A systems biology approach to predictive developmental neurotoxicity of a larvicide used in the prevention of Zika virus transmission

Karine Audouze, Olivier Taboureau, Philippe Grandjean

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Abstract

The need to prevent developmental brain disorders has led to an increased interest in efficient neurotoxicity testing. When an epidemic of microcephaly occurred in Brazil, Zika virus infection was soon identified as the likely culprit. However, the pathogenesis appeared to be complex, and a larvicide used to control mosquitoes responsible for transmission of the virus was soon suggested as an important causative factor. Yet, it is challenging to identify relevant and efficient tests that are also in line with ethical research defined by the 3Rs rule (Replacement, Reduction and Refinement). Especially in an acute situation like the microcephaly epidemic, where little toxicity documentation is available, new and innovative alternative methods, whether in vitro or in silico, must be considered. We have developed a network-based model using an integrative systems biology approach to explore the potential developmental neurotoxicity, and we applied this method to examine the larvicide pyriproxyfen widely used in the prevention of Zika virus transmission. Our computational model covered a wide range of possible pathways providing mechanistic hypotheses between pyriproxyfen and neurological disorders via protein complexes, thus adding to the plausibility of pyriproxyfen neurotoxicity. Although providing only tentative evidence and comparisons with retinoic acid, our computational systems biology approach is rapid and inexpensive. The case study of pyriproxyfen illustrates its usefulness as an initial or screening step in the assessment of toxicity potentials of chemicals with incompletely known toxic properties.

Original languageEnglish
JournalToxicology and Applied Pharmacology
Volume354
Pages (from-to)56-63
ISSN0041-008X
DOIs
Publication statusPublished - Sep 2018

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Keywords

  • Journal Article
  • Pesticide
  • Predictive toxicology
  • Systems biology
  • Toxicity testing
  • Pyriproxyfen
  • Developmental neurotoxicity
  • Computational biology
  • Microcephaly/chemically induced
  • Insecticides/adverse effects
  • Zika Virus/pathogenicity
  • Humans
  • Mosquito Control/methods
  • Larva/drug effects
  • Culicidae/drug effects
  • Insect Vectors
  • Risk Assessment
  • Neurotoxicity Syndromes/etiology
  • Signal Transduction/drug effects
  • Protein Interaction Maps/drug effects
  • Pyridines/adverse effects
  • Animals
  • Zika Virus Infection/prevention & control
  • Toxicity Tests
  • Systems Biology/methods

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