Sublethal oral exposure to the marine toxin PbTx3: Neurotoxicity assessment in mice

Brevetoxins (PbTxs) are marine polyether compounds produced by the alga Karenia brevis, which accumulate in shellfish and fish, and transferred through the marine food web. These toxins impact both marine ecosystems and human health. Consumption of contaminated shellfish is the primary cause of Neurotoxic Shellfish Poisoning (NSP), which presents with neurological, gastrointestinal, and/or cardiovascular symptoms that appear in a few hours and typically resolves within 1-3 days, although some disturbances may persist for weeks or months. The acute toxicity of PbTxs involves activation of voltage-gated sodium channels, leading to sodium influx and membrane depolarization. However, the long-term neurotoxic effects remain poorly understood. To investigate this, we conducted a 14-day neurotoxicity assay in male and female mice that received a single oral dose of PbTx3. Early neurological signs were observed, but muscle strength remained unaffected over the long term. Cold nociceptive sensitivity decreased over time, resulting in sensory hypoalgesia that was particularly pronounced in males. Creatinine levels increased in females at day 14, though no associated kidney histopathology was observed. At the highest dose (750 µg/kg), ultrastructural changes in skeletal muscle, including sarcomere disorganization, calcium overload, and autophagy, were noted. To explore potential mechanisms of action responsible for neurotoxicity, whole-cell patch-clamp recordings were performed in HEK293 cells expressing transient receptor potential vanilloid 1 (TRPV1) channel. PbTx3 modulated TRPV1 currents in a dose-dependent manner, suggesting this receptor may mediate some of the observed sensory effects. Our findings reveal persistent, sex-dependent alterations after PbTx3 exposure and provide insight into mechanisms of sublethal toxicity. The combination of functional testing, histopathology, and electrophysiology offers a sensitive approach for assessing neurotoxicity risk of marine toxins.