Non-redox cycling mechanisms of oxidative stress induced by PM metals

Abstract

Metallic compounds contribute to the oxidative stress of ambient particulate matter (PM) exposure. The toxicity of redox inert ions of cadmium, mercury, lead and zinc, as well as redox-active ions of vanadium and chromium is underlain by dysregulation of mitochondrial function and loss of signaling quiescence. Central to the initiation of these effects is the interaction of metal ions with cysteinyl thiols on glutathione and key regulatory proteins, which leads to impaired mitochondrial electron transport and persistent pan-activation of signal transduction pathways. The mitochondrial and signaling effects are linked by the production of H₂O₂, generated from mitochondrial superoxide anion or through the activation of NADPH oxidase, which extends the range and amplifies the magnitude of the oxidative effects of the metals. This oxidative burden can be further potentiated by inhibitory effects of the metals on the enzymes of the glutathione and thioredoxin systems. Along with the better-known Fenton-based mechanisms, the non-redox cycling mechanisms of oxidative stress induced by metals constitute significant pathways for cellular injury induced by PM inhalation.

Fig. 1.

Non-cycling mechanisms of oxidative stress induced by metals in ambient air particulate matter. Redox inert PM metal ions of Pb, Cr, Cd, Zn and As, as well as those of some redox active metals like V and Hg, can interact with cysteinyl thiols in glutathione (GSH) and regulatory proteins. Direct or H₂O₂-mediated inhibition of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) increases levels of reduced nicotinamide adenine dinucleotide phosphate (NADPH) through the pentose phosphate pathway (PPP), while inhibition of protein tyrosine phosphatases (PTP) allows unopposed basal kinase activity in the epidermal growth factor receptor (EGFR) and downstream signaling through mitogen activating kinase (MAPK), nuclear factor kappa B (NFkB) and phosphatidyl-inositol-3 kinase (PI3K/Akt), leading to downstream signaling, inflammatory gene expression and activation of NADPH oxidase (NOX), a source of H₂O₂. Metal effects on mitochondrial proteins impairs electron flow, increasing the production of superoxide anion (O₂^.−) which is dismutated to H₂O₂ by superoxide dismutase (SOD). Dysregulation of Ca²⁺ transport increases its levels in the mitochondria and the cytosol, promoting the opening of the membrane permeability transition pore (MPTP) and the activation of NOX by kinases such as protein kinase C (PKC). Oxidative effects are potentiated by direct metal interaction with thiol-containing antioxidant enzymes glutathione reductase (GR), thioredoxin (Trx) and Trx-system proteins thioredoxin reductase (TrxR) and peroxiredoxin (Prx). Evidence is mounting for a pro-oxidant role of Prx in mediating intracellular reactions of H₂O₂. Binding to the metal sensing module in Keap1 leads to the activation of nuclear erythroid factor 2 kinase, hemeoxygenase-1 expression and adaptation. Metal-induced activation of B-cell lymphoma 2 (Bcl-2) can lead to apoptosis through the activation of the mitochondrial apoptosis-induced channel (MAC). Activating processes are depicted by blue arrows, inhibitory effects are shown in red arrows.