Lead (Pb)-Induced Neurotoxicity in Zebrafish (Danio rerio): A Narrative Review of Mechanisms, Biomarkers and Behavioral Outcomes.

Abstract

Background: Lead (Pb) is present in the environment and is a neurotoxic substance that has important implications for global public health and ecosystem stability. Given its high genetic similarity and short developmental time, the zebrafish (Danio rerio) has become a model organism of choice to study these effects. A clear mechanistic link between molecular triggers and functional neurobehavioral deficits is crucial to improve environmental risk assessment. Methods: Literature published in PubMed, Scopus and Web of Science (2013-2026) was used for the synthesis, which was organized into a structured narrative format. This review concentrated on the molecular signalling, developmental biomarkers and the changes in behaviour induced by exposure to Pb that have been studied during the past decade. Results: Oxidative stress is synthesized evidence as a major initiating event that leads to involvement of mitochondrial dysfunction, lipid peroxidation and apoptotic signaling. The main molecular alterations are related to alterations of dopaminergic and cholinergic pathways and they are related to a specific ontogenetic transition - hyperactivity in the larvae and anxiety-like behavior and cognitive impairment in the adults. Markers of acute stress, like Heme Oxygenase-1 (HO-1) and Brain-Derived Neurotrophic Factor (BDNF), are sensitive markers but new evidence points to transgenerational risks through epigenetic remodeling. Conclusions: Zebrafish is a powerful tool to map the neurotoxic cascade. There are, however, methodological variations among studies and a lack of consistency in the doses applied, with supra-environmental doses used that are not representative of in situ aquatic hotspots (10-50 mg/L). Future studies should focus on standardization of behavioral testing methods and chronic low-dose exposures to mimic the exposures used in the Ecological Risk Assessment (ERA) framework to increase translational relevance (Figure 1).