Astrocyte-microglia crosstalk in Lead-induced neurotoxicity: Molecular signaling and downstream pathological sequelae

This review strives to examine lead-induced neurotoxicity with emphasis on glial-astrocytes, microglia, and oligodendrocytes responses in the context of pervasive environmental pollution and cognitive deficits. It further emphasizes dysregulated neurotrophins and growth-factor signaling as key contributors to impaired neuronal health and cognition. It underscores the interplay among oxidative stress, DNA damage, neurotransmitter imbalance, and altered cellular signaling, emphasizing the central role of glial cells. These cells maintain neural integrity and mediate responses to environmental pollutants; however, lead exposure disrupts their function, suppressing antioxidant defences, activating inflammatory pathways, and ultimately driving neuronal dysfunction. Pb cytotoxicity arises from a coordinated network of cellular responses, with PKC-MAPK-AP, TLR4-NF-κB, and IL-6/TGF-β etc., transcription-factor (NF-κB/Nrf2), and mTOR-mediated autophagy pathways playing key roles in driving dysregulated inflammatory and oxidative-stress processes. Comprehensive interrogation of lead-driven perturbations in glial morphology, activation dynamics, and mitochondrial integrity delineates a cascading sequence of neuroinflammatory and neurodegenerative pathologies initiated upon exposure. The review advocates a multidisciplinary investigative framework, highlighting the critical roles of the neural microenvironment, epigenetic methylation processes, and Pb-protein complex formation in neurotoxicity. It stresses the integration of environmental science, neurobiology, and toxicology to develop omics (proteomics, metabolomics, and ionomics)-based targeted therapeutic and preventive approaches. By dissecting glial cell dynamics, the review seeks to propel public-health and neurotoxicology initiatives aimed at mitigating Pb-induced cognitive decline and neurodegenerative pathology, ultimately advancing global disease-burden reduction.