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<p>Lead is a persistent environmental heavy metal and a potent neurotoxin that continues to threaten global public health despite regulatory restrictions. Chronic and developmental exposure, particularly during early life, leads to persistent structural and functional disturbances in the central nervous system. This review provides a comprehensive analysis of the mechanisms underlying lead-induced neurotoxicity, integrating molecular, cellular, histopathological, and behavioral evidence from both rodent and zebrafish models. The review further summarizes blood–brain barrier disruption, oxidative stress, mitochondrial dysfunction, synaptic impairment, neuroinflammation, apoptosis, neurotransmitter dysregulation, and neurodevelopmental alterations associated with lead exposure in experimental animal models. Lead crosses the blood–brain barrier by mimicking essential divalent cations such as Ca<sup>2</sup>⁺, Zn<sup>2</sup>⁺, and Fe<sup>2</sup>⁺, thereby disrupting calcium signalling and impairing neuronal communication. Once in the brain, lead induces oxidative stress through excessive reactive oxygen species generation, mitochondrial dysfunction, lipid peroxidation, DNA damage, and depletion of antioxidant defenses. Lead also impairs synaptic plasticity by altering NMDA receptor subunit composition, reducing synaptic protein expression, and dysregulating genes involved in neurodevelopment. In parallel, it activates both intrinsic and extrinsic apoptotic pathways and enhances neuroinflammatory signaling through microglial and astrocytic activation, further contributing to neuronal injury. Experimental studies demonstrate hippocampal degeneration, Purkinje cell loss, synaptic ultrastructural alterations, impaired long-term potentiation, and cognitive dysfunction in rodents. Zebrafish models reveal disrupted neurodevelopment, altered expression of gfap, huC, neurexin, and antioxidant-related genes, behavioral abnormalities, and circadian rhythm disturbances. Overall, the study indicates that lead neurotoxicity arises from interconnected mechanisms involving oxidative stress, synaptic dysfunction, apoptosis, mitochondrial impairment, and neuroinflammation. A comprehensive understanding of these pathways is essential for early risk assessment, therapeutic target identification, and the development of effective neuroprotective interventions against lead-induced brain injury.</p> Graphical abstract <p></p>

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Molecular and cellular mechanisms of lead-induced neurotoxicity: comparative insights from rodent and zebrafish models

  • 期刊论文

  • 发表日期：

    2026年8月1日

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  • Sayed Mohammed Firdous,
  • Durga Maity,
  • Souvik Marick

摘要

Lead is a persistent environmental heavy metal and a potent neurotoxin that continues to threaten global public health despite regulatory restrictions. Chronic and developmental exposure, particularly during early life, leads to persistent structural and functional disturbances in the central nervous system. This review provides a comprehensive analysis of the mechanisms underlying lead-induced neurotoxicity, integrating molecular, cellular, histopathological, and behavioral evidence from both rodent and zebrafish models. The review further summarizes blood–brain barrier disruption, oxidative stress, mitochondrial dysfunction, synaptic impairment, neuroinflammation, apoptosis, neurotransmitter dysregulation, and neurodevelopmental alterations associated with lead exposure in experimental animal models. Lead crosses the blood–brain barrier by mimicking essential divalent cations such as Ca2⁺, Zn2⁺, and Fe2⁺, thereby disrupting calcium signalling and impairing neuronal communication. Once in the brain, lead induces oxidative stress through excessive reactive oxygen species generation, mitochondrial dysfunction, lipid peroxidation, DNA damage, and depletion of antioxidant defenses. Lead also impairs synaptic plasticity by altering NMDA receptor subunit composition, reducing synaptic protein expression, and dysregulating genes involved in neurodevelopment. In parallel, it activates both intrinsic and extrinsic apoptotic pathways and enhances neuroinflammatory signaling through microglial and astrocytic activation, further contributing to neuronal injury. Experimental studies demonstrate hippocampal degeneration, Purkinje cell loss, synaptic ultrastructural alterations, impaired long-term potentiation, and cognitive dysfunction in rodents. Zebrafish models reveal disrupted neurodevelopment, altered expression of gfap, huC, neurexin, and antioxidant-related genes, behavioral abnormalities, and circadian rhythm disturbances. Overall, the study indicates that lead neurotoxicity arises from interconnected mechanisms involving oxidative stress, synaptic dysfunction, apoptosis, mitochondrial impairment, and neuroinflammation. A comprehensive understanding of these pathways is essential for early risk assessment, therapeutic target identification, and the development of effective neuroprotective interventions against lead-induced brain injury.

Graphical abstract