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Toxicity tests in animals are grounded on two main assumptions: first, the effects observed in laboratory animals can be extrapolated to humans, especially when adjusted for body surface area; second, high-dose exposure in animals is essential to identify potential human hazards from lower doses. This is based on the quantal dose-response concept, which faces the challenge of extrapolating results from relatively few test animals to much larger human populations. For example, a 0.01% incidence...
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PeriTox-M, a Cell-Based Assay for Peripheral Neurotoxicity with Improved Sensitivity to Mitochondrial Inhibitors.

Anna-Katharina Holzer1, Mira Dürr1, Selina Multrus1

  • 1In Vitro Toxicology and Biomedicine, Department Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, 78457 Konstanz, Germany.

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|December 10, 2025
PubMed
Summary

Optimizing the PeriTox assay with a galactose switch enhances detection of mitochondrial toxicants in peripheral neurons (PNs). This improved assay (PeriTox-M) boosts sensitivity and specificity for identifying chemicals causing peripheral neuropathies.

Keywords:
high-throughput toxicity screeningmetabolic switchmitochondrial toxicityperipheral neurotoxicity

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Area of Science:

  • Neuroscience
  • Toxicology
  • Cell Biology

Background:

  • Human cell-based assays for neurotoxicity (NT) and developmental neurotoxicity (DNT) need improved detection of mitochondrial toxicants.
  • The PeriTox assay predicts chemical-induced peripheral neuropathies using peripheral neurons (PNs).

Purpose of the Study:

  • To optimize the PeriTox assay for enhanced sensitivity and specificity in detecting mitochondrial toxicants.
  • To investigate the impact of a glucose-to-galactose metabolic switch on PN response to neurotoxicants.

Main Methods:

  • Peripheral neurons (PNs) were cultured in glucose (Glc) or galactose (Gal) medium to induce metabolic shifts.
  • Assays measured neurite outgrowth, ATP levels, and oxygen consumption.
  • Sensitivity and specificity to mitochondrial respiratory chain (MRC) inhibitors were evaluated.

Main Results:

  • Galactose adaptation induced a metabolic shift with increased oxygen consumption in PNs.
  • Gal-adapted neurons showed up to 7500-fold increased sensitivity to MRC complex I and III inhibitors.
  • The modified PeriTox assay (PeriTox-M) improved distinction between cytotoxic and neurite-specific effects.

Conclusions:

  • Running the PeriTox assay in galactose (PeriTox-M) significantly enhances sensitivity and specificity for mitochondrial toxicants.
  • The optimized assay demonstrates no general disadvantages and may improve in vitro test batteries for regulatory applications.