Review
Environmental toxicity, nutrition, and gene interactions in the development of atherosclerosis

https://doi.org/10.1016/j.numecd.2006.01.003Get rights and content

Abstract

There is substantial evidence from epidemiological studies that the pathology of cardiovascular diseases is linked in part to environmental pollution. Many environmental contaminants, and especially persistent organic pollutants, are risk factors for atherosclerosis because they may exacerbate an underlying disease by altering gene expression patterns. Many mechanisms and signaling pathways associated with the pathology of “modern” diseases are similarly modulated by poor dietary habits and environmental pollutants. Many genes induced in diseases associated with vascular dysfunction such as atherosclerosis are oxidative stress-sensitive, suggesting that an imbalance in cellular oxidative stress and antioxidant status is a critical underlying factor. One of the emerging issues in modern toxicological sciences is the modification of environmental toxicity by nutrients. Evidence is emerging which suggests that antioxidant nutrients and related bioactive compounds common in fruits and vegetables protect against environmental toxic insult to the vascular endothelium by down-regulation of signaling pathways involved in inflammatory responses associated with vascular diseases such as atherosclerosis. Thus, the concept that nutrition may modify or ameliorate the toxicity of environmental chemicals may have implications for understanding the complex interaction of environmental toxicity and disease development.

Introduction

Cardiovascular disease (CVD) is estimated to affect over 70.1 million Americans, making it the number one killer in the United States nearly every year to date since 1900 [1]. Atherosclerosis, a thickening of artery walls, leading to heart attack and stroke has been attributed to approximately 75% of these deaths [1]. A number of possible factors have led to this incredible stability of CVD as a killer among developed countries, including lack of exercise, poor diet, and smoking. More recently both environmental and occupational chemical exposures have been shown to contribute to chronic heart disease. With scientific evidence supporting this fact increasing in the last few years, the necessity of a new field of study has been created termed “Environmental Cardiology” [2]. Traditional cardiovascular groups such as the American Heart Association have surrendered to the same notion shown in a June 2004 Statement, concluding that air pollutants at present-day concentrations pose a severe threat to the public health [3].

Atherosclerosis has traditionally been attributed to hyperlipidemia and disordered cholesterol balance; however, it has been seen that only half of the patients that develop atherosclerosis actually manifest hyperlipidemia [4]. This has led to the paradigm of inflammation as a key modulator of atherosclerosis. This inflammatory response is a multi-step, life-long disease with events as early as in the first decade of life. Endothelial dysfunction, characterized by changes in adhesiveness, permeability, proliferation, and thrombogenesis [4], is still considered the inaugural event in the formation of atherosclerotic plaque. In addition to genetic predisposition and interaction of risk factors associated with chronic diseases, endothelial dysfunction also can be caused by a number of environmental factors including certain dietary fats and environmental toxins such as polychlorinated biphenyls (PCBs) [5], [6] and 2,4,6-trinitrotoluene [7]. Up-regulation of adhesion molecules such as intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and platelet-endothelial cell adhesion molecule-1 (PECAM-1), integrins, and selectins (L, E, and P) will lead to the attachment and buildup of immune cells (monocytes, macrophages, platelets, and T lymphocytes) on the endothelial wall. This activation of the endothelium leads to the release of pro-inflammatory cytokines, surface receptors, and proteinase enzymes including, but not limited to, interleukins, interferons, monocyte chemoattractant protein-1 (MCP-1), MCP-4, cyclooxygenase-2 (COX-2), and matrix metalloproteinases (MMP) [4]. The endothelium becomes more permeable to lipid particles and immune cells, which leads to a situation where macrophages engulf oxidized low-density lipoprotein (LDL) particles and other modified lipoproteins, thus becoming foam cells. Foam cells in turn lead to an increase in inflammatory cytokine production. This proliferating immune response activates the vascular smooth muscle cell (VSMC) layer to proliferate and migrate as well as leads to local vasoconstriction, collagen and matrix deposition, fibrous cap production, and immune cell and platelet recruitment and activation [4]. Each step in the progression of atherosclerotic lesions has the possibility of promotion from environmental pollutants and possibly the alleviation from nutritional intervention.

Another emerging issue in the field of “Environmental Cardiology” includes the modulation of these disease-causing environmental agents by dietary elements. Research over the last few decades clearly indicates that the pathology of virtually all age-related or chronic diseases (sometimes referred to as “diseases of civilization”) is regulated by multifactorial dietary elements along with other environmental agents and genetic susceptibility [8], [9]. There is a great need to further explore this nutritional paradigm in environmental toxicology to improve our understanding of the relationship between nutrition, exposure to environmental toxins, and disease [10]. Emerging issues of nutritional biomarkers, new research technologies and a clearer understanding of the relationship of nutrients and bioactive compounds with the etiology of age-related diseases appear to be of critical significance, because nutrition may be the most sensible means to develop intervention and prevention strategies of diseases associated with many environmental toxic insults.

Section snippets

Air pollutants and atherosclerosis

Recent attention has been brought to an increasing correlation between air pollution (particulate matter less than 2.5 μm, PM2.5) and CVD hospitalization. Long-term exposure to fine particulate air pollution has been linked to increased risk of death from cardiopulmonary disease likely caused by systemic inflammation, accelerated atherosclerosis, and altered cardiac autonomic function in a large cohort study (n  319,000–500,000) [11]. The risk of short-term exposure (within a few to 24 h) of PM2.5

Persistent organic pollutants and atherosclerosis

There is clear evidence that persistent organic pollutants (POP) as well as heavy metals are risk factors for atherosclerosis [6]. A recent study found clear evidence that residing in and around sites contaminated with POPs, such as PCBs, is associated with increased rates of hospitalization for coronary heart disease and acute myocardial infarction [21]. High blood levels of the potent aryl hydrocarbon receptor (AhR) agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), has been shown to cause

Heavy metals and atherosclerosis

In addition to certain POP, blood lead and cadmium, and urinary cadmium levels were associated with increased incidents of peripheral arterial diseases; however, underlying mechanisms of these effects have not been determined [38], [39]. Furthermore, epidemiological evidence has correlated inorganic arsenic exposure with increases in carotid atherosclerosis [40]. Arsenic exposure can result in increases in oxidant levels leading to the up-regulation of inflammatory mediating genes. Arsenic

Nutritional intervention

Little is known about the interaction of dietary nutrients with mechanisms of a toxicant insult. Because most environmental pollutants are highly persistent and lipophilic in nature, one would suspect possible interactions among the cellular lipid milieu with such environmental pollutants like PCBs and other related toxins. These metabolic interactions could be on structural, functional and molecular levels of metabolism. Furthermore, many underlying mechanisms of diseases associated with

Conclusion

Environmental pollutants are a significant risk factor for vascular diseases such as atherosclerosis. An imbalance in oxidative stress/antioxidant balance appears to be a critical underlying denominator in the pathology of atherosclerosis. Interestingly, many environmental pollutants exhibit human toxicity and disease via oxidative stress-sensitive signaling pathways. It is therefore possible that certain nutrients (e.g., dietary fats) that can contribute to cellular oxidative stress also can

Acknowledgement

Supported in part by grants from NIH/NIEHS (ES 07380) and the KY AES.

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