Screening the ToxCast phase II libraries for alterations in network function using cortical neurons grown on...

Area of Science:

• Neuroscience
• Toxicology
• Computational Biology

Background:

• Rapid screening methods for environmental compound neurotoxicity are crucial, especially those assessing functional impacts.
• Existing toxicological assays often lack functional assessments of neural networks.

Purpose of the Study:

• To evaluate microelectrode array (MEA)-based approaches as a tool for rapid neurotoxicity screening.
• To assess the functional effects and cytotoxicity of 1055 chemicals from the EPA's ToxCast library on neural networks.

Main Methods:

• Primary cortical networks were cultured on multi-well MEA (mwMEA) plates.
• Baseline neural activity was recorded, followed by compound exposure (40 µM).
• Changes in mean firing rate (MFR) and cell viability were assessed post-exposure.

Main Results:

• 326 out of 1055 compounds significantly altered MFR, indicating neurofunctional effects.
• Most identified neurotoxicants (86%) were pharmaceuticals, pesticides, fungicides, chemical intermediates, and herbicides.
• Only eight compounds exhibited cytotoxicity, demonstrating functional changes occurred independently of cell death.

Conclusions:

• Large-scale functional screening using MEAs effectively identifies neurotoxic potential within the ToxCast library.
• Data mining revealed enriched ToxPrint chemotypes among active compounds, enabling structure-activity relationship inferences.
• This approach provides valuable insights for mechanistic associations and future neurotoxicity research.