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Experimental Biology and Medicine 229:361-364 (2004)
© 2004 Society for Experimental Biology and Medicine

ORIGINAL RESEARCH ARTICLE

Nitrogen Dioxide Air Pollution near Ambient Levels Is an Atherogenic Risk Primarily in Obese Subjects: A Brief Communication

Hirohisa Takano*,{dagger},1, Rie Yanagisawa*, Ken-Ichiro Inoue*, Akinori Shimada{ddagger}, Takamichi Ichinose§, Kaori Sadakane§, Shin Yoshino||, Kouya Yamaki||, Masatoshi Morita* and Toshikazu Yoshikawa{dagger}

* Pathophysiology Research Team, National Institute for Environmental Studies, Tsukuba 305-0053, Japan; {dagger} First Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; {ddagger} Department of Veterinary Pathology, Tottori University, Tottori 680-0995, Japan; § Department of Health Science, Oita University of Nursing and Health Sciences, Oita 870-1201, Japan; and || Department of Pharmacology, Kobe Pharmaceutical University, Kobe 658-8558, Japan

1 To whom requests for reprints should be addressed at Pathophysiology Research Team, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba 305-0053, Japan. E-mail: htakano{at}nies.go.jp


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Ambient exposure to nitrogen dioxide, a critical air pollutant in developed countries, is positively associated with cardiovascular mortality and morbidity. Although its cardiovascular effects are predominantly shown in patients with high risk of atherogenesis, no studies have elucidated whether daily exposure to nitrogen dioxide air pollution enhances atherogenic metabolisms, primarily in obese subjects who are susceptible to atherogenesis and subsequent cardiovascular diseases. We used male Otsuka Long-Evans Tokushima Fatty (OLETF) rats as obese subjects and Long-Evans Tokushima (LETO) rats as nonobese controls. The animals were continuously exposed to nitrogen dioxide at a concentration of 0, 0.16, 0.8, or 4.0 ppm from 8 weeks of age through 32 weeks. At 40 weeks of age, levels of body weight, triglyceride, and total cholesterol were significantly greater in the OLETF rats than in the LETO rats. A ratio of high-density lipoprotein (HDL) to total cholesterol was significantly smaller in the former than in the latter. In the LETO rats, nitrogen dioxide exposure significantly decreased only the levels of HDL as compared with clean air exposure. In the OLETF rats, however, nitrogen dioxide exposure at a concentration of 0.16 ppm significantly elevated triglyceride concentration and decreased the ratio of HDL to total cholesterol as well as the levels of HDL. Nitrogen dioxide air pollution near ambient levels is an atherogenic risk primarily in obese subjects.

Key Words: atherosclerosis • obesity • cholesterol • lipids • nitrogen dioxide


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Obesity, which enhances the risk of death from cardiovascular diseases, is increasing in the population of developed countries. The relative risk associated with an increment of body mass index has been reported to be 1.10 for mortality from cardiovascular diseases (1). Furthermore, abdominal obesity is frequently associated with highly atherogenic metabolic complications such as hypertension, dyslipidemia, and glucose intolerance (2). On the other hand, air pollution has also been reported to increase the risk of death from cardiovascular diseases. Recent studies have linked air pollution to tens of thousands of premature cardiovascular deaths per year (3). Among a variety of air pollutants, an interquartile range increase in nitrogen dioxide is associated with an increase of 6.1% of cardiovascular mortality (4, 5). Furthermore, concentration of nitrogen dioxide is associated with daily hospital emergency transports for ischemic heart diseases such as angina pectoris and myocardial infarction (6), as well as for subsequent cardiac insufficiency (7) and arrhythmia (8). Intriguing aspects of these epidemiologic data are that the cardiovascular effects of nitrogen dioxide are predominantly observed in patients with diabetes mellitus (9) and those with cardiovascular diseases aged 65 years or older who have high risks of atherogenesis (10).

However, no studies have elucidated the effect of nitrogen dioxide air pollution on atherogenic lipid metabolisms primarily in obese subjects who are susceptible to atherogenesis and subsequent cardiovascular diseases. The present study was undertaken to determine whether daily exposure to nitrogen dioxide air pollution near ambient levels is an atherogenic risk primarily in obese subjects.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Four-week-old male Otsuka Long-Evans Tokushima Fatty (OLETF) rats and Long-Evans Tokushima (LETO) rats serving as normal controls were kindly supplied from the Otsuka Tokushima Research Institute (Otsuka Pharmaceutical, Tokushima, Japan). The OLETF rat strain was established by Kawano et al. (11) as an inbred strain of spontaneous mutants that show obesity, hypertriglycemia, hypertension, and insulin resistance. The rats were housed in an animal facility that was maintained at 24º–26ºC with 55%–75% humidity and a 14:10-hr light:dark cycle; they were fed a commercial diet (Japan Clea Co., Tokyo, Japan) and water ad libitum.

The animals were continuously exposed to nitrogen dioxide at a concentration of 0, 0.16, 0.8, or 4.0 ppm from 8 weeks of age for 32 weeks in our exposure chambers. The volume of chambers was 1.39 m3. Filtered clean air flowed through one chamber, and in the other chambers for nitrogen dioxide exposure, filtered clean air was mixed with 5000 ppm NO2/N2 (>99.9%; Sumitomo Seika Chemicals, Tokyo, Japan) from a bomb before it entered the chambers. The chambers were operated under dynamic conditions at 25ºC ± 1ºC, 55% ± 5% humidity, -5 mm H2O relative to atmospheric pressure with an air flow of 110 m3/hr. The concentrations of nitrogen dioxide were controlled by continuous monitoring with an NOx analyzer (Monitor Labs model 8440, San Diego, CA) that operates on a chemiluminescence principle. NO was undetectable in each chamber.

At 40 weeks of age, body weight of the animals was measured. Routine laboratory examinations including triglyceride, high-density lipoproteins (HDL), total cholesterol, and sugar on peripheral blood were conducted after exsanguination under deep anesthesia with diethyl ether. The lungs were fixed in 10% neutral phosphate-buffered formalin, and sections were stained with hematoxylin and eosin as previously reported (12).

Data were reported as mean ± SD. Differences among groups were determined using analysis of variance (ANOVA; Stat-View version 4.0; Abacus Concepts, Inc., Berkeley, CA). If differences among groups were significant (P < 0.05), Fisher’s protected least significant difference test was used to distinguish between pairs of groups.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The levels of body weight, triglyceride, and total cholesterol were significantly greater in the OLETF rats than in the LETO rats under exposure to nitrogen dioxide at each concentration (P < 0.01, but P < 0.05 for triglyceride at 4.0 ppm of nitrogen dioxide; Table 1Go). A ratio of HDL to total cholesterol was significantly smaller in the OLETF rats than in the LETO rats under exposure to nitrogen dioxide at each concentration (P < 0.01). The levels of blood sugar were greater in the OLETF rats than in the LETO rats under exposure to nitrogen dioxide at each concentration (P < 0.05 at 0 and 4.0 ppm of nitrogen dioxide).


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  		Table 1. Body Weights and the Levels of Triglyceride, High-Density Lipoproteins (HDL), Total Cholesterol, and Sugar in the Blood of Obese (Otsuka Long-Evans Tokushima Fatty [OLETF]) Rats and Normal Control (Long-Evans Tokushima [LETO]) Rats1
 
In the LETO rats, nitrogen dioxide exposure at each concentration significantly decreased only the levels of HDL compared with clean air exposure (P < 0.05; Table 1Go). In the OLETF rats, however, nitrogen dioxide exposure at a concentration of 0.16 ppm significantly elevated triglyceride concentration (P < 0.05), and significantly decreased the ratio of HDL to total cholesterol (P < 0.01) as well as the levels of HDL (P < 0.01) in comparison with clean air exposure. As compared with clean air exposure, nitrogen dioxide exposure at a concentration of 0.8 ppm also showed a significant decrease in the levels of HDL (P < 0.05). However, nitrogen dioxide exposure at a concentration of 4.0 ppm did not show any significant changes in the OLETF rats. The levels of blood sugar were not affected by nitrogen dioxide exposure in both strains. Histological studies revealed that nitrogen dioxide exposure dose-dependently increased infiltration of lymphocytes and hyperplasia of the bronchial epitheliums. However, there were no significant differences between the OLETF rats and the LETO rats.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present study has demonstrated that daily exposure to nitrogen dioxide air pollution near ambient levels (0.16 ppm) enhances atherogenic lipid metabolisms primarily in the OLETF rats, but less in the LETO rats.

The OLETF rats have been reported to show obesity, hypertriglycemia, hypertension, insulin resistance, a late onset of hyperglycemia, hyperplastic foci of pancreatic islets, and renal nodular lesions with a chronic disease course, which is a good animal model of human obesity usually accompanied by Type 2 diabetes mellitus (11). Also in the present study, the OLETF rats developed obesity and atherogenic lipid metabolisms, whereas the control LETO rats did not. Thus, the OLETF rats and the LETO rats are useful to determine the differential effects of air pollution on the atherogenic lipid metabolisms in obese and nonobese subjects.

In the present study, nitrogen dioxide exposure at a concentration of 0.16 ppm enhanced atherogenic lipid metabolisms including triglyceride, HDL, and a ratio of HDL to total cholesterol in the OLETF rats, whereas it enhanced only HDL levels in the LETO rats. These results clearly indicate that obese subjects who have a high risk of atherogenesis and cardiovascular diseases are susceptible further to the atherogenic cardiovascular effects of nitrogen dioxide air pollution at a relatively low concentration.

Although the National Ambient Air Quality Standards of nitrogen dioxide is 0.053 ppm per annual arithmetic mean, continuous monitoring of in-vehicle (13) or commuter exposures (14) to nitrogen dioxide have ranged from 0.03 to 0.17 ppm in the United States. In addition, levels as high as 0.5–0.6 ppm of nitrogen dioxide have been demonstrated in the vicinity of an operating gas stove (15). In the present study, it is striking that the atherogenic effects of nitrogen dioxide are shown primarily at a concentration of 0.16 ppm, which is near ambient levels, but less at higher toxic concentrations. Comparable results have been demonstrated by a previous human study: nitrogen dioxide exposure significantly increased airway resistance at a relatively low concentration (1.5 ppm), but not at higher concentrations up to 8.0 ppm (16). It has been reported that several of the dose-response curves for health effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin are U-shaped, which appears to result because the integrated toxicologic response depends on multiple underlying processes, each of which has a different relationship with respect to the pollutant (17).

Although nitrogen dioxide is in vivo counteracted by an arsenal of antioxidants (18), the levels of lipid peroxides were not significantly different among the experimental groups (data not shown).

In conclusion, nitrogen dioxide air pollution near ambient levels is an atherogenic risk primarily in obese subjects. Future epidemiologic and experimental studies should focus on the atherogenic cardiovascular effects of air pollution primarily in obese subjects.


   Footnotes
 
This work was funded in part by a grant from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.

Received for publication October 6, 2003. Accepted for publication January 9, 2004.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Stevens J, Cai J, Pamuk ER, Williamson DF, Thun MJ, Wood JL. The effect of age on the association between body mass index and mortality. N Engl J Med 338:1–7, 1998.[Abstract/Free Full Text]
  2. Poiliot MC, Despres JP, Nadeeau A, Moorjani S, Prud’Homme D, Lupien PJ, Tremblay A, Bouchard C. Visceral obesity in men. Associations with glucose tolerance, plasma insulin, and lipoprotein levels. Diabetes 41:826–834, 1992.[Abstract]
  3. Schwartz J. Air pollution and blood markers of cardiovascular risk. Environ Health Perspect 109:405–409, 2001.
  4. Zeghnoun A, Czernichow P, Beaudeau P, Hautemaniere A, Froment L, Le Tertre A, Quenel P. Short-term effects of air pollution on mortality in the cities of Rouen and Le Havre, France, 1990–1995. Arch Environ Health 56:327–335, 2001.[Medline]
  5. Mar TF, Norris GA, Koenig JQ, Larson TV. Associations between air pollution and mortality in Phoenix, 1995–1997. Environ Health Perspect 108:347–353, 2000.[Medline]
  6. Ye F, Piver WT, Ando M, Portier CJ. Effects of temperature and air pollutants on cardiovascular and respiratory diseases for males and females older than 65 years of age in Tokyo, July and August 1980–1995. Environ Health Perspect 109:355–359, 2001.[Medline]
  7. Ponka A, Virtanen M. Low-level air pollution and hospital admissions for cardiac and cerebrovascular diseases in Helsinki. Am J Public Health 86:1273–1280, 1996.[Abstract/Free Full Text]
  8. Peters A, Liu E, Verrier RL, Schwartz J, Gold DR, Mittleman M, Baliff J, Oh JA, Allen G, Mnahan K, Dockery DW. Air pollution and incidence of cardiac arrhythmia. Epidemiology 11:11–17, 2000.[Medline]
  9. Lin WS, Szlachcic Y, Gong H Jr, Kinney PL, Berhane KT. Air pollution and daily hospital admissions in metropolitan Los Angeles. Environ Health Perspect 108:427–434, 2000.[Medline]
  10. Wong TW, Lau TS, Yu TS, Neller A, Wong SL, Tam W, Pang SW. Air pollution and hospital admissions for respiratory and cardiovascular diseases in Hong Kong. Occup Environ Med 56:679–683, 1999.[Abstract/Free Full Text]
  11. Kawano K, Hirashima T, Mori S, Saitoh Y, Kurosumi M, Natori T. Spontaneous long-term hyperglycemic rat with diabetic complications. Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes 41:1422–1428, 1992.[Abstract]
  12. Takano H, Yoshikawa T, Ichinose T, Miyabara Y, Imaoka K, Sagai M. Diesel exhaust particles enhance antigen-induced airway inflammation and local cytokine expression in mice. Am J Respir Crit Care Med 156:36–42, 1997.[Abstract/Free Full Text]
  13. Baker PE, Beals SA, Cunningham SJ, Colome SD, Wilson AL, Shikiya D. Measurements of personal nitrogen dioxide exposure inside automobiles while commuting. In: Hapers JP, Ed. Combustion Processes and the Quality of the Indoor Environment. Pittsburgh: Air & Waste Management Association, pp149–150, 1990.
  14. Harlos DP. Acute exposures to nitrogen dioxide during cooking or commuting. PhD thesis, Harvard School of Public Health, Boston, 1998.
  15. Goldstein IF, Lieber K, Andrews LR, Foutrakis G, Kazembe F, Huange P, Hayes C. Acute respiratory effects of short term exposures to nitrogen dioxide. Arch Environ Health 43:138–142, 1988.[Medline]
  16. von Nieding G, Wagner HM. Effects of NO2 on chronic bronchitics. Environ Health Perspect 29:137–142, 1979.[Medline]
  17. Andersen ME, Barton HA. The use of biochemical and molecular parameters to estimate dose-response relationships at low levels of exposure. Environ Health Perspect 106(Suppl 1):349–355, 1998.
  18. Kirsch M, Korth HG, Sustmann R, de Groot H. The pathobiochemistry of nitrogen dioxide. Biol Chem 383:389–399, 2002.[Medline]



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