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PreprintCited by 0Mercury impact and mitigation studiesEnvironmental Toxicology and EcotoxicologyComputational Drug Discovery Methods

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Integrative network-based construction of ecologically relevant computational adverse outcome pathways for organic mercury-induced toxicity

Madgaonkar, Shreyes Rajan, Chivukula, Nikhil, Garisetti, Vasavi, Marigoudar, Shambanagouda Rudragouda, Sharma, Krishna Venkatarama, Samal, Areejit·2025·Environmental Toxicology and Chemistry
DOI 10.1101/2025.10.25.684520

Preprint — published as 10.1093/etojnl/vgag026 · Paper page

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Abstract

Adverse outcome pathways (AOPs) describe mechanisms of toxicity by connecting molecular events with outcomes at higher levels of biological organization. Computational AOPs (cAOPs), constructed using existing toxicological data, can accelerate the early stages of AOP development, which is often a time-consuming and resource-intensive process. In this study, an integrative network-based framework was developed to construct cAOPs, with a particular focus on elucidating the toxicity of organic mercury in fish. First, 124 organic mercury compounds, corresponding fish-specific toxicity endpoints, and proteins were curated from CTD and ECOTOX. Next, molecular docking investigations were performed to determine novel molecular interactions with 16 zebrafish protein orthologs. Subsequently, the toxicity endpoints, including the identified molecular interactions, were standardized and harmonized using data from AOP-Wiki, Gene Ontology, and MeSH. These endpoints were integrated with event relationship information from AOP-Wiki and published literature to construct an organic mercury-associated toxicity network comprising 197 nodes and 243 edges. Thereafter, node- and edge-level filtration criteria were designed based on AOP definitions and utilized to identify biologically relevant pathways within the toxicity network. Further, these pathways were ranked based on their novelty with respect to existing AOPs within AOP-Wiki. Finally, based on extensive evidence from published literature, four top-ranked novel pathways that describe binding with glutathione peroxidase or alterations in metallothionein levels leading to neurologic manifestations or dysbiosis in fish were proposed as cAOPs. Overall, this study presents an integrative network-based framework for constructing cAOPs applicable to diverse contaminants and species, supporting New Approach Methodologies for toxicological risk assessment.

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Metadata

Authors
Madgaonkar, S. R., Chivukula, N., Garisetti, V., Marigoudar, S. R., Sharma, K. V., & Samal, A.
Affiliations
  • Homi Bhabha National Institute (IN)
  • Institute of Mathematical Sciences (IN)
  • Government of India (IN)
Corresponding author
Samal, Areejit
ORCID
Venue
Environmental Toxicology and Chemistry
Publisher
openRxiv
Published
2025-10-26
Volume
45
Issue
3
Pages
731-747
ISSN
0730-7268 (ISSN-L)
DOI
10.1101/2025.10.25.684520
OpenAlex
W7125951084
Cited by
0
References
1
FWCI
0.00
Type
journal article
Language
en
Open access
closed
Licence
www.biorxiv.org/about/FAQ#license (vor)
Locations
  • Environmental Toxicology and Chemistry (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
Funders
  • Department of Atomic Energy, Government of India
  • Australian Mathematical Sciences Institute
Topics
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Mercury impact and mitigation studies
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Environmental Toxicology and Ecotoxicology
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
Keywords
adverse outcome pathways, organic mercury, fish toxicity, zebrafish, molecular docking, glutathione peroxidase, metallothionein, neurotoxicity, dysbiosis, AOP-Wiki, new approach methodologies, toxicological risk assessment, Comparative Toxicogenomics Database
MeSH terms
Adverse Outcome Pathways, Animals, Mercury, Organomercury Compounds, Water Pollutants, Chemical, Zebrafish, Mercury Compounds, Molecular Docking Simulation

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