Benzene exposure is associated with cardiovascular disease risk

Abstract

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.

Fig 1. Association between cigarette smoke exposure and t,t-MA levels.

Associations of t,t-MA with cotinine (A) and 3-HPMA (B) were established by regression analysis. Cigarette smoke is the major source of benzene exposure in the smoking sub-group.

Fig 2. Volatile benzene exposure decreases murine CACs and increases lipoprotein levels.

(A) Flk-1⁺/Sca-1⁺ cells were measured in C57Bl/6 mice after 6 weeks of exposure to volatile benzene (50ppm, 6h/d) and filtered air. The benzene exposed animals showed an approximate 48% decrease in these cells after six weeks of benzene exposure. Levels of total plasma cholesterol (B), LDL (C), HDL (D), triglycerides (F) were also quantified in the exposed mice. An LDL:HDL ratio was also calculated (E). All plasma variables except triglycerides were elevated in benzene-exposed mice compared with the filtered air exposed controls. n = 22-39/treatment group; *: p<0.05.

Fig 3. Association between t,t-MA and CVD risk.

Associations between low (< 20; n = 44) and high (≥ 20 or experienced a cardiovascular event; n = 166) Framingham Risk Score and t,t-MA were determined for the total population (A; p = 0.024) and in non-smokers (B; p = 0.006).