The influence of chemical composition, aerosol acidity, and metal dissolution on the oxidative potential of fine particulate matter and redox potential of the lung lining fluid

Air pollution is a major environmental health risk and it contributes to respiratory and cardiovascular diseases and excess mortality worldwide. The adverse health effects have been associated with the inhalation of fine particulate matter (PM2.5) and induction of respiratory oxidative stress. In this work, we quantified the oxidative potential (OP) of PM2.5 from several Canadian cities (Toronto, Hamilton, Montreal, Vancouver) using a recently developed bioanalytical method which measures the oxidation of lung antioxidants, glutathione, cysteine, and ascorbic acid, the formation of glutathione disulfide and cystine, and the related redox potential (RP) in a simulated epithelial lining fluid (SELF). We evaluated the application of empirical SELF RP as a new metric for aerosol OP. We further investigated how PM2.5 chemical composition and OP are related across various emission source sectors and whether these features are linked to specific properties of aerosol aqueous phase, such as pH and metal-ligand complexation. The OP indicators including SELF RP were strongly correlated among each other, indicating that the empirical RP could be used as a reliable metric in future studies. OP based on ascorbic acid showed dependency on the emission source sectors, most likely due to variation in the solubility of Fe. Traffic emissions resulted in the highest OP, followed by industrial emissions and resuspended crustal matter. OP presented low correlation with PM2.5 concentrations, low-moderate correlation with the aerosol organic matter, and moderate-strong association with black carbon and transition metals across the sites. We did not find strong association between the concentration of biomass burning tracers and OP. Copper was the only metal that showed high association with OP across all sites, whereas the correlation with other metals, such as iron, manganese, and titanium, showed clear dependency on the source sectors. The aerosol pH correlated negatively with ambient temperature and positively with biomass burning tracers and the levels of nitrate, ammonium, and aerosol liquid water content. The solubility of Fe was associated with sulfate and aerosol pH at most sites, suggesting the involvement of proton-mediated dissolution pathway, while this was not visible at the site influenced by industrial emission, most likely due to the abundance of pyrogenic Fe. The effect of metal-ligand complexation on the solubility of transition metals, in particular Fe, was clearly observed at all sites, whereas a combined effect with aerosol pH, and a subsequent impact on OP, was only seen at the traffic site in Toronto. The enhanced solubility of Fe due to proton- and ligand-mediated dissolution pathways and subsequent formation of reactive oxygen species may in part explain the health effects of PM2.5 seen in previous epidemiological studies.

Highly Acidic Ambient Particles, Soluble Metals, and Oxidative Potential: A Link between Sulfate and Aerosol Toxicity

Hairun Guo, Athanasios Nenes

Soluble transition metals in particulate matter (PM) can generate reactive oxygen species in vivo by redox cycling, leading to oxidative stress and adverse health effects. Most metals, such as those from roadway traffic, are emitted in an insoluble form, but must be soluble for redox cycling. Here we present the mechanism of metals dissolution by highly acidic sulfate aerosol and the effect on particle oxidative potential (OP) through analysis of size distributions. Size-segregated ambient PM were collected from a road-side and representative urban site in Atlanta, GA. Elemental and organic carbon, ions, total and water-soluble metals, and water-soluble OP were measured. Particle pH was determined with a thermodynamic model using measured ionic species. Sulfate was spatially uniform and found mainly in the fine mode, whereas total metals and mineral dust cations were highest at the road-side site and in the coarse mode, resulting in a fine mode pH < 2 and near neutral coarse mode. Soluble metals and OP peaked at the intersection of these modes demonstrating that sulfate plays a key role in producing highly acidic fine aerosols capable of dissolving primary transition metals that contribute to aerosol OP. Sulfate-driven metals dissolution may account for sulfate-health associations reported in past studies. © 2017 American Chemical Society.

American Chemical Society2017

Analysis of mice with conditional ferritin H deletion

Liviu Vanoaica

Iron is a transitional metal required by virtually all organisms as a dietary micromineral, indispensable for cellular survival and proliferation. The management of iron absorption and distribution in the organism and inside the cell must be tightly regulated in order to avoid the deleterious consequences of free iron-induced oxidative stress. Ferritin is the major protein responsible for iron storage and release of intracellular iron. Ferritin shells are formed from two types of subunits, known as H and L. The present work investigates the effects of conditional ferritin H deletion in mice. A broad ferritin H deletion in liver, spleen, bone marrow and thymus results in an alteration of iron metabolism, characterized by increased transferrin saturation and hepcidin mRNA levels and decreased liver iron deposits. Iron loading prior to deletion leads to liver failure early after deletion, showing that ferritin H is indispensable for limiting iron toxicity through iron sequestration. A hepatocyte-specific deletion fails to reproduce the same phenotype, suggesting an important role for Kupffer macrophages in liver iron detoxification. Ferritin H is also required for B lymphocyte survival, as indicated by the loss of mature B cells in an CD19-specific ferritin H deletion mouse strain, where this population is substantially reduced because of massive reactive oxygen species generation. Conditional deletion in heart leads to fibrosis, increased oxidative stress and to a switch towards a gene expression profile characteristic for cardiac hypertrophy, while iron loading prior to deletion causes a dramatic alteration of the cardiac output function and ultimately to heart failure. An intestine-specific ferritin H deletion results in a typical hemochromatotic phenotype, characterized by increased transferrin saturation and liver iron stores, increased hepcidin expression and decreased IRP2 activity. Hepcidin-mediated ferroportin downregulation at protein level is also shown not to be sufficient to limit the intestinal iron export. An modified version of the current model of intestinal iron absorption is proposed, that includes the function of ferritin H as an iron sink in intestine. This work contributes to a better understanding of iron metabolism in general and intestinal iron absorption in particular, and it might have an impact on the development of treatments against human hemochomatosis and anemia.

EPFL2009

Therapeutic potential of glutathione-enhancers in stress-related psychopathologies

Fiona Hollis, Laia Morato Fornaguera, Eva Ramos Fernandez, Maria del Carmen Sandi Perez, Sarah Catherine Sonnay, Pascal Steiner, Ioannis Zalachoras

The mammalian brain has high energy demands, which may become higher in response to environmental challenges such as psychogenic stress exposure. Therefore, efficient neutralization of reactive oxygen species that are produced as a by-product of ATP synthesis is crucial for preventing oxidative damage and ensuring normal energy supply and brain function. Glutathione (GSH) is arguably the most important endogenous antioxidant in the brain. In recent years, aberrant GSH levels have been implicated in different psychiatric disorders, including stress-related psychopathologies. In this review, we examine the available data supporting a role for GSH levels and antioxidant function in the brain in relation to anxiety and stress-related psychopathologies. Additionally, we identify several promising compounds that could raise GSH levels in the brain by either increasing the availability of its precursors or the expression of GSH-regulating enzymes through activation of Nuclear factor erythroid-2-related factor 2 (Nrf2). Given the high tolerability and safety profile of these compounds, they may represent attractive new opportunities to complement existing therapeutic manipulations against stress-related psychopathologies.

2020

Analysis of mice with conditional ferritin H deletion

Liviu Vanoaica

EPFL2009