title: Inhaled environmental combustion particles cause myocardial injury in the Wistar Kyoto rat.
abstract: Epidemiologists have associated particulate matter (PM) air pollution with cardiovascular morbidity and premature mortality worldwide. However, experimental evidence demonstrating causality and pathogenesis of particulate matter (PM)-induced cardiovascular damage has been insufficient. We hypothesized that protracted, repeated inhalation by rats of oil combustion-derived, fugitive emission PM (EPM), similar in metal composition to selected sources of urban air PM, causes exposure duration- and dose-dependent myocardial injury in susceptible rat strains. Zinc was the only primary water-leachable/bioavailable element of this EPM. Male Sprague-Dawley (SD), Wistar Kyoto (WKY), and spontaneously hypertensive (SH) rats were exposed nose-only to EPM (2, 5, or 10 mg/m(3), 6 h/day for 4 consecutive days or 10 mg/m(3), 6 h/day, 1 day/week for 4 or 16 consecutive weeks). Two days following the last EPM exposure, cardiac and pulmonary tissues were examined histologically. The results showed that particle-laden alveolar macrophages were the only pulmonary lesions observed in all three rat strains. However, WKY rats exposed to EPM (10 mg/m(3) 6 h/day, 1 day/week for 16 weeks) demonstrated cardiac lesions with inflammation and degeneration. To further characterize the nature of EPM-associated lesions, more rigorous histopathological and histochemical techniques were employed for WKY and SD rats. We examined the hearts for myocardial degeneration, inflammation, fibrosis, calcium deposits, apoptosis, and the presence of mast cells. Decreased numbers of granulated mast cells, and multifocal myocardial degeneration, chronic-active inflammation, and fibrosis were present in 5 of 6 WKY rats exposed to EPM for 16 weeks. None of these lesions were present in WKY exposed to clean air. EPM-related cardiac lesions were indistinguishable from air-exposed controls in SD and SH rats. This study demonstrates that long-term inhalation exposures to environmentally relevant PM containing bioavailable zinc can cause myocardial injury in sensitive rats. These findings provide supportive evidence for the epidemiological associations of cardiovascular morbidity and ambient PM.
authors.affiliation: Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27709, USA. kodavanti.urmila@epa.gov
authors.forename: Urmila P
authors.initials: UP
authors.lastname: Kodavanti
authors.forename: Carolyn F
authors.initials: CF
authors.lastname: Moyer
authors.forename: Allen D
authors.initials: AD
authors.lastname: Ledbetter
authors.forename: Mette C
authors.initials: MC
authors.lastname: Schladweiler
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Costa
authors.forename: Russ
authors.initials: R
authors.lastname: Hauser
authors.forename: David C
authors.initials: DC
authors.lastname: Christiani
authors.forename: Abraham
authors.initials: A
authors.lastname: Nyska
mesh_terms: D000280:Administration, Inhalation; D000393:Air Pollutants / Q000032:analysis / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis / Q000139:chemically induced / Q000473:pathology; D006321:Heart / Q000187:drug effects; D020287:In Situ Nick-End Labeling; D019570:Inhalation Exposure; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000473:pathology; D008297:Male; D009205:Myocarditis / Q000139:chemically induced* / Q000473:pathology; D009206:Myocardium / Q000473:pathology*; D010316:Particle Size; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013047:Specific Pathogen-Free Organisms; D013194:Staining and Labeling; D001335:Vehicle Emissions / Q000032:analysis / Q000633:toxicity*; D015032:Zinc / Q000032:analysis
chemical_list: D000393:Air Pollutants; D001335:Vehicle Emissions; D015032:Zinc