Mechanistic Convergence of the Chemical Exposome in Nephrotoxicity: A Systems Toxicology Network Approach

Introduction

The chemical exposome comprises the cumulative environmental and pharmacological exposures that shape biological systems over time. In the kidney, these exposures may influence inflammatory and metabolic pathways that contribute to renal injury. Nevertheless, nephrotoxicity assessment still predominantly evaluates substances individually, which may overlook shared mechanistic patterns. This study investigates whether different nephrotoxic agents converge on common molecular pathways within renal interaction networks.

Methods

The approach is entirely computational and aligned with New Approach Methodologies (NAMs). Substances associated with nephrotoxicity were retrieved from CTD, GeneCards, and UniProt. Genes linked to these exposures were integrated to construct protein–protein interaction networks using STRING (Homo sapiens; confidence ≥ 0.700). Network topology was evaluated in Cytoscape through degree distribution, centrality measures, and modular organization. Functional enrichment analysis was conducted in Reactome to identify recurrent biological pathways.

Results

Preliminary network integration suggests the presence of overlapping interaction modules across chemically distinct exposures. Shared highly connected nodes are observed within pathways related to inflammation, oxidative stress, mitochondrial dysfunction, and immune signaling. Ongoing topological evaluation is being conducted to further characterize recurrent structural patterns within the renal interaction network.

Conclusions
The results support the hypothesis that nephrotoxicity in the context of the chemical exposome involves shared molecular architectures rather than isolated effects. A systems-level network perspective may contribute to more integrative and mechanistically grounded renal risk assessment models.