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Aop: 288

AOP Title

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Inhibition of 17α-hydrolase/C 10,20-lyase (Cyp17A1) activity leads to birth reproductive defects (cryptorchidism) in male (mammals)

Short name:

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Cyp17A1 inhibition leads to undescended testes in mammals

Graphical Representation

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Authors

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Bérénice Collet; Bart van der Burg

BioDetection Systems (Science Park 406,1098 XH Amsterdam - The Netherlands)

Corresponding author: berenice.collet@bds.nl; bart.van.der.burg@bds.nl

Point of Contact

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Bérénice COLLET   (email point of contact)

Contributors

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  • Bérénice COLLET
  • Bart van der Burg

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 Do not cite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 10, 2019 05:33

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Revision dates for related pages

Page Revision Date/Time
Inhibition, Cytochrome P450 enzyme (CYP17A1) activity April 10, 2019 05:13
Reduction, 17-OH-pregnenolone conversion in DHEA April 10, 2019 05:15
Reduction, 17-OH-progesterone conversion in androstenedione April 10, 2019 05:33
Decrease, testosterone synthesis/level April 10, 2019 05:20
Decrease, dihydrotestosterone (DHT) level April 10, 2019 05:22
Decrease, androgen receptors (AR) activation April 10, 2019 05:24
Impaired inguinoscrotal testicular descent phase April 10, 2019 05:25
Malformation, cryptorchidism - maldescended testis April 10, 2019 05:27
Inhibition of Cyp17A1 activity leads to Reduction, DHEA April 10, 2019 05:31
Inhibition of Cyp17A1 activity leads to Reduction, androstenedione April 10, 2019 05:35

Abstract

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This Adverse Outcome Pathway describes the linkage between a decrease in 7α-hydroxylase/C17,20-lyase (Cyp17a1) activity and a specific reproductive malformation in male newborns : impaired testicular descent also called cryptorchidism.

Cyp17a1 enzyme is known to mediate 17 alpha-hydroxylase and 17,20-lyase activities, the distinction between the two being functional and not genetic or structural. Mainly expressed in Leydig cells, this steroidogenic enzyme catalyzes the conversion of 17-OH-pregnenolone and 17-OH-progesterone to dehydroepiandrosterone (DHEA) and androstenediol, respectively. In that way, a decrease in Cyp17a1 activity would inevitably lead to a decline in both steroid precursors’ levels. As a result, this succession of key events will affect testosterone (T) and dihydrotestosterone (DHT) synthesis and circulating levels. A direct consequence to such a drop in major androgens levels would be a decline in androgen receptor activation, causing potential disturbances in development and maintenance of the male reproductive system such as cryptorchidism. To understand this AOP, it is important to notice that the second stage of the testicular descent process called “inguinoscrotal“ is an androgen-dependent event that can be dramatically affected by variations in androgenic activity.

The present AOP is linked to EU-ToxRisk Case Study 7: Read across evaluation of reproductive toxicity of conazoles. Conazoles are fungicide used in agriculture and as pharmaceuticals for treatment of human fungal diseases. They are known to act through inhibition of CYP51 which can be related to cross-reactivity with human enzymes involved in steroid metabolism, such as CYP17a1. In that respect, the proposed AOP and associated methods can be used as a basis to assess the effects of conazoles on steroidogenesis and reproductive development.


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 1609 Inhibition, Cytochrome P450 enzyme (CYP17A1) activity Inhibition of Cyp17A1 activity
2 KE 1610 Reduction, 17-OH-pregnenolone conversion in DHEA Reduction, DHEA
3 KE 1611 Reduction, 17-OH-progesterone conversion in androstenedione Reduction, androstenedione
4 KE 1612 Decrease, testosterone synthesis/level Decrease, testosterone level
5 KE 1613 Decrease, dihydrotestosterone (DHT) level Decrease, DHT level
6 KE 1614 Decrease, androgen receptors (AR) activation Decrease, AR activation
7 KE 1615 Impaired inguinoscrotal testicular descent phase Impaired inguinoscrotal phase
8 AO 1616 Malformation, cryptorchidism - maldescended testis Malformation, cryptorchidism

Relationships Between Two Key Events
(Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
Inhibition of Cyp17A1 activity leads to Reduction, DHEA adjacent High
Inhibition of Cyp17A1 activity leads to Reduction, androstenedione adjacent High

Network View

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Stressors

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Life Stage Applicability

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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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References

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