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. 2022 Mar 18:3:100069.
doi: 10.1016/j.crtox.2022.100069. eCollection 2022.

AOP Key Event Relationship report: Linking decreased retinoic acid levels with disrupted meiosis in developing oocytes

Monica Kam Draskau  1 , Anne-Sofie Ravn Ballegaard  1 , Louise Ramhøj  1 , Josephine Bowles  2 , Terje Svingen  1 , Cassy M Spiller  2
Affiliations

AOP Key Event Relationship report: Linking decreased retinoic acid levels with disrupted meiosis in developing oocytes

Monica Kam Draskau et al. Curr Res Toxicol. .

Abstract

The Adverse Outcome Pathway (AOP) concept is an emerging tool in regulatory toxicology that uses simplified descriptions to show cause-effect relationships between stressors and toxicity outcomes in intact organisms. The AOP structure is a modular framework, with Key Event Relationships (KERs) representing the unit of causal relationship based on existing knowledge, describing the connection between two Key Events. Because KERs are the only unit to support inference it has been argued recently that KERs should be recognized as the core building blocks of knowledge assembly within the AOP-Knowledge Base. Herein, we present a first case to support this proposal and provide a full description of a KER linking decreased all-trans retinoic acid (atRA) levels in developing ovaries with disrupted meiotic entry of oogonia. We outline the evidence to support a role for atRA in inducing meiosis in oogonia across mammals; this is important because elements of the RA synthesis/degradation pathway are recognized targets for numerous environmental chemicals. The KER we describe will be used to support an intended AOP linking inhibition of the atRA producing ALDH1A enzymes with reduced fertility in women.

Keywords: Adverse Outcome Pathway; Germ cells; Infertility; Key event relationship; Meiosis; Ovary; Retinoic acid.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

None
Graphical abstract
Fig. 1
Fig. 1
Graphical representation of AOP 398. The AOP proposes a causal link between inhibition of ALDH1A action during ovary development and impaired fertility in females at reproductive age. A key step is a decrease in all-trans retinoic acid (atRA) in the fetal ovaries at the time when germ cells (oocytes) normally enter meiosis. As atRA is a key meiosis-inducing factor, decreased levels of atRA prevents or impairs a critical step in oocyte development (meiosis onset); subsequently this negatively affects oocyte development, the size of the oocyte pool (ovarian reserve) and ultimately, female fertility. Key Event Relationship (KER) 2477 describes the biologically-plausible link between decreased atRA in fetal ovaries and disrupted meiotic onset in oocytes.
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