Abstract

Diarrheic shellfish poisoning (DSP) is caused by the consumption of shellfish contaminated with a group of phycotoxins that includes okadaic acid (OA), dinophysistoxin-1 (DTX-1), and dinophysistoxin-2 (DTX-2). These toxins are inhibitors of serine/threonine protein phosphatases 1 (PP1) and 2A (PP2A), but show distinct levels of toxicity. Aside from a difference in protein phosphatases (PP) inhibition potency that would explain these differences in toxicity, others mechanisms of action are thought to be involved. Therefore, we investigated and compared which mechanisms are involved in the toxicity of these three analogues. As the intestine is one of the target organs, we studied the transcriptomic profiles of human intestinal epithelial Caco-2 cells exposed to OA, DTX-1, and DTX-2. The pathways specifically affected by each toxin treatment were further confirmed through the expression of key genes and markers of toxicity. Our results did not identify any distinct biological mechanism for OA and DTX-2. However, only DTX-1 induced up-regulation of the MAPK transduction signalling pathway, and down-regulation of gene products involved in the regulation of DNA repair. As a consequence, based on transcriptomic results, we demonstrated that the higher toxicity of DTX-1 compared to OA and DTX-2 was consistent with certain specific pathways involved in intestinal cell response.

Highlights

  • Phycotoxins, mainly produced by dinoflagellates, are natural metabolites that can accumulate in shellfish, especially in bivalves due to their high level of filter-feeding activity [1]

  • As studies exploring exploringthe thecomparison comparisonof of toxicological mechanisms induced by okadaic acid (OA), DTX-1, DTX-2 are lacking, we investigated and compared the cellular and molecular mechanisms involved and DTX-2 are lacking, we investigated and compared the cellular and molecular mechanisms in the toxicity of these three analogues in undifferentiated human intestinal epithelial

  • The sub-toxic concentration tested in the transcriptomic study for the three phycotoxins was established by a cytotoxicity assay. m, a concentration-dependent decrease of viability of Caco-2 cells was observed after 24 h treatment

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Summary

Introduction

Phycotoxins, mainly produced by dinoflagellates, are natural metabolites that can accumulate in shellfish, especially in bivalves due to their high level of filter-feeding activity [1]. Okadaic acid (OA) and its main analogues, dinophysistoxin-1 (DTX-1) and dinophysistoxin-2 (DTX-2), are produced by certain species belonging to the genera Prorocentrum and Toxins 2020, 12, 783; doi:10.3390/toxins12120783 www.mdpi.com/journal/toxins. NoREVIEW human fatalities have been reported so far, the recurrent presence of these Toxins[3,4]. 2020, 12, x FOR PEER toxins in shellfish remains a public health concern [5]. OA and DTXs are inhibitors of serine/threonine protein phosphatases 1 (PP1) and 2A (PP2A) [6]. DTXsare areinvolved inhibitors serine/threonine protein phosphatases 1 (PP1) [6]

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