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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.

SUBMITTER: Pogrmic-Majkic K

PROVIDER: S-EPMC9352620 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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

Pogrmic-Majkic Kristina K Samardzija Nenadov Dragana D Tesic Biljana B Fa Nedeljkovic Svetlana S Kokai Dunja D Stanic Bojana B Andric Nebojsa N

Archives of toxicology 20220705 10

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) ...[more]

PMID: 35790550

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Project description:BackgroundAdverse outcome pathways (AOPs) are conceptual frameworks that organize knowledge about biological interactions and toxicity mechanisms. They present a sequence of events commencing with initial interaction(s) of a stressor, which defines the perturbation in a biological system (molecular initiating event, MIE), and a dependent series of key events (KEs), ending with an adverse outcome (AO). AOPs have recently become the subject of intense studies in a view to better understand the mechanisms of nanomaterial (NM) toxicity. Silver nanoparticles (Ag NPs) are one of the most explored nanostructures and are extensively used in various application. This, in turn, has increased the potential for interactions of Ag NPs with environments, and toxicity to human health. The aim of this study was to construct a putative AOPs (pAOP) related to reproductive toxicity of Ag NPs, in order to lay the groundwork for a better comprehension of mechanisms affecting both undesired toxicity (against human cell) and expected toxicity (against microorganisms).MethodsPubMed and Scopus were systematically searched for peer-reviewed studies examining reproductive toxicity potential of Ag NPs. The quality of selected studies was assessed through ToxRTool. Eventually, forty-eight studies published between 2005 and 2022 were selected to identify the mechanisms of Ag NPs impact on reproductive function in human male. The biological endpoints, measurements, and results were extracted from these studies. Where possible, endpoints were assigned to a potential KE and an AO using expert judgment. Then, KEs were classified at each major level of biological organization.ResultsWe identified the impairment of intracellular SH-containing biomolecules, which are major cellular antioxidants, as a putative MIE, with subsequent KEs defined as ROS accumulation, mitochondrial damage, DNA damage and lipid peroxidation, apoptosis, reduced production of reproductive hormones and reduced quality of sperm. These successive KEs may result in impaired male fertility (AO).ConclusionThis research recapitulates and schematically represents complex literature data gathered from different biological levels and propose a pAOP related to the reproductive toxicity induced by AgNPs. The development of AOPs specific to NMs should be encouraged in order to provide new insights to gain a better understanding of NP toxicity.

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

Publications

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

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