HPA-Axis Dysregulation in Metal and Metalloid-Associated Neurotoxicity: Distinguishing Causal Mediation, Stress Interactions and Secondary Responses

Environmental metal and metalloid exposure are associated with altered hypothalamic–pituitary–adrenal (HPA) axis activity and neurological dysfunction, but the causal role of neuroendocrine changes remains uncertain. This critical review evaluates four competing explanations: HPA-axis dysregulation mediates neural injury; independent stress modifies toxicant effects; endocrine and neuronal disturbances arise through parallel mechanisms; or endocrine changes follow neural or systemic injury. We critically appraise evidence linking glucocorticoid dynamics, glucocorticoid/mineralocorticoid receptor signalling, inflammation and neural dysfunction, emphasising temporality, endocrine sampling, intervention specificity, internal toxicant burden and confounding. Selected experimental studies support glucocorticoid receptor (GR) involvement in particular neural outcomes, but general mediation of metal-associated neurotoxicity by systemic HPA-axis dysfunction remains unestablished. Likewise, greater injury under combined toxicant and stress exposure does not by itself demonstrate biological synergy or endocrine mediation. We distinguish associative findings from temporal support, experimentally tested pathway dependence and convergent functional evidence, while considering alternative mechanisms, including altered toxicant disposition. Priority studies should integrate longitudinal endocrine phenotyping, exposure-relevant factorial designs, receptor-selective interventions, tissue toxicant quantification and neurological outcomes. These approaches could distinguish causal neuroendocrine mechanisms from parallel or secondary responses and improve the interpretation of metal-associated neurological injury.