[
Cold Spring Harb Symp Quant Biol,
2000]
Genomic instability is believed to be an enabling characteristic of cancer (Hanahan and Weinberg 2000). Therefore, it is not surprising that sophisticated mechanisms exist to maintain the integrity of the genome. Damage to DNA triggers checkpoint controls that result in cell cycle arrest and repair of the lesion (Nurse, 1997, 2000; Weinert 1998). In multicellular organisms, when DNA damage is extensive, these potentially harmful cells are eliminated by apoptosis (Enoch and Norbury 1995; Evan and Littlewood 1998)...
Moore, Jacob, Hegarty, Evan, Kagias, Konstantinos, Mondal, Sudip, Lim, Yunki, Laing, Adam, Ben-Yakar, Adela
[
International Worm Meeting,
2021]
Direct exposure of humans to different chemicals becomes more prevalent as society is progressing further into industrialization. In addition, an increasing number of medical drugs are being developed at different non-clinical and clinical stages aiming to treat a variety of conditions. In order to protect the public from potential deleterious effects of these chemicals, toxicology analysis is necessary to ensure early identification of toxic effects. The most common type of chemically-induced toxicity is neurotoxicity. Therefore, screening for chemical compounds, which can cause specific neuronal damage, can help identify toxic chemicals and potentially help elucidate specific neurodegeneration mechanisms, which can lead to the development of novel targeted therapeutic approaches. Current neurotoxicity assays rely mainly on mammalian models' mortality tests and are associated with high screening costs and long experimental times. To overcome these limitations, we developed a high throughput in vivo neurotoxicity assay using C. elegans. We screened animals treated with a number of well-characterized reference chemicals using Newormics' proprietary microfluidic device (vivoChip), which enabled us to perform high-resolution imaging and multi-parametric structural analysis of GFP-labeled neurons in a high-throughput manner. We characterized the chemical-induced neurotoxicity in the dopaminergic, cholinergic, GABAergic, and serotonergic neurons generating a complete set of imaging data for each reference chemical. Semi-automatic analysis of this dataset identified the cellular and sub-cellular neuronal defects and created neuron-specific degeneration metrics for the reference chemicals. We hope to gain valuable insights into potential mechanisms of action for these neurotoxic compounds while at the same time progressing towards a more complete screen through an increasing number of chemicals using our high-content and high-throughput system.