Mapping DEHP to the adverse outcome pathway network for human female reproductive toxicity

Abstract

Adverse outcome pathways (AOPs) and AOP networks are tools for mechanistic presentation of toxicological effects across different levels of biological organization. These tools are used to better understand how chemicals impact human health. In this study, a four-step workflow was used to derive the AOP network of human female reproductive toxicity (HFRT-AOP) from five AOPs available in the AOP-Wiki and ten AOPs obtained from the literature. Standard network analysis identified key events (KEs) that are point of convergence and divergence, upstream and downstream KEs, and bottlenecks across the network. To map di-(2-ethylhexyl) phthalate (DEHP) to the HFRT-AOP network, we extracted DEHP target genes and proteins from the Comparative Toxicogenomic and the CompTox Chemicals Dashboard databases. Enriched GO terms analysis was used to identify relevant biological processes in the ovary that are DEHP targets, whereas screening of scientific literature was performed manually and automatically using AOP-helpFinder. We combined this information to map DEHP to HFRT-AOP network to provide insight on the KEs and system-level perturbations caused by this endocrine disruptor and the emergent paths. This approach can enable better understanding of the toxic mechanism of DEHP-induced human female reproductive toxicity and reveal potential novel DEHP female reproductive targets for experimental studies.

Leveraging integrative toxicogenomic approach towards development of stressor-centric adverse outcome pathway networks for plastic additives

“…An AOP network constructed from stressor-specific AOPs can highlight interactions among the associated AOPs, thereby aiding in the assessment of stressor-induced toxicity (Chai et al, 2021; Pogrmic-Majkic et al, 2022; Rugard et al, 2020; Sahoo et al, 2024; Yang et al, 2022). Among the 15 plastic additives, we observed that Benzo[a]pyrene (B[a]P or CAS:50-32-8) has the largest number of associated AOPs (28 AOPs), all of which were solely identified through our systematic data integrative approach (Table 1).…”

Building an adverse outcome pathway network for estrogen-, androgen- and steroidogenesis-mediated reproductive toxicity

“…Several studies describe the development of AOPNs containing novel pathways as an alternative to postulating single AOPs, for example, related to disrupted female pubertal onset ( Franssen et al, 2022 ), male reproductive tract abnormalities ( Palermo et al, 2021 ), and for effects on male and female reproductive function in fish ( Ankley et al, 2023 ; Morshead et al, 2023 ). Others describe AOPNs for specific types of endocrine mediated toxicities and stressors, such as exploring male reproductive toxicity of silver nanoparticles ( Kose et al, 2023 ) and inorganic arsenic ( Chai et al, 2021 ), or the impact of phthalates on female reproduction ( Pogrmic-Majkic et al, 2022 ). In contrast, the AOPN developed here combines existing AOPs related to mammalian reproductive toxicity and provides a broad view of mechanisms and effects related to disruption of the EAS modalities for the purpose of further AOP development.…”

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.…”