Particulate pollutants cause adverse health effects through the generation of oxidative stress. A key question is whether these effects are mediated by the particles or their chemical compounds. In this article we show that aliphatic, aromatic, and polar organic compounds, fractionated from diesel exhaust particles (DEPs), exert differential toxic effects in RAW 264.7 cells. Cellular analyses showed that the quinone-enriched polar fraction was more potent than the polycyclic aromatic hydrocarbon (PAH)-enriched aromatic fraction in O
2·
- generation, decrease of membrane potential (
m), loss of mitochondrial membrane mass, and induction of apoptosis. A major effect of the polar fraction was to promote cyclosporin A (CsA)-sensitive permeability transition pore (PTP) opening in isolated liver mitochondria. This opening effect is dependent on a direct effect on the PTP at low doses as well as on an effect on
m at high doses in calcium (Ca
2+)-loaded mitochondria. The direct PTP effect was mimicked by redox-cycling DEP quinones. Although the aliphatic fraction failed to perturb mitochondrial function, the aromatic fraction increased the Ca
2+ retention capacity at low doses and induced mitochondrial swelling and a decrease in
m at high doses. This swelling effect was mostly CsA insensitive and could be reproduced by a mixture of PAHs present in DEPs. These chemical effects on isolated mitochondria could be reproduced by intact DEPs as well as ambient ultrafine particles (UFPs). In contrast, commercial polystyrene nanoparticles failed to exert mitochondrial effects. These results suggest that DEP and UFP effects on the PTP and
m are mediated by adsorbed chemicals rather than the particles themselves.
Key words: apoptosis, DEPs, diesel exhaust particles, PAHs, permeability transition pore, polycyclic aromatic hydrocarbons, quinones, ultrafine particles.
Environ Health Perspect 112:1347-1358 (2004). [Online 7 July 2004]
Address correspondence to A. Nel, Department of Medicine, Division of Clinical Immunology and Allergy, UCLA School of Medicine, 52-175 CHS, 10833 Le Conte Ave., Los Angeles, CA 90095-1680 USA. Telephone: (310) 825-6620. Fax: (310) 206-8107. E-mail: anel@mednet.ucla.edu
This work was supported by U.S. Public Health Service grants PO1 AI50495, RO1 ES10553, and RO1 ES10253 and by a U.S. Environmental Protection Agency (EPA) STAR award to the Southern California Particle Center and Supersite.
This work has not been subjected to the U.S. EPA for peer and policy review.
The authors declare they have no competing financial interests.
Received 8 April 2004; accepted 7 July 2004.
