期刊
REPRODUCTIVE TOXICOLOGY
卷 112, 期 -, 页码 136-147出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.reprotox.2022.07.004
关键词
Adverse outcome pathway; Key event relationship; Androgen receptor; Ovary; Ovarian follicle; Folliculogenesis; Granulosa cell; Fertility
资金
- Swedish Chemicals Agency (KEMI)
- Swedish Research Council for Sustainable Development FORMAS [2018-02280, 2020-01621]
- EU [825100 [116]]
- ERIN [EU952516]
- Vinnova [2018-02280] Funding Source: Vinnova
- Swedish Research Council [2020-01621] Funding Source: Swedish Research Council
- Formas [2020-01621, 2018-02280] Funding Source: Formas
This article proposes a method for formally recognizing Key Event Relationships (KERs) as building blocks of Adverse Outcome Pathways (AOPs), and provides an independent KER example. The KER connects androgen receptor (AR) antagonism to reduced fertility in females. The article presents systematic retrieval of relevant supporting evidence, highlighting the importance of early-stage follicular development and providing both biological plausibility and empirical evidence.
We recently proposed to formally recognize Key Event Relationships (KERs) as building blocks of Adverse Outcome Pathways (AOPs) that can be independently developed and peer-reviewed. Here, we follow this approach and provide an independent KER from AOP345, which describes androgen receptor (AR) antagonism leading to decreased female fertility. This KER connects AR antagonism to reduced granulosa cell proliferation of gonadotropin-independent follicles (KER2273). We have developed both the KER and the two adjacent Key Events (KEs). A systematic approach was used to ensure that all relevant supporting evidence for KER2273 was retrieved. Supporting evidence for the KER highlights the importance of AR action during the early stages of follicular development. Both biological plausibility and empirical evidence are presented, with the latter also assessed for quality. We believe that tackling isolated KERs instead of whole AOPs will accelerate the AOP development. Faster AOP development will lead to the development of simple test methods that will aid screening of chemicals, endocrine disruptor identification, risk assessment, and subsequent regulation.
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