Novel approaches to predictive developmental and reproductive toxicology

Thesis

Toxicity assessments are important for evaluating the potential harm caused by chemicals such as pesticides, which are released into the environment. However, assessing the developmental and reproductive toxicity (DART) of these chemicals is a complex process that requires a thorough examination of the entire life cycle. The traditional method for DART testing involves using animal models such as rats and rabbits, but this approach has drawbacks. It is time-consuming, expensive, requires large amounts of test substances, and involves a significant number of animals. Moreover, the reliability of these tests in predicting the toxicity outcomes in humans remains uncertain.

This thesis focused on establishing and validating predictive toxicology approaches in non-vertebrate organisms to understand the relationship between developmental outcome and mechanism of action. Specifically, I wanted to investigate whether testing a combination of organisms added value. I first compared different methods for conducting developmental toxicity assays in Caenorhabditis elegans (C. elegans) and Dictyostelium discoideum (Dictyostelium) and identified an optimal experimental approach to detect developmental perturbations. By using both model organisms, I was able to detect developmental disruptions and changes in fatty acid accumulation caused by a selection of Acetyl-CoA Carboxylase (ACCase) inhibitors known to be teratogenic in mammals. Some effects would have been missed by testing in one system alone, highlighting the superiority of testing in multiple species for assessing developmental toxicity and mechanism of action.

Using a C. elegans mutant resistant to the insecticidal ACCase inhibitor Spirotetramat, I was able to validate the assays to assess developmental effects and mode of action for a selection of ACCase inhibitors of unknown chemistry. I then exploited a range of natural variants with varying sensitivity to a subset of compounds to provide proof of principle that the compounds could be classified according to a sensitivity signature which has the potential to illuminate mode of action studies.

Overall, this thesis has successfully established and validated predictive toxicology approaches using C. elegans and Dictyostelium as model organisms, especially in a combinatorial approach, demonstrating the potential for cross-species comparisons to assess compound toxicity and mechanism of action. The research contributes valuable insights into predictive toxicology and the evaluation of compound toxicity using alternative model organisms.

Authors: Verslype, A

• DOI: 10.5287/ora-0okebvx5m
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Subjects: Developmental toxicology