Acrolein consumption induces systemic dyslipidemia and lipoprotein modification

Abstract

Aldehydes such as acrolein are ubiquitous pollutants present in automobile exhaust, cigarette, wood, and coal smoke. Such aldehydes are also constituents of several food substances and are present in drinking water, irrigation canals, and effluents from manufacturing plants. Oral intake represents the most significant source of exposure to acrolein and related aldehydes. To study the effects of short-term oral exposure to acrolein on lipoprotein levels and metabolism, adult mice were gavage-fed 0.1 to 5 mg acrolein/kg bwt and changes in plasma lipoproteins were assessed. Changes in hepatic gene expression related to lipid metabolism and cytokines were examined by qRT-PCR analysis. Acrolein feeding did not affect body weight, blood urea nitrogen, plasma creatinine, electrolytes, cytokines or liver enzymes, but increased plasma cholesterol and triglycerides. Similar results were obtained with apoE-null mice. Plasma lipoproteins from acrolein-fed mice showed altered electrophoretic mobility on agarose gels. Chromatographic analysis revealed elevated VLDL cholesterol, phospholipids, and triglycerides levels with little change in LDL or HDL. NMR analysis indicated shifts from small to large VLDL and from large to medium-small LDL with no change in the size of HDL particles. Increased plasma VLDL was associated with a significant decrease in post-heparin plasma hepatic lipase activity and a decrease in hepatic expression of hepatic lipase. These observations suggest that oral exposure to acrolein could induce or exacerbate systemic dyslipidemia and thereby contribute to cardiovascular disease risk.

Introduction

Aldehydes such as acrolein are toxic components of automobile exhaust and smog, and have been detected in high concentrations in cigarette, cotton, wood and coal smoke. They constitute 1 to 2% of the volatiles generated from automobile exhaust and the burning of fossil fuels (Feron et al., 1991). Volatile aldehydes are also present in drinking water. Several aldehydes are generated upon storage of carbonated or non-carbonated water in plastic bottles (Nawrocki et al., 2002). At least 36 different aldehydes are found in water of which acrolein and endrin aldehyde have been classified as the two highest priority pollutants (Committee on Aldehydes, 1981). The recommended maximum concentration of acrolein in water is 65 μg/l and that of glutaraldehyde is 70 μg/l, but these limits are often exceeded (Beauchamp et al., 1985, Ghilarducci and Tjeerdema, 1995). High levels of acrolein (20–100 μg/l) have been detected in effluents of industrial wastes, particularly paper manufacturing plants and in irrigation canals in which acrolein is used as a fungicide and herbicide (Ghilarducci and Tjeerdema, 1995).

Food substances are an additional source of aldehyde exposure. More than 300 different aldehydes have been detected in different food substances (Feron et al., 1991, Committee on Aldehydes, 1981, Ghilarducci and Tjeerdema, 1995). Typically, aldehydes are found at a concentration of 10 to 20 mg/kg, although very high concentrations of specific aldehydes are present in some foods and spices. High levels of acrolein have been detected in beer, wine, rum, bread and other foods (Feron et al., 1991). The formation of acrolein in foods, especially cooking oils, is further increased by cooking and frying and re-heating (Fullana et al., 2004). Furthermore, the concentration of non-volatile aldehydes increases when foods are heated in oil. Several of the aldehydes that appear on heating are unsaturated like acrolein because the process of frying or heating decreases the cis-double bond content of triglycerides and increases the formation of trans-unsaturated aldehydes (Fullana et al., 2004). Other aldehydes present in food are furfural, formaldehyde, and acetaldehyde (Committee on Aldehydes, 1981). Furfural has been detected in 150 types of food. It is particularly abundant in white bread and coffee. Crotonaldehyde is another, acrolein-like α,β-unsaturated aldehyde present in several natural foods. Overall, our estimates indicate that maximal daily human consumption of unsaturated aldehydes is nearly 5 mg/kg and the total aldehyde consumption (unsaturated and saturated) is about 7 mg/kg (Wang et al., 2008).

Despite high levels of estimated exposure, little is known in regard to the in vivo effects of aldehydes. In vitro experiments with cell culture systems show that exposure to low concentrations of acrolein or related aldehydes depletes reduced glutathione, which in turn, induces oxidative stress. Acrolein also reacts readily with nucleophilic DNA bases and protein side chains, and these reactions of acrolein have been linked to DNA modification and the modification of several transcription factors and phospholipids (Feng et al., 2006, Zemski Berry and Murphy, 2007). Exposure to high concentrations of acrolein, however, triggers necrotic or apoptotic cell death (Li et al., 1997). Previous studies have shown that low doses of acrolein elicit vasopressor effects suggesting changes in systolic blood pressure (Egle and Hudgins, 1974, Green and Egle, 1983), and repeated exposure to α-ethylacrolein has been found to cause mild cardiac hypertrophy in rats (Appelman et al., 1981). Continuous 1 year oral exposure to acrolein in dogs revealed little toxicity except for a mild and persistent depression of serum albumin, calcium, and decrease in protein values (Parent et al., 1992). Also, variable changes in coagulation times were observed, but the significance of these findings remains uncertain. Our studies show that acrolein feeding in rodents suppresses phenylephrine-mediated vasopressor responses, exacerbates cardiac ischemia/reperfusion-induced injury, and blocks NO donor-mediated cardioprotection (Tsakadze et al., 2003, Luo et al., 2007, Wang et al., 2008).

In the current study, we examined the effects of acrolein on circulating lipoprotein levels and metabolism. Plasma lipoprotein levels are exquisitely sensitive to systemic inflammation and injury and previous studies have shown that exposure to reactive toxicants or infectious agents induces dyslipidemia (Khovidhunkit et al., 2004, Tous et al., 2005, Kitagawa et al., 1992). Given that ingesting water and food represents an abundant source of environmental aldehydes, we tested whether short-term oral exposure to acrolein affects plasma lipoproteins. Our results show that acrolein feeding increases total plasma cholesterol and VLDL levels and induces lipoprotein modification. Such changes in plasma lipoproteins could contribute to cardiovascular disease risk due to environmental exposure to acrolein.