Abstract
Brevetoxins (PbTx) are a well-recognized group of neurotoxins associated with harmful algal blooms, and specifically recurrent “Florida Red Tides,” in marine waters that are linked to impacts on both human and ecosystem health including well-documented “fish kills” and marine mammal mortalities in affected coastal waters. Understanding mechanisms and pathways of PbTx toxicity enables identification of relevant biomarkers to better understand these environmental impacts, and improve monitoring efforts, in relation to this toxin. Toward a systems-level understanding of toxicity, and identification of potential biomarkers, high-resolution magic angle spinning nuclear magnetic resonance (HRMAS NMR) was utilized for metabolic profiling of zebrafish (Danio rerio) embryos, as an established toxicological model, exposed to PbTx-2 (the most common congener in marine waters). Metabolomics studies were, furthermore, complemented by an assessment of the toxicity of PbTx-2 in embryonic stages of zebrafish and mahi-mahi (Coryphaena hippurus), the latter representing an ecologically and geographically relevant marine species of fish, which identified acute embryotoxicity at environmentally relevant (i.e., parts-per-billion) concentrations in both species. HRMAS NMR analysis of intact zebrafish embryos exposed to sub-lethal concentrations of PbTx-2 afforded well-resolved spectra, and in turn, identification of 38 metabolites of which 28 were found to be significantly altered, relative to controls. Metabolites altered by PbTx-2 exposure specifically included those associated with (1) neuronal excitotoxicity, as well as associated neural homeostasis, and (2) interrelated pathways of carbohydrate and energy metabolism. Metabolomics studies, thereby, enabled a systems-level model of PbTx toxicity which integrated multiple metabolic, molecular and cellular pathways, in relation to environmentally relevant concentrations of the toxin, providing insight to not only targets and mechanisms, but potential biomarkers pertinent to environmental risk assessment and monitoring strategies.
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•PbTx-2 is toxic to embryos of both zebrafish and mahi-mahi.•Embryotoxicity was observed at environmentally relevant concentrations.•PbTx-2 altered levels of metabolites associated with neurotoxicity and energy metabolism.•An integrated systems-level model of toxicity of PbTx-2 was enabled by metabolic profiles.•Metabolic profiles suggest potential biomarkers for environmental monitoring.
