Publications

BACKGROUND

There is growing evidence for the role of oxidative damage in chronic diseases. Although ozone (O3) is an oxidant pollutant to which many people are exposed, few studies have examined whether O3 induces oxidative stress in humans.

OBJECTIVES

This study was designed to assess the effect of short-and long-term O(3) exposures on biomarkers of oxidative stress in healthy individuals.

METHODS

Biomarkers of lipid peroxidation, 8-isoprostane (8-iso-PGF), and antioxidant capacity ferric reducing ability of plasma (FRAP) were analyzed in two groups of healthy college students with broad ranges of ambient O3 exposure during their lifetimes and previous summer recess either in Los Angeles (LA, n = 59) or the San Francisco Bay Area (SF, n = 61).

RESULTS

Estimated 2-week, 1-month, and lifetime O3 exposures were significantly correlated with elevated 8-iso-PGF. Elevated summertime exposures resulted in the LA group having higher levels of 8-iso-PGF than the SF group (p = 0.02). Within each location, males and females had similar 8-iso-PGF. No regional difference in FRAP was observed, with significantly higher FRAP in males in both groups (SF: p = 0.002; LA: p = 0.004). An exposure chamber substudy (n = 15) also showed a significant increase in 8-iso-PGF as well as an inhibition of FRAP immediately after a 4-hr exposure to 200 ppb O3, with near normalization by 18 hr in both biomarkers.

CONCLUSIONS

Long-term exposure to O3 is associated with elevated 8-iso-PGF, which suggests that 8-iso-PGF is a good biomarker of oxidative damage related to air pollution.

Activation of the nuclear enzyme poly(ADP-ribose)-1 leads to the death of neurons and other types of cells by a mechanism involving NAD(+) depletion and mitochondrial permeability transition. It has been proposed that the mitochondrial permeability transition (MPT) is required for NAD(+) to be released from mitochondria and subsequently consumed by PARP-1. In the present study we used the MPT inhibitor cyclosporine-A (CsA) to preserve mitochondrial NAD(+) pools during PARP-1 activation and thereby provide an estimate of mitochondrial NAD(+) pool size in different cell types. Rat cardiac myocytes, mouse cardiac myocytes, mouse cortical neurons, and mouse cortical astrocytes were incubated with the genotoxin N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in order to activate PARP-1. In all four cell types MNNG caused a reduction in total NAD(+) content that was blocked by the PARP inhibitor 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone. Inhibition of the mitochondrial permeability transition with cyclosporine-A (CsA) prevented PARP-1-induced NAD(+) depletion to a varying degree in the four cell types tested. CsA preserved 83.5% +/- 5.2% of total cellular NAD(+) in rat cardiac myocytes, 85.7% +/- 8.9% in mouse cardiac myocytes, 55.9% +/- 12.9% in mouse neurons, and 22.4% +/- 7.3% in mouse astrocytes. CsA preserved nearly 100% of NAD(+) content in mitochondria isolated from these cells. These results confirm that it is the cytosolic NAD(+) pool that is consumed by PARP-1 and that the mitochondrial NAD(+) pool is consumed only after MPT permits mitochondrial NAD(+) to exit into the cytosol. These results also suggest large differences in the mitochondrial and cytosolic compartmentalization of NAD(+) in these cell types.