of Sex Differences 6:26
  8. Sex Steroids and Their Involvement in the Cortisol-Induced Inhibition of Pubertal Development in Male Common Carp, BIOLOGY OF REPRODUCTION 67, 465–472
  9. Natural sex change in fish Current Topics in Developmental Biology, Volume 134
  10. Absence of 11-keto reduction of cortisone and 11-ketotestosterone in the model organism zebrafish Journal of Endocrinology 232,323–335
  11. Endocrine disruptors and other inhibitors of 11b-hydroxysteroid dehydrogenase 1 and 2: Tissue-specific consequences of enzyme inhibition.Journal of Steroid Biochemistry & Molecular Biology 155(Pt B):207-16.