Investigation of a derived adverse outcome pathway (AOP) network for endocrine-mediated perturbations

Abstract

An adverse outcome pathway (AOP) is a compact representation of the available mechanistic information on observed adverse effects upon environmental exposure. Sharing of events across individual AOPs has led to the emergence of AOP networks. Since AOP networks are expected to be functional units of toxicity prediction, there is current interest in their development tailored to specific research question or regulatory problem. To this end, we have developed a detailed workflow to construct an endocrine-relevant AOP (ED-AOP) network based on the existing information available in AOP-Wiki. We propose a cumulative weight of evidence (WoE) score for each ED-AOP based on the WoE scores assigned to key event relationships (KERs) by AOP-Wiki, revealing gaps in AOP development. Connectivity analysis of the ED-AOP network comprising 48 AOPs reveals 7 connected components and 12 isolated AOPs. Subsequently, we apply standard network measures to perform an in-depth analysis of the two largest connected components of the ED-AOP network. Notably, the graph-theoretic analyses led to the identification of important events including points of convergence or divergence in the ED-AOP network. These findings can suggest potential adverse outcomes and facilitate the development of new endpoints or assays for chemical risk assessment. Detailed analysis of the largest component in the ED-AOP network gives insights on the systems-level perturbations caused by endocrine disruption, emergent paths, and stressor-event associations. In sum, the derived ED-AOP network can provide a broader view of the biological events disrupted by endocrine disruption, as well as facilitate better risk assessment of environmental chemicals.

Keywords: AOP network; Adverse outcome pathway (AOP); Endocrine disrupting chemicals (EDCs); Endocrine disruption; Graph theory; Risk assessment.