The developing nervous system is a sensitive target for chemical exposure in both humans and animal models, and early life-stage exposures can lead to long-term effects on motor activity, sensory function, and cognition. Developed and issued by the Organization for Economic Co-operation and Development (OECD), the developmental neurotoxicity (DNT) test guideline (OECD TG 426) is used to assess the potential effects of pre- and postnatal chemical (mainly pesticide) exposure on the morphology and function of the developing nervous system within pre-weaning, adolescent, and young adult rodents. Commonly used strains of rats are preferred for this guideline, and each DNT study requires approximately 640-1200 rats (excluding dams) per chemical. While DNT data are lacking for tens of thousands of chemicals used in commerce, it is impractical to screen these chemicals using the existing DNT test guideline, as this test relies on a large number of animals and is expensive, low-throughput, and labor-intensive. Therefore, there is a recognized need to rely on cell-based assays and alternative non-mammalian models to support rapid and cost-effective screening and prioritization of chemicals for DNT testing in rodents. Currently, the vast majority of high-throughput screening (HTS) and high-content screening (HCS) assays used for DNT testing utilize cell-free and cell-based methods that model key biological events across a wide range of toxicologically-relevant pathways. However, these assays do not adequately reflect the complex physiology of an intact organism. Therefore, the use of smaller, alternative non-mammalian animal models (such as nematodes, flies, and fish embryos) have been proposed as complementary models to cell-free and cell-based methods, as these models are also suitable for microplate-based HTS/HCS assays and mechanism-based neurotoxicological research.
