Résumé
Ciguatera (CG) is a syndrome caused by ciguatoxins (CTXs), natural phycotoxins produced by benthic dinoflagellates, among the most harmful known. CG results from food poisoning due to the consumption of contaminated fish meat along the food chain, from herbivorous to higher carnivorous fish. It is the most prevalent non-bacterial seafood poisoning worldwide, with an annual increase of 50,000 to 100,000 new cases, although only 2 to 10% are reported. CG presents with multiple undefined symptoms (gastrointestinal, cardiovascular, neurosensory, skin, and inflammatory) in the form of a polymorphic syndrome. CTXs are known to modify cellular membrane permeability, acting on ion channels (Na+, K+, Ca2+) essential for excitable cells like cardiomyocytes (CMs) and neurons (NRs).
Our primary aim is to understand and characterize the impact of CTXs on human cardiac and neuronal physiology. We hypothesize that CTXs can influence intracellular calcium handling, affecting cardiac excitation-contraction coupling (ECC) and neuronal functional and molecular properties.
We differentiated human induced pluripotent stem cell-derived ventricular-like cardiomyocytes (hiPSC-CMs) and neurons of the central nervous system (hiPSC-NRs) from healthy and pathological patients and employed two types of purified CTXs (CTX1B and CTX3C). We investigated CTXs effects on cytosolic calcium, cellular morphology, CMs contractile properties, and RyR2 channel activity. Additionally, we used zebrafish embryos as a live model to monitor embryonic development, behavior and cardiac function.
CTXs exposure resulted in intracellular calcium leaks, increased cardiac and neuronal basal calcium levels, and altered CMs and NRs single-cell morphology. It heightened RyR2 channel activity, reflected by a higher opening frequency and reduced closing time. CTX exposure also led to reduced contractions of hiPSC-derived cardiac sheets. In vivo studies with CTXs demonstrated high zebrafish embryos mortality, skeletal and physical malformations, and alterations in cardiac function and behavior.
We discovered that CTXs caused RyR2 aberrant kinetic properties, abnormal intracellular calcium handling, reduced beat rate, and altered hiPSC-CMs/NRs morphology. In vivo studies confirmed cardiac and neuronal damage, with embryonic malformations and high mortality.