Integrated approach for identifying the molecular, cellular, and host responses to chemical insults

We performed a pilot study to characterize the molecular, cellular, and whole-organism response to nonlethal chemical agent exposure in the central nervous system. Multiple methodologies were applied to measure in vitro enzyme inhibition, neuronal cell pathway signaling, and in vivo zebrafish neural development in response to challenge with two different classes of chemical compounds. While all compounds tested exhibited expected enzyme inhibitory activity against acetylcholinesterase (AChE), a well-characterized target of chemical agents, distinct differences between chemical exposures were detected in cellular toxicity and pathway target responses and were tested in a zebrafish model. Some of these differences have not been detected using conventional chemical toxicity screening methods. Taken together, the data demonstrate the potential value of an integrated, multimethodological approach for improved target and pathway identification for subsequent diagnostic and therapeutic biomarker development.