Acrolein consumption induces systemic dyslipidemia and lipoprotein modification

Diabetes and Obesity Center, University of Louisville, Louisville, KY 40202, USA.
Toxicology and Applied Pharmacology (Impact Factor: 3.71). 02/2010; 243(1):1-12. DOI: 10.1016/j.taap.2009.12.010
Source: PubMed


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.

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    • "That this idea has toxico logical plausibility is suggested by epidemio logical and experimental research indicating an association between environmental toxicant exposure (e.g., pesti cides, heavy metals, industrial chemicals) and an increase in the incidence and severity of many human diseases (Brown et al. 2005, 2006; Grandjean and Landrigan 2006; Kamel and Hoppin 2004; Landrigan et al. 2005; O'Toole et al. 2008). With specific reference to environmental type-2 alkene exposure, research has shown that dietary consumption of acrolein exacerbates myocardial ischemic injury and atherosclerosis in mice by interacting with endogenous unsaturated aldehydes generated during ongoing oxidative stress (Conklin et al. 2010; Ismahil et al. 2011; Luo et al. 2007; Srivastava et al. 2011; Wang et al. 2008). On the basis of these studies it has been proposed that chronic environmental exposure to unsaturated aldehydes is a significant risk factor for cardio vascular diseases (Luo et al. 2007; O'Toole et al. 2008; Wang et al. 2008). "
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    ABSTRACT: Background: Acrylamide (ACR) produces cumulative neurotoxicity in exposed humans and laboratory animals through a direct inhibitory effect on presynaptic function. Objectives: In this review, we delineate how knowledge of chemistry provided an unprecedented understanding of the ACR neurotoxic mechanism. We also show how application of the hard and soft, acids and bases (HSAB) theory led to the recognition that the α,β-unsaturated carbonyl structure of ACR is a soft electrophile that preferentially forms covalent bonds with soft nucleophiles. Methods: In vivo proteomic and in chemico studies demonstrated that ACR formed covalent adducts with highly nucleophilic cysteine thiolate groups located within active sites of presynaptic proteins. Additional research showed that resulting protein inactivation disrupted nerve terminal processes and impaired neurotransmission. Discussion: ACR is a type-2 alkene, a chemical class that includes structurally related electrophilic environmental pollutants (e.g., acrolein) and endogenous mediators of cellular oxidative stress (e.g., 4-hydroxy-2-nonenal). Members of this chemical family produce toxicity via a common molecular mechanism. Although individual environmental concentrations might not be toxicologically relevant, exposure to an ambient mixture of type-2 alkene pollutants could pose a significant risk to human health. Furthermore, environmentally derived type-2 alkenes might act synergistically with endogenously generated unsaturated aldehydes to amplify cellular damage and thereby accelerate human disease/injury processes that involve oxidative stress. Conclusions: These possibilities have substantial implications for environmental risk assessment and were realized through an understanding of ACR adduct chemistry. The approach delineated here can be broadly applied because many toxicants of different chemical classes are electrophiles that produce toxicity by interacting with cellular proteins.
    Environmental Health Perspectives 10/2012; 120(12). DOI:10.1289/ehp.1205432 · 7.98 Impact Factor
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    • "The daily human consumption of unsaturated aldehydes is estimated to be Ϸ5 mg/kg b.wt. No hepatocellular damage was observed in mice exposed to this dose of acrolein (Conklin et al., 2010), indicating that 5 mg/kg b.wt. is a sublethal concentration of acrolein. Significant damage to the liver was observed when mice were administered an acrolein dose of 10 mg/kg. "
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    Molecular pharmacology 06/2012; 82(4):601-13. DOI:10.1124/mol.112.078147 · 4.13 Impact Factor
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    • "Total cholesterol and triglycerides in the plasma were measured using commercial kits as described before [5] [11]. Lipoprotein subclasses in the plasma were analyzed by NMR spectroscopy as described before [5] "
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