Acute or developmental exposure of primary rat cortical cells to Emamectin Benzoate disrupts gene expression

As the number of chemicals lacking neurotoxicity assessment increases, there is an increased demand for data and tools that can quickly prioritize and identify hazardous chemicals. Using sub-cytotoxic concentrations of Emamectin Benzoate (EMB), an avermectin class pesticide, we explored the use of transcriptomic assessment to provide foundational molecular data for understanding the modes of action for the toxic effects of these chemicals. Primary cortical cell cultures from Long Evans rats were exposed to varying concentrations of EMB and assessed for toxicity following a short-term exposure and a continuous exposure during a key developmental differentiation and synapse formation window. The goals of this study were to determine if EMB exposure disrupted gene expression, whether those changes varied across cortical cell development, compare with proteomic and phenotypic changes, and understand how these gene expression changes could provide critical information on molecular initiating and key events for developmental neurotoxicity. At acute exposure concentrations up to 2.5 μM, minimal transcriptomic effects were observed under the presented analysis framework. Following prolonged developmental exposure, concentration-responsive differential expression was observed across all timepoints, with notable overlap in some key pathways and distinct expression patterns in others. Gene expression changes occurred at similar concentration with proteomic and phenotypic changes. DIV7 emerged as the most sensitive developmental window, with strong dose-responsive effects affecting synaptic and myelin-related genes. These data link transcriptomic and multi-omic molecular changes to apical endpoints and support mechanisms related to GABA signaling, ribosomal protein disruption, inflammation, neurite outgrowth, and synaptogenesis.