Toxicology Letters 194 (2010) 58–65 Contents lists available at ScienceDirect Toxicology Letters journal homepage: www.elsevier.com/locate/toxlet Time-course effects of systemically administered diesel exhaust particles in rats Abderrahim Nemmar a,∗ , Suhail Al-Salam b , Shaheen Zia a , Subramanian Dhanasekaran a , Munjusha Shudadevi b , Badreldin H. Ali c a Department of Physiology, Faculty of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, Abu Dhabi, United Arab Emirates b Department of Pathology, Faculty of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates c Department of Pharmacology and Clinical Pharmacy, College of Medicine & Health Sciences, Sultan Qaboos University, P.O. Box 35, Muscat 123, Al-Khod, Oman article info Article history: Received 22 June 2009 Received in revised form 1 February 2010 Accepted 1 February 2010 Available online 7 February 2010 Keywords: Diesel exhaust particles Lung inflammation Systemic inflammation Rats abstract Nanosized fraction of particulate air pollution has been reported to translocate from the airways into the bloodstream and act on different organs. However, the direct effect of these translocated particles is not well understood. In this study, we determined the time-course (6h, 18 h, 48 h and 168 h) effects of the systemic administration of 0.02 mg/kg diesel exhaust particles (DEP) on systolic blood pressure (SBP), sys- temic inflammation, oxidative status, and morphological alterations in lungs, heart, liver and kidneys in Wistar rats. SBP was significantly decreased at 6 h (P < 0.05) but no significant effects have been observed at later time points. The leukocyte numbers were increased at 6 h (P < 0.05) and 18 h (P < 0.05). However, the platelet numbers were significantly decreased (P < 0.05) 6 h following the systemic administration of DEP. The IL-6 concentrations in plasma was increased at 6 h (P < 0.05) and 18 h (P < 0.05). Similarly, superoxide dismutase activity was significantly increased at 6 (P = 0.01) and 18 h (P < 0.05) following DEP exposure. The direct addition of DEP (0.1–1 g/ml) to untreated rat blood significantly induced in vitro platelet aggregation in a dose-dependent fashion. The activation of intravascular coagulation was con- firmed by a dose-dependent shortening of activated partial thromboplastin time and the prothrombin time following in vitro exposure to DEP (0.25–1 g/ml). Histological analysis revealed the presence of DEP in the lungs, heart, liver and kidneys. However, the morphological changes were only observed in the lungs, where the presence of infiltration of inflammatory cells was observed as early as 6 h, increased at 18 h, and decreased in intensity at 48 h and at 168 h. We conclude that the direct systemic adminis- tration of DEP caused acute effect on SBP (6 h) and systemic inflammation and oxidative stress mainly at 6 h and 18 h. Despite the presence of DEP in lungs, heart, liver and kidneys, the histopathological changes were only seen in the lung which suggests that, at the dose and time-points investigated, DEP cause inflammation and have a predilection for pulmonary tissue. © 2010 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Although air pollution consists of a heterogeneous mixture of gaseous and particulate matter, adverse cardiovascular events are most strongly associated with exposure to fine particulate matter (diameter < 2.5 m, PM2.5) (Brook et al., 2004; Mills et al., 2009). An important component of PM2.5 is nanoparticulate matter gen- erated during the combustion of diesel fuel (Shi et al., 2000). These particles, with an aerodynamic diameter ≤100 nm, readily deposit within human alveoli and possess a considerable surface area that may contribute to their toxicity (Oberdorster, 2001; Oberdorster et al., 2005). Despite the consistency of the epidemiologic observations, the pathophysiological mechanisms linking air pollution with adverse ∗ Corresponding author. Tel.: +971 37137533; fax: +971 3 7671966. E-mail addresses: anemmar@uaeu.ac.ae, anemmar@hotmail.com (A. Nemmar). cardiovascular events remain unclear. There are three primary hypotheses being investigated to explain the extrapulmonary effect of nanoparticles (Oberdorster et al., 2005; Vermylen et al., 2005). The first one relates the effect of particles to their ability to impact the autonomic nervous system, leading to changes in the pattern of breathing, heart rate and heart rate variability. Inhaled parti- cles may affect the cardiovascular system through inflammatory mediators (e.g., cytokines, histamine) produced in the lungs and released into the circulation (Oberdorster et al., 2005; Vermylen et al., 2005). Moreover, several studies have showed that nanopar- ticles, owing to their small size, could avoid normal phagocytic defenses in the respiratory system and gain access to the sys- temic circulation and, therefore to different extrapulmonary sites (Oberdorster et al., 2002; Elder et al., 2006; Kreyling et al., 2002; Nemmar et al., 2001, 2002, 2009b; Wallenborn et al., 2007; Pery et al., 2009). To specifically determine the effect of translocated particles, we recently demonstrated in Wistar Kyoto rats that 24 h follow- 0378-4274/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.toxlet.2010.02.001