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

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.