C. elegans as a powerful model for neurotoxicity assessment

The small nematode Caenorhabditis elegans (C. elegans) has emerged as a valuable tool in neurotoxicology due to its well-characterized nervous system, genetic tractability, and high conservation of molecular pathways with humans. These characteristics allow to study cellular and molecular mechanisms triggered by neurotoxic substances. In C. elegans, behavioral, molecular, neurophysiological, and neuronal morphology assays, together with genetic models targeting dopaminergic, glutamatergic, GABAergic, and cholinergic neurons, as well as models for mitochondrial dysfunction and oxidative stress, are valuable for elucidating mechanisms of neurotoxicity. Additionally, C. elegans is widely used for high-throughput neurotoxicity screenings, with automated systems enhancing scalability and accuracy. Despite its advantages, C. elegans has some limitations for translating data to humans, including the absence of a blood-brain barrier and complex brain regions, as well as differences in metabolism. However, it remains a strong model for neurotoxic screening and mechanistic studies. This review offers a broader, updated perspective by addressing not only classical neurotoxicants (e.g., heavy metals, pesticides) but also increasingly relevant substances like microplastics and industrial chemicals, psychotropic medications, and drugs of abuse. It also provides a detailed overview of diverse C. elegans behavioral, molecular, and neurophysiological neurotoxicity assays, and genetic models for neurotransmitter signaling, mitochondrial dysfunction, and oxidative stress. Importantly, it also discusses the relevance of C. elegans within regulatory frameworks such as adverse outcome pathways (AOPs), a connection largely overlooked in prior reviews. These features address gaps in the current literature and distinguish this work from existing reviews on the topic.