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      Developmental Exposure to Second-Hand Smoke Increases Adult Atherogenesis and Alters Mitochondrial DNA Copy Number and Deletions in apoE −/− Mice

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          Abstract

          Cardiovascular disease is a major cause of morbidity and mortality in the United States. While many studies have focused upon the effects of adult second-hand smoke exposure on cardiovascular disease development, disease development occurs over decades and is likely influenced by childhood exposure. The impacts of in utero versus neonatal second-hand smoke exposure on adult atherosclerotic disease development are not known. The objective of the current study was to determine the effects of in utero versus neonatal exposure to a low dose (1 mg/m 3 total suspended particulate) of second-hand smoke on adult atherosclerotic lesion development using the apolipoprotein E null mouse model. Consequently, apolipoprotein E null mice were exposed to either filtered air or second-hand smoke: (i) in utero from gestation days 1–19, or (ii) from birth until 3 weeks of age (neonatal). Subsequently, all animals were exposed to filtered air and sacrificed at 12–14 weeks of age. Oil red-O staining of whole aortas, measures of mitochondrial damage, and oxidative stress were performed. Results show that both in utero and neonatal second-hand smoke exposure significantly increased adult atherogenesis in mice compared to filtered air controls. These changes were associated with changes in aconitase and mitochondrial superoxide dismutase activities consistent with increased oxidative stress in the aorta, changes in mitochondrial DNA copy number and deletion levels. These studies show that in utero or neonatal exposure to second-hand smoke significantly influences adult atherosclerotic lesion development and results in significant alterations to the mitochondrion and its genome that may contribute to atherogenesis.

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          Most cited references17

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          Cardiovascular effects of secondhand smoke: nearly as large as smoking.

          Secondhand smoke increases the risk of coronary heart disease by approximately 30%. This effect is larger than one would expect on the basis of the risks associated with active smoking and the relative doses of tobacco smoke delivered to smokers and nonsmokers. We conducted a literature review of the research describing the mechanistic effects of secondhand smoke on the cardiovascular system, emphasizing research published since 1995, and compared the effects of secondhand smoke with the effects of active smoking. Evidence is rapidly accumulating that the cardiovascular system--platelet and endothelial function, arterial stiffness, atherosclerosis, oxidative stress, inflammation, heart rate variability, energy metabolism, and increased infarct size--is exquisitely sensitive to the toxins in secondhand smoke. The effects of even brief (minutes to hours) passive smoking are often nearly as large (averaging 80% to 90%) as chronic active smoking. The effects of secondhand smoke are substantial and rapid, explaining the relatively large risks that have been reported in epidemiological studies.
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            Atherosclerosis: Basic Mechanisms

            Circulation, 91(9), 2488-2496
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              ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree.

              Initial description of apolipoprotein (apo) E-deficient transgenic mice demonstrated the development of severe hypercholesterolemia due to probable delayed clearance of large atherogenic particles from the circulation. Examination of these mice demonstrated foam cell accumulation in the aortic root and pulmonary arteries by 10 weeks of age. In the present study, the animals were fed either chow or a high-fat, Western-type diet and examined at ages ranging from 6 to 40 weeks. Gross examination by dissection microscopy revealed a predilection for development of lesions in the aortic root, at the lesser curvature of the aortic arch, the principal branches of the aorta, and in the pulmonary and carotid arteries. Monocyte attachment to endothelial cells was observed by light and electron microscopic examination at 6 weeks, the earliest time point examined. Foam cell lesions developed as early as 8 weeks, and after 15 weeks advanced lesions (fibrous plaques) were observed. The latter consisted of a fibrous cap containing smooth muscle cells surrounded by connective tissue matrix that covered a necrotic core with numerous foamy macrophages. Mice fed the Western-type diet generally had more advanced lesions than those fed a chow diet. The apoE-deficient mouse contains the entire spectrum of lesions observed during atherogenesis and is the first mouse model to develop lesions similar to those in humans. This model should provide numerous opportunities to study the pathogenesis and therapy of atherosclerosis in a small, genetically defined animal.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                25 June 2013
                : 8
                : 6
                : e66835
                Affiliations
                [1 ]The University of Alabama at Birmingham, Division of Molecular and Cellular Pathology, Birmingham, Alabama, United States of America
                [2 ]University of California at Davis, Center for Health and Environment, Davis, California, United States of America
                [3 ]Department of Pathology, Division of Molecular and Cellular Pathology, 535 BMR2, 1720 2nd Ave S, Birmingham
                University of Medicine and Dentistry of New Jersey, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: SWB KEP JLF. Performed the experiments: JLF MP DGW DU JB. Analyzed the data: JLF KEP SWB DGW MP JB. Contributed reagents/materials/analysis tools: SWB KEP. Wrote the paper: JLF SWB.

                Article
                PONE-D-13-08101
                10.1371/journal.pone.0066835
                3692512
                23825571
                8f1b923b-f32a-4888-86de-d0b83e09528c
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 22 February 2013
                : 10 May 2013
                Page count
                Pages: 9
                Funding
                This work was supported by National Institutes of Health (NIH) grants HL77419 and HL94518 (SWB) and by the NIH funded Diabetes Research Training Center (P60 DK079626). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Biochemistry
                Bioenergetics
                Energy-Producing Organelles
                Model Organisms
                Animal Models
                Mouse
                Toxicology
                Predictive Toxicology
                Medicine
                Cardiovascular
                Atherosclerosis
                Public Health
                Toxicology

                Uncategorized
                Uncategorized

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