Associating diethylhexyl phthalate to gestational diabetes mellitus via adverse outcome pathways using a network-based approach

Gestational diabetes mellitus (GDM) is a common pregnancy complication that is harmful to both the woman and fetus. Several epidemiological studies have found that exposure to diethylhexyl phthalate (DEHP), an endocrine disruptor ubiquitous in the environment, may be associated with GDM. This study aims to investigate the mechanism between DEHP and GDM using the adverse outcome pathway (AOP) framework, which can integrate information from different sources to elucidate the causal pathways between chemicals and adverse outcomes. We applied a network-based workflow to integrate diverse information to generate computational AOPs and accelerate the AOP development. The interactions among DEHP, genes, phenotypes, and GDM were retrieved from several publicly available databases, including the Comparative Toxicogenomics Database (CTD), Computational Toxicology (CompTox) Chemicals Dashboard, DisGeNET, MalaCards, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG). Based on the above interactions, a DEHP-Gene-Phenotype-GDM network consisting of 52 nodes and 227 edges was formed to support AOP construction. The filtered genes and phenotypes were assembled as molecular initiating events (MIEs) and key events (KEs) according to the upstream and downstream relationships, generating a computational AOP (cAOP) network. Based on the Organization for Economic Co-operation and Development handbook of AOPs, a cAOP was assessed and applied to determine the effects of DEHP on GDM. DEHP could increase TNF-α, downregulate the glucose uptake process, and lead to GDM. Overall, this study revealed the utility of computational methods in integrating a variety of datasets, supporting AOP development, and facilitating a better understanding of the underlying mechanism of exposure to chemicals on human health.