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Effects of 5α-reductase inhibition by dutasteride on reproductive gene expression and hormonal responses in zebrafish embryos

Steroid 5α-reductase (SRD5A) is a crucial enzyme involved in steroid metabolism, primarily converting testosterone to dihydrotestosterone (DHT). Dutasteride, an inhibitor of SRD5A types 1 and 2, is widely used for treating benign prostatic hyperplasia. An adverse outcome pathway (AOP) has been docum...

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Main Authors: Cho, HyunKi (Author) , Jun, Indong (Author) , Adnan, Karim Md (Author) , Park, Chang Gyun (Author) , Lee, Sang-Ah (Author) , Yoon, Juyong (Author) , Ryu, Chang Seon (Author) , Kim, Young Jun (Author)
Format: Article (Journal)
Language:English
Published: January 2025
In: Comparative biochemistry and physiology. Part C, Toxicology & pharmacology
Year: 2025, Volume: 287, Pages: 1-124
ISSN:1878-1659
DOI:10.1016/j.cbpc.2024.110048
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.cbpc.2024.110048
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S1532045624002163
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Author Notes:Hyunki Cho, Indong Jun, Karim Md Adnan, Chang Gyun Park, Sang-Ah Lee, Juyong Yoon, Chang Seon Ryu, Young Jun Kim
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Summary:Steroid 5α-reductase (SRD5A) is a crucial enzyme involved in steroid metabolism, primarily converting testosterone to dihydrotestosterone (DHT). Dutasteride, an inhibitor of SRD5A types 1 and 2, is widely used for treating benign prostatic hyperplasia. An adverse outcome pathway (AOP) has been documented wherein SRD5A inhibition decreases DHT synthesis, leading to reduced levels of 17β-estradiol (E2) and vitellogenin (VTG), subsequently impairing fecundity in fish (AOP 289). However, the molecular and cellular mechanisms underlying these effects remain poorly understood. In this study, we assessed the impact of SRD5A inhibition on zebrafish embryos (Danio rerio). Exposure to dutasteride resulted in decreased DHT, E2, and VTG levels, showing a positive correlation. Dutasteride also downregulated the expression of reproduction-related genes (srd5a2, cyp19a1, esr1, esr2a, esr2b, and vtg), with interrelated reductions observed across these levels. Docking studies suggested that dutasteride's effects may operate independently of androgen receptor (AR) and estrogen receptor (ER) interactions. Furthermore, co-exposure of dutasteride (0.5 or 2 μM) with 0.5 μM DHT revealed gene expression levels comparable to the control group. These findings underscore DHT's pivotal role in modulating estrogenic function and the interplay between estrogenic and androgenic responses in vertebrates. Our proposed AOP model offers insights into mechanistic gaps, thereby enhancing current understanding and bridging knowledge disparities.
Item Description:Online verfügbar: 21. September 2024, Dokumentversion: 26. September 2024
Gesehen am 29.04.2025
Physical Description:Online Resource
ISSN:1878-1659
DOI:10.1016/j.cbpc.2024.110048

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