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<p>Brazil is the world’s leading exporter of beef and chicken. Therefore, a wide range of veterinary products are employed to manage these animals, including the endectocide moxidectin (MOX), which is widely used for routine control of ticks, lice and helminths. From an ecotoxicological standpoint, this compound has the potential to enter the environment and harm non-target organisms, thereby causing individual and ecosystem damage. Recent studies have demonstrated that MOX induces oxidative stress and delays hatching in zebrafish embryos - defining manifestations of developmental toxicity (DT). The present study investigated MOX’s involvement with DT-related biological targets and pathways through computational approaches. To this end, network toxicology approaches were employed to predict potential molecular targets and pathways. In addition, molecular docking and molecular dynamics simulations were used to analyze the interactions between the compound and the identified targets. The primary identified targets comprised key components of the γ-secretase complex, an enzymatic assembly that is essential for Notch signaling pathway activation - a critical regulator of developmental processes and neurophysiological homeostasis. The docking analysis revealed favorable binding energies between MOX and the catalytic subunits of the γ-secretase complex, presenilin 1 and presenilin 2. Furthermore, molecular dynamics demonstrated that the target-MOX complex-maintained stability within a simulated physiological environment. The analyses of data from γ-secretase and other key targets, which are detailed throughout this study, reveal a novel mechanistic basis for MOX-induced toxicity. The present findings suggest a mode of action that may account for the developmental impairments previously observed in zebrafish embryos resulting from the targeted disruption of cellular signaling and proteostasis networks.</p>

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Identification of potential mediators of moxidectin-induced developmental toxicity using network toxicology and structure-based analyses

  • 期刊论文

  • 发表日期：

    2025年12月4日

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  • Cleyton de Sousa Gomes,
  • Juliana Alves da Costa Ribeiro Souza,
  • Natália Ferreira de Sousa,
  • Mayara dos Santos Maia,
  • Rafael Xavier Martins,
  • Marcus Tullius Scotti,
  • Davi Farias

摘要

Brazil is the world’s leading exporter of beef and chicken. Therefore, a wide range of veterinary products are employed to manage these animals, including the endectocide moxidectin (MOX), which is widely used for routine control of ticks, lice and helminths. From an ecotoxicological standpoint, this compound has the potential to enter the environment and harm non-target organisms, thereby causing individual and ecosystem damage. Recent studies have demonstrated that MOX induces oxidative stress and delays hatching in zebrafish embryos - defining manifestations of developmental toxicity (DT). The present study investigated MOX’s involvement with DT-related biological targets and pathways through computational approaches. To this end, network toxicology approaches were employed to predict potential molecular targets and pathways. In addition, molecular docking and molecular dynamics simulations were used to analyze the interactions between the compound and the identified targets. The primary identified targets comprised key components of the γ-secretase complex, an enzymatic assembly that is essential for Notch signaling pathway activation - a critical regulator of developmental processes and neurophysiological homeostasis. The docking analysis revealed favorable binding energies between MOX and the catalytic subunits of the γ-secretase complex, presenilin 1 and presenilin 2. Furthermore, molecular dynamics demonstrated that the target-MOX complex-maintained stability within a simulated physiological environment. The analyses of data from γ-secretase and other key targets, which are detailed throughout this study, reveal a novel mechanistic basis for MOX-induced toxicity. The present findings suggest a mode of action that may account for the developmental impairments previously observed in zebrafish embryos resulting from the targeted disruption of cellular signaling and proteostasis networks.