Metabolomics profiling of haloperidol and validation of thromboxane-related signaling in the early development of zebrafish.

Haloperidol is a common butyrophenone-derivative antipsychotic drug that is used clinically to treat schizophrenia and to control Tourette disorder. Haloperidol has been shown to be an embryonic toxicant and to cause a variety of adverse effects that affect human embryonic development. However, the pathway impaired by haloperidol during the developmental stages remains unclear. To elucidate the innate toxicological pathway of haloperidol, we investigated the lethality of haloperidol during the embryonic development of zebrafish. We observed that haloperidol caused serious morphological changes, with an LD₅₀ of 9.7 x 10^-6 ± 2.4 x 10^-6 μg/L. Next, we established a systematic approach to perform metabolite profiling in embryonic zebrafish with various concentrations of haloperidol and analyzed the metabolites using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS). A total of 304 metabolites were identified and 86 metabolites were chosen to predict potential pathways. Among the metabolites, we found through prediction that numerous metabolomics-biological pathways are associated with haloperidol, including peroxisome-proliferator-activated receptor (ppar), thromboxane, and mTOR signaling. Quantitative real time-qPCR was then used to validate the gene expression potentially associated with the thromboxane, which is a metabolic product of arachidonic acid and considered to be important for cell proliferation and the inflammatory response. To sum up, analysis of metabolites in the zebrafish model provides a system for mining biomarkers that reflect biological significance and highlight the therapeutic potency in humans. In addition, it may show potential for application to other pharmaceuticals to identify their various activities and clarify functional mechanisms in the future.

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