Environmentally relevant lanthanum chloride exposure induces neurotoxicity in zebrafish through serotonergic disruption and synaptic dysfunction.

Abstract

Rare earth elements are emerging environmental contaminants with potential neurological effects. Lanthanum (La), a widely used rare earth element, has drawn attention for its potential neurotoxicity. However, whether environmentally relevant La exposure induces neurobehavioral dysfunction and the associated neural mechanisms remains unclear. In the present study, adult zebrafish were treated with environmentally relevant concentrations of LaCl3 (0, 1, and 10 μM) for 21 days, after which neurobehavioral and neurotoxic effects were evaluated using behavioral assays, histopathology, ultrastructural analysis, and multi-omics analysis. We demonstrated that LaCl3 exposure increased dark preference and bottom-dwelling behavior and reduced exploratory activity. Histological examination further revealed neuropathological alterations, including interstitial vacuolation, neuronal degeneration, and reduction of Nissl bodies. Targeted metabolomics revealed significant alterations in serotonin-related metabolites, including TP, 5-HTP, and 5-HIAA. In addition, immunofluorescence analysis demonstrated reduced 5-HT levels, collectively indicating serotonergic system impairment. Transcriptomic analysis further indicated the suppression of serotonergic signaling, as reflected by the downregulation of the serotonin receptor gene htr2b. Meanwhile, the marked decreases in Egr family genes, including egr1, egr2b, and egr4, suggested that altered Egr signaling may be associated with the synaptic dysfunction observed following LaCl3 exposure. This interpretation is further supported by synaptic ultrastructural damage and reduced PSD-95 and Syn levels. Importantly, pharmacological activation of 5-HT2 receptors with DOI alleviated the behavioral, neuropathological, and synaptic abnormalities induced by LaCl3. Together, these findings indicate that environmentally relevant LaCl3 exposure disrupts serotonergic signaling and synaptic integrity, leading to neurotoxicity in zebrafish. This study provides mechanistic insight into La-induced neurotoxicity and highlights the potential neurological risks associated with environmental rare earth contamination.