The pathophysiology of neurological risk from environmental toxins: Microcystin-LR leads to a decrease in neuron...

Area of Science:

• Environmental toxicology
• Neuroscience
• Cellular biology

Background:

• Microcystin-LR (MC-LR) is a potent cyanotoxin with suspected neurotoxic effects.
• The precise mechanisms of MC-LR neurotoxicity and its impact on brain health remain incompletely understood.
• Understanding MC-LR's effects is crucial for public health and ecosystem protection.

Purpose of the Study:

• To investigate the neurotoxic effects of MC-LR exposure using brain organoid and mouse models.
• To elucidate the underlying molecular mechanisms of MC-LR-induced neurotoxicity.
• To assess the impact of MC-LR on neuronal viability, inflammation, and cell death pathways.

Main Methods:

• Utilized microelectrode array (MEA) and TUNEL staining in human brain organoids to assess neuronal activity and death.
• Administered varying concentrations of MC-LR to 12-month-old mice, followed by histopathological and biochemical analyses.
• Employed qPCR and Western blot to analyze the activation of JNK/NF-κB signaling and inflammatory markers (nlrp3, caspase-1, il-18, il-6, gsdmd) in mouse hippocampal tissue.

Main Results:

• Acute MC-LR exposure significantly reduced neuronal discharge activity and neuron numbers in brain organoids.
• MC-LR exposure led to increased neuronal death and decreased neuron counts in both organoid and mouse models.
• Long-term MC-LR exposure activated the JNK/NF-κB pathway, inducing neuroinflammation and pyroptosis in mouse hippocampus.

Conclusions:

• MC-LR exhibits significant neurotoxic potential, causing neuronal loss and functional impairment.
• Prolonged MC-LR exposure triggers JNK/NF-κB signaling, leading to neuroinflammation and neuronal pyroptosis.
• These findings highlight the critical risk of MC-LR to brain health and necessitate further investigation into mitigation strategies.