Linking Diethylhexyl Phthalate (DEHP) to Gestational Diabetes Mellitus (GDM) via Adverse Outcome Pathways Using a Network-Based Approach

Abstract

Several epidemiologic studies have revealed exposure to diethylhexyl phthalate (DEHP), a ubiquitous endocrine disruptor in the environment, might associate with gestational diabetes mellitus (GDM). However, the studies are few and demonstrated contradictory results. This study aims to investigate the causal relationship between DEHP and GDM using the adverse outcome pathway (AOP) framework, which can combine information from different sources to elucidate causal pathways between chemicals and adverse outcomes. We used a computational approach to construct and validate AOPs from DEHP to GDM based upon information from publicly available databases. Associations of DEHP to genes were extracted from the CTD and CompTox databases, interactions between genes and GDM were obtained from the DisGeNET and MalaCards databases. Based on these data, we developed a DEHP-Gene-Phenotype-GDM network, and then constructed a computational AOP (cAOP) network and verified the tumor necrosis factor (TNF)-initiated cAOP. The results demonstrated that TNF plays a significant role for exposure to DEHP in GDM via downregulating the glucose uptake process. This study illustrates the utility of computational methods in supporting AOP development, and so facilitating a better understanding of the toxic mechanism in the pathogenesis of chemicals on human health.