Rationale : Acute and chronic exposures to airborne particulate matter (PM) have been linked in epidemiological studies to a wide spectrum of cardiovascular disorders that are characterized by a dysfunctional endothelium. The pathophysiological mechanisms underlying these associations are unclear. Objective : To examine whether exposure to fine PM with an aerodynamic diameter of <2.5 μm (PM _2.5 ) affects the circulating levels of endothelial progenitor cell (EPC) populations, systemic inflammation and coagulation. Methods and Results : Phenotypically distinct EPC populations were quantified by flow cytometry in young (18 to 25 years) adult humans exposed to episodic increases in PM _2.5 along the Wasatch Mountain Front in Utah. In addition, Sca-1 ⁺ /Flk-1 ⁺ cells were measured in the peripheral blood of mice exposed to concentrated particles from ambient air in Louisville, Ky. In both studies, PM exposure was negatively correlated with circulating EPC levels. In humans, statistically significant associations between PM _2.5 exposure and the plasma levels of platelet–monocyte aggregates, high-density lipoprotein, and nonalbumin protein were also observed. Episodic increases in PM _2.5 did not change plasma levels of C-reactive protein, interleukin-1β, interleukin-6, fibrinogen, or serum amyloid A. Conclusions : Episodic exposure to PM _2.5 induces reversible vascular injury, reflected in part by depletion of circulating EPC levels, and increases in platelet activation and the plasma level of high-density lipoprotein. These changes were also accompanied by an increase in nonalbumin protein and may be related to mechanisms by which exposure to particulate air pollution increases the risk of cardiovascular disease and adverse cardiovascular events.

Vast amounts of plastic materials are produced in the modern world and despite recycling efforts, large amounts are disposed in water systems and landfills. Under these storage conditions, physical weathering and photochemical processes break down these materials into smaller particles of the micro- and nano-scale. In addition, ecosystems can be contaminated with plastic particles which are manufactured in these size ranges for commercial purposes. Independent of source, microplastics are abundant in the environment and have found their way into water supplies and the food cycle where human exposure is inevitable. Nevertheless, the health consequences of microplastic ingestion, inhalation, or absorption are largely unknown. In this study we sought to determine if ingestion of microplastics promoted pre-clinical cardiovascular disease (CVD). To do this, we supplied mice with normal drinking water or that supplemented with polystyrene beads of two different sizes (0.5μm and 5μm) and two different doses (0.1μg/ml and 1μg/ml) each for 12 weeks and measured several indices of metabolism and glucose homeostasis. As early as 3 weeks of consumption, we observed an accelerated weight gain with a corresponding increase in body fat for some exposure groups versus the control mice. Some exposure groups demonstrated increased levels of fasting plasma glucose. Those mice consuming the smaller sized beads (0.5μm) at the higher dose (1μg/ml), had increased levels of fasting plasma insulin and higher homeostatic model assessment of insulin resistance (HOMA-IR) scores as well. This was accompanied by changes in the gut microbiome consistent with an obese phenotype. Using samples of perivascular adipose tissue collected from the same group, we observed changes in gene expression consistent with increased adipogenesis. These results suggest that ingestion of polystyrene beads promotes a cardiometabolic disease phenotype and thus may be an unrecognized risk factor for CVD.

Benzene is a ubiquitous, volatile pollutant present at high concentrations in toxins (e.g. tobacco smoke) known to increase cardiovascular disease (CVD) risk. Despite its prevalence, the cardiovascular effects of benzene have rarely been studied. Hence, we examined whether exposure to benzene is associated with increased CVD risk. The effects of benzene exposure in mice were assessed by direct inhalation, while the effects of benzene exposure in humans was assessed in 210 individuals with mild to high CVD risk by measuring urinary levels of the benzene metabolite trans,trans-muconic acid (t,t-MA). Generalized linear models were used to assess the association between benzene exposure and CVD risk. Mice inhaling volatile benzene had significantly reduced levels of circulating angiogenic cells (Flk-1⁺/Sca-1⁺) as well as an increased levels of plasma low-density lipoprotein (LDL) compared with control mice breathing filtered air. In the human cohort, urinary levels of t,t-MA were inversely associated several populations of circulating angiogenic cells (CD31⁺/34⁺/45⁺, CD31⁺/34⁺/45⁺/AC133^–, CD34⁺/45⁺/AC133⁺). Although t,t-MA was not associated with plasma markers of inflammation or thrombosis, t,t-MA levels were higher in smokers and in individuals with dyslipidemia. In smokers, t,t-MA levels were positively associated with urinary metabolites of nicotine (cotinine) and acrolein (3-hydroxymercapturic acid). Levels of t,t-MA were also associated with CVD risk as assessed using the Framingham Risk Score and this association was independent of smoking. Thus, benzene exposure is associated with increased CVD risk and deficits in circulating angiogenic cells in both smokers and non-smokers.

Objective—: Exposure to fine particulate matter (PM _2.5 ) air pollution is associated with the depletion of circulating endothelial progenitor cells (EPCs), as well as vascular injury and dysfunction. Nevertheless, it remains unclear whether PM _2.5 exposure leads to significant impairments in EPC function. Hence, we studied the effects of PM _2.5 on EPC-mediated recovery of vascular perfusion after hindlimb ischemia and examined the mechanisms whereby PM _2.5 exposure affects EPC abundance and function. Approach and Results—: In comparison with EPCs isolated from mice breathing filtered air, EPCs from mice exposed for 9 consecutive days (6 hours per day) to concentrated ambient PM _2.5 (CAP) had defects in both proliferation and tube formation. However, CAP exposure of mice overexpressing extracellular superoxide dismutase (ecSOD-Tg) in the lungs did not affect EPC tube formation. Exposure to CAP also suppressed circulating EPC levels, VEGF (vascular endothelial growth factor)-stimulated aortic Akt phosphorylation, and plasma NO levels in wild-type but not in ecSOD-Tg mice. EPCs from CAP-exposed wild-type mice failed to augment basal recovery of hindlimb perfusion when injected into unexposed mice subjected to hindlimb ischemia; however, these deficits in recovery of hindlimb perfusion were absent when using EPCs derived from CAP-exposed ecSOD-Tg mice. The improved reparative function of EPCs from CAP-exposed ecSOD-Tg mice was also reflected by greater expression of Mmp-9 and Nos3 when compared with EPCs from CAP-exposed wild-type mice. Conclusions—: Exposure to PM _2.5 impairs EPC abundance and function and prevents EPC-mediated vascular recovery after hindlimb ischemia. This defect is attributed, in part, to pulmonary oxidative stress and was associated with vascular VEGF resistance and a decrement in NO bioavailability.

Benzene is a ubiquitous pollutant associated with hematotoxicity but its metabolic effects are unknown. We sought to determine if and how exposure to volatile benzene impacted glucose handling. We exposed wild type C57BL/6 mice to volatile benzene (50ppm x 6h/d) or HEPA-filtered air for 2 or 6wk and measured indices of oxidative stress, inflammation and insulin signaling. Compared to air controls, we found that mice inhaling benzene demonstrated increased plasma glucose (p = 0.05), insulin (p = 0.03), and HOMA-IR (p = 0.05), establishing a state of insulin and glucose intolerance. Moreover, insulin-stimulated Akt phosphorylation was diminished in the liver (p = 0.001) and skeletal muscle (p = 0.001) of benzene-exposed mice, accompanied by increases in oxidative stress and NF-κB phosphorylation (p = 0.025). Benzene-exposed mice also demonstrated elevated levels of MIP1-α transcripts and SOCS1 (p = 0.001), but lower levels of IRS-2 tyrosine phosphorylation (p = 0.0001). Treatment with the superoxide dismutase mimetic, TEMPOL, reversed benzene-induced effects on oxidative stress, NF-κB phosphorylation, SOCS1 expression, IRS-2 tyrosine phosphorylation, and systemic glucose intolerance. These findings suggest that exposure to benzene induces insulin resistance and that this may be a sensitive indicator of inhaled benzene toxicity. Persistent ambient benzene exposure may be a heretofore unrecognized contributor to the global human epidemics of diabetes and cardiovascular disease