Lead and arsenic toxicity: emerging mechanisms, immunotoxic effects, and future research perspectives.

Abstract

Lead (Pb) and arsenic (As) are two of the most widespread environmental toxicants, posing significant immunological and systemic health risks worldwide. This review synthesizes current knowledge on the immunotoxicity of Pb and As, highlighting their shared and unique cellular mechanisms, with a focus on oxidative stress, mitochondrial dysfunction, immune dysregulation, and epigenetic modifications. Pb exposure has been shown to suppress CD4⁺ T cell populations, alter CD8⁺ and NK cell ratios, elevate Th2 cytokines like IL-4 and IL-6, and increase IgE levels, contributing to heightened allergy risk and systemic inflammation. Arsenic disrupts IL-6/STAT3 signaling, suppresses IFN-α/β-mediated antiviral responses, and promotes chronic inflammation through NF-κB and HIF-1α activation. Both metals generate reactive oxygen species (ROS), impair mitochondrial membrane potential, trigger apoptotic cascades, and induce genotoxic markers such as γH2AX and micronuclei. Co-exposure to Pb and As results in enhanced toxicity, with synergistic increases in lipid peroxidation (MDA), nitric oxide, cytokine release, and histopathological damage in liver and kidney tissues. However, most toxicological models overlook low-dose, chronic, and combined exposures. We emphasize the urgent need for chronic exposure studies, prospective human cohorts, multi-metal models, and omics-integrated approaches to identify early biomarkers of dysfunction. This review underscores the global public health urgency of addressing Pb and As co-exposure through multidisciplinary research, regulatory reform, and targeted interventions, particularly in vulnerable populations across high-risk regions.