Environmental Arsenic Exposure and Stress-Related Mental Health Disorders: Mechanisms Shaping Stress Vulnerability

Arsenic is a major public health concern due to associated adverse health effects and widespread exposure through contaminated drinking water, food, and soil. Although traditionally recognized for its carcinogenic and systemic toxicity, increasing evidence indicates that developmental arsenic exposure disrupts neuroendocrine function and may increase susceptibility to stress-related mental health disorders. However, the mechanisms linking arsenic exposure to altered stress responsiveness remain poorly understood. This review summarizes current epidemiological and experimental evidence on how developmental arsenic exposure affects the hypothalamic-pituitary-adrenal (HPA) axis and stress-regulatory circuitry. We discuss the influence of arsenic species, exposure timing, and dose on corticotropin-releasing hormone (CRH) signaling, adrenocorticotropic hormone (ACTH) release, glucocorticoid receptor (GR) function, and glucocorticoid homeostasis. We further highlight emerging mechanisms underlying HPA-axis dysregulation, including epigenetic remodeling, altered neuronal excitability, impaired GR signaling, oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and neuroinflammation. Collectively, these mechanisms provide biologically plausible pathways by which developmental arsenic exposure may increase vulnerability to anxiety, depression, posttraumatic stress disorder, and related neurobehavioral disorders. Finally, we identify key knowledge gaps and research priorities needed to improve developmental neurotoxicity risk assessment and inform regulatory strategies aimed at protecting vulnerable populations from early-life arsenic exposure.