Aluru, Neelakanteswar, Chapman, Daniel P., Becker, Kevin W. , Van Mooy, Benjamin A.S., Karchner, Sibel I., Stegeman, John J. and Hahn, Mark E. (2024) Developmental exposure of zebrafish to saxitoxin causes altered expression of genes associated with axonal growth. NeuroToxicology, 105 . pp. 303-312. DOI 10.1016/j.neuro.2024.11.003.

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Abstract

Highlights

• Saxitoxin exposure during embryogenesis caused neurodevelopmental gene expression changes and axonal defects in zebrafish.
• High performance liquid chromatography revealed saxitoxin retention in embryos up to 72 h post-fertilization.
• Saxitoxin altered the expression of genes related to canonical and noncanonical functions of voltage gated sodium channels.

Abstract

Saxitoxin (STX) is a potent neurotoxin naturally produced by dinoflagellates and cyanobacteria. STX inhibits voltage-gated sodium channels (VGSCs), affecting the propagation of action potentials. Consumption of seafood contaminated with STX is responsible for paralytic shellfish poisoning (PSP). Humans are among the species most sensitive to PSP; neurological symptoms of exposure range from tingling of the extremities to severe paralysis. The objective of this study was to determine the effects of STX exposure on developmental processes during early embryogenesis. This study was designed to test the hypothesis that early developmental exposure to STX would disrupt key processes, particularly those related to neural development. Zebrafish embryos were exposed to STX (24 or 48 pg) or vehicle (0.3 mM HCl) at 6 h post fertilization (hpf) via microinjection. There was no overt toxicity but starting at 36 hpf there was a temporary lack of pigmentation in STX-injected embryos, which resolved by 72 hpf. Using high performance liquid chromatography, we found that STX was retained in embryos up to 72 hpf in a dose-dependent manner. Temporal transcriptional profiling of embryos exposed to 48 pg STX per embryo revealed no differentially expressed genes (DEGs) at 24 hpf, but at 36 and 48 hpf, there were 3547 and 3356 DEGs, respectively. KEGG pathway analysis revealed significant enrichment of genes related to focal adhesion, adherens junction and regulation of actin cytoskeleton, suggesting that cell-cell and cell-extracellular matrix interactions were affected by STX. Genes affected are critical for axonal growth and the development of functional neural networks. We confirmed these findings by visualizing axonal defects in transgenic zebrafish with fluorescently labeled sensory neurons. In addition, our gene expression results suggest that STX exposure affects both canonical and noncanonical functions of VGSCs. Given the fundamental role of VGSCs in both physiology and development, these findings offer valuable insights into effects of exposure to neurotoxins.

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