Convergent molecular mechanisms of chronic heavy metal exposure and repetitive mild traumatic brain injury in neurodegenerative processes.

Repetitive mild traumatic brain injury (rmTBI) and chronic environmental exposure to heavy metals represent widespread contributors to neurological dysfunction that are typically studied independently. However, emerging evidence indicates that these insults converge on overlapping cellular pathways that disrupt neuronal homeostasis, redox balance, genomic stability and proteostasis, including tau regulation. Notably, environmental metals including mercury, lead, arsenic, cadmium, and hexavalent chromium induce oxidative stress, mitochondrial dysfunction, and neuroinflammatory signaling, processes that are also central to rmTBI pathophysiology. In this review, we synthesize mechanistic and clinical evidence linking chronic heavy metal exposure and rmTBI and examine how their interaction may influence long-term vulnerability to neurodegeneration. To our knowledge, this is the first review to integrate these two domains within a unified mechanistic framework. We first summarize shared and metal-specific mechanisms of heavy metal neurotoxicity and integrate these findings with the cellular and systemic consequences of rmTBI. Attention is given to higher-order convergent processes, including disruption of the blood-brain barrier, dysregulation of the gut-brain axis, protein misfolding and tau pathology, ferroptosis, and impairment of proteostatic and autophagic pathways. We also discuss emerging biomarker signatures and therapeutic targets relevant to combined environmental and traumatic exposures. Collectively, current evidence supports a model in which chronic heavy metal burden may diminish neural resilience and could increase vulnerability to the cumulative effects of rmTBI. Although direct evidence of their interaction remains limited, the substantial mechanistic overlap provides a framework for future studies investigating environmental contributions to post-traumatic neurodegeneration, biomarker discovery, and potential therapeutic strategies.