Systemic crosstalk between liver and brain is associated with microplastic-induced neurobehavioral toxicity in zebrafish

Microplastics (MPs) are widespread environmental contaminants that have entered the human food chain, whose systemic health effects remain largely unknown. Using zebrafish as a vertebrate model, we investigated the mechanistic impacts of MPs on the liver-brain axis. After 18 days of exposure, zebrafish exhibited inhibited growth and neurobehavioral deficits, including reduced feeding, hyperactivity, spatial disorientation, and impaired sensorimotor responses. MPs accumulated in the brain, leading to structural damage, oxidative stress, and neurotransmitter depletion. Molecular docking revealed that MP monomers competitively bound to acetylcholinesterase (AChE), disrupting cholinergic signaling and inducing neuroexcitation. Simultaneously, MPs triggered hepatic inflammation, enzyme dysfunction, and lipid metabolic disturbances. Biochemical analysis showed elevated inflammatory markers (IL-1β, TNF-α, HSP90), compromised antioxidant defenses, increased transaminase leakage, and mitochondrial dysfunction. Untargeted metabolomics revealed hepatic metabolic reprogramming, with disrupted glycolysis, lipid turnover, and redox homeostasis. Pathway analysis implicated liver injury as a driver of neurotoxicity, potentially via altered metabolites and cytokines crossing the blood-brain barrier to influence neuroinflammatory and neuroendocrine responses. These findings highlight a mechanistic link between hepatic dysfunction and neural impairment, suggesting hepatic metabolic dysfunction as a potential systemic contributor to MP-induced neurotoxicity, and offering novel insights into the potential human health risks of MP exposure.