While it has been hypothesized that the adverse health effects associated with ambient particulate matter (PM) are due to production of hydroxyl radical (·OH), few studies have quantified ·OH production from PM. Here we report the amounts of ·OH produced from ambient fine particles (PM 2.5 ) collected in northern California and extracted in a cell-free surrogate lung fluid (SLF). On average, the extracted particles produced 470 nmol ·OH mg −1 -PM 2.5 during our 15-month collection period. There was a clear seasonal pattern in the efficiency with which particles generated ·OH, with highest production during spring and summer and lowest during winter. In addition, nighttime PM was typically more efficient than daytime PM at generating ·OH. Transition metals played the dominant role in ·OH production: on average (± σ), the addition of desferoxamine (a chelator that prevents metals from forming ·OH) to the SLF removed (90 ± 5) % of ·OH generation. Furthermore, based on the concentrations of Fe in the PM 2.5 SLF extracts, and the measured yield of ·OH as a function of Fe concentration, dissolved iron can account for the majority of ·OH produced in most of our PM 2.5 extracts.
Epidemiological research has linked exposure to atmospheric particulate matter (PM) to several adverse health effects, including cardiovascular and pulmonary morbidity and mortality. Despite these links, the mechanisms by which PM causes adverse health effects are poorly understood. The generation of hydroxyl radical (.OH) and other reactive oxygen species (ROS) through transition metal-mediated pathways is one of the main hypotheses for PM toxicity. In order to better understand the ability of particulate transition metals to produce ROS, we have quantified the amounts of .OH produced from dissolved iron and copper in a cell-free, surrogate lung fluid (SLF). We also examined how two important biological molecules, citrate and ascorbate, affect the generation of .OH by these metals. We have found that Fe(II) and Fe(III) produce little .OH in the absence of ascorbate and citrate, but that they efficiently make .OH in the presence of ascorbate and this is further enhanced when citrate is also added. In the presence of ascorbate, with or without citrate, the oxidation state of iron makes little difference on the amount of .OH formed after 24 hours. In the case of Cu(II), the production of .OH is greatly enhanced in the presence of ascorbate, but is inhibited by the addition of citrate. The mechanism for this effect is unclear, but appears to involve formation of a citrate-copper complex that is apparently less reactive than free, aquated copper in either the generation of HOOH or in the Fenton-like reaction of copper with HOOH to make .OH. By quantifying the amount of .OH that Fe and Cu can produce in surrogate lung fluid, we have provided a first step into being able to predict the amounts of .OH that can be produced in the human lung from exposure to PM containing known amounts of transition metals.
The present work describes a two-stage approach to analyzing combustion-generated samples for their potential to produce oxidant stress. This approach is illustrated with the two commonly encountered transition metals, copper and iron. First, their abilities to generate hydroxyl radical were measured in a cell-free, phosphate-buffered saline solution containing ascorbate and/or citrate. Second, their abilities to induce heme oxygenase-1 in cultured human epidermal keratinocytes were assessed in cell culture. Combustion-generated copper oxide nanoparticles were active in both assays and were found to be soluble in culture medium. Depletion of glutathione in the cells or loading the cells with ascorbate greatly increased heme oxygenase-1 induction in the presence of copper. By contrast, iron oxide nanoparticles were active in the phosphate buffered saline but not in cell culture, and they aggregated in culture medium. Soluble salts of copper and iron exhibited the same contrast in activities as the respective combustion-generated particles. The results suggest that the capability of combustion-generated environmental samples to produce oxidant stress can be screened effectively in a two step process, first in phosphate buffered saline with ascorbate and subsequently in epithelial cell culture for those exhibiting activity initially. The results also point to an unanticipated interaction in cells of oxidant stress-generating metals with an anti-oxidant (ascorbate) that is usually missing in culture medium formulations. Thus, ascorbate supplementation of cultured human cells is likely to improve their ability to model the in vivo effects of particulate matter containing copper and other redox-active metals.
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