Capturing a Comprehensive Picture of Biological Events From Adverse Outcome Pathways in the Drug Exposome

Abstract

Background: The chemical part of the exposome, including drugs, may explain the increase of health effects with outcomes such as infertility, allergies, metabolic disorders, which cannot be only explained by the genetic changes. To better understand how drug exposure can impact human health, the concepts of adverse outcome pathways (AOPs) and AOP networks (AONs), which are representations of causally linked events at different biological levels leading to adverse health, could be used for drug safety assessment.Methods: To explore the action of drugs across multiple scales of the biological organization, we investigated the use of a network-based approach in the known AOP space. Considering the drugs and their associations to biological events, such as molecular initiating event and key event, a bipartite network was developed. This bipartite network was projected into a monopartite network capturing the event–event linkages. Nevertheless, such transformation of a bipartite network to a monopartite network had a huge risk of information loss. A way to solve this problem is to quantify the network reduction. We calculated two scoring systems, one measuring the uncertainty and a second one describing the loss of coverage on the developed event–event network to better investigate events from AOPs linked to drugs.Results: This AON analysis allowed us to identify biological events that are highly connected to drugs, such as events involving nuclear receptors (ER, AR, and PXR/SXR). Furthermore, we observed that the number of events involved in a linkage pattern with drugs is a key factor that influences information loss during monopartite network projection. Such scores have the potential to quantify the uncertainty of an event involved in an AON, and could be valuable for the weight of evidence assessment of AOPs. A case study related to infertility, more specifically to “decrease, male agenital distance” is presented.Conclusion: This study highlights that computational approaches based on network science may help to understand the complexity of drug health effects, with the aim to support drug safety assessment.

An integrative data-centric approach to derivation and characterization of an adverse outcome pathway network for cadmium-induced toxicity

“…Therefore, to assess inorganic cadmium-induced toxicity, it is imperative to construct an AOP network specific to cadmium and its inorganic compounds. Till date, AOP-Wiki has been leveraged to build over 32 different AOP networks for a variety of adverse outcomes such as reproductive disorders [30][31][32][33], neurologic disorders [34][35][36][37], endocrine disorders [25,[38][39][40][41][42][43], developmental disorders [30,40,44,45], hepatic disorders [25,46,47], pulmonary disorders [48][49][50], and others [26,27,[51][52][53][54][55][56][57][58]. Importantly, Chai et al [33] had integrated the data within Comparative Toxicogenomics Database (CTD) [59] and AOP-Wiki to construct an AOP network specific to arsenic-induced reproductive toxicity.…”

An integrative data-centric approach to derivation and characterization of an adverse outcome pathway network for cadmium-induced toxicity

“…Therefore, to assess inorganic cadmium-induced toxicity, it is imperative to construct an AOP network specific to cadmium and its inorganic compounds. Till date, AOP-Wiki has been leveraged to build over 32 different AOP networks for a variety of adverse outcomes such as reproductive disorders [30][31][32][33], neurologic disorders [34][35][36][37], endocrine disorders [25,[38][39][40][41][42][43], developmental disorders [30,40,44,45], hepatic disorders [25,46,47], pulmonary disorders [48][49][50], and others [26,27,[51][52][53][54][55][56][57][58]. Importantly, Chai et al [33] had integrated the data within Comparative Toxicogenomics Database (CTD) [59] and AOP-Wiki to construct an AOP network specific to arsenic-induced reproductive toxicity.…”