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American Journal of Epidemiology Advance Access originally published online on July 5, 2007
American Journal of Epidemiology 2007 166(5):552-560; doi:10.1093/aje/kwm119
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American Journal of Epidemiology © The Author 2007. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

ORIGINAL CONTRIBUTIONS

Plasma Fluorescent Oxidation Products as Potential Markers of Oxidative Stress for Epidemiologic Studies

Tianying Wu1, Walter C. Willett1,2,3, Nader Rifai4 and Eric B. Rimm1,2,3

1 Department of Nutrition, Harvard School of Public Health, Boston, MA
2 Department of Epidemiology, Harvard School of Public Health, Boston, MA
3 Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA
4 Department of Laboratory Medicine, Children's Hospital and Harvard Medical School, Boston, MA

Correspondence to Dr. Tianying Wu, Department of Nutrition, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA 02115 (e-mail: hptwu{at}channing.harvard.edu; tianying.wu{at}uc.edu).

Received for publication June 20, 2006. Accepted for publication March 9, 2007.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Currently lacking are stable and easily measured biomarkers that can reflect oxidative stress in humans. Fluorescent oxidation products may fulfill all three of these criteria. Fasting plasma levels of fluorescent oxidation products were measured in 286 controls in a study of coronary heart disease among US men aged 47–81 years; the study concluded in 2006. Other biomarkers in plasma were also measured, and cardiovascular risk factors such as smoking, hypertension, age, and physical activity were assessed by questionnaire. Indicators of oxidative stress, including smoking, hypertension, and reduced renal function, were associated with greater fluorescent oxidation products in both age- and multivariate-adjusted analyses (for each, p for trend < 0.01). In a multivariate-adjusted analysis, levels of fluorescent oxidation products were 45% higher in current smokers than in never smokers and 61% higher in men who smoked more than 25 cigarettes/day versus 1–4 cigarettes/day. The levels of this marker were 17% higher in hypertensive men than in normotensive men and 20% higher in men in the lowest versus the highest quartile of glomerular filtration rate. Levels were 57% higher in men with both hypertension and reduced renal function than in men with neither. The association of fluorescent oxidation products with several indicators of oxidative stress suggests that this measure could be a useful global marker of oxidative stress for large epidemiologic studies.

biological markers; coronary disease; epidemiologic studies; fluorescence; oxidation-reduction; oxidative stress; plasma; risk factors

Abbreviations: CHD, coronary heart disease; FI, fluorescent intensity; GFR, glomerular filtration rate


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Measurement of fluorescent oxidation products is recognized as a sensitive measure of oxidation (1–10). This assay is 10–100 times more sensitive than the commonly used lipid oxidation measurement, the colorimetric thiobarbituric acid–reactive substances assay (1, 2). However, this method has not been widely used in human studies for several reasons. First, this marker has been viewed as a nonspecific measurement of oxidation because it reflects a mixture of oxidation products from lipids, proteins, and DNA instead of a single oxidation product (2, 11). Second, this marker may reflect not only oxidation because other products not related to oxidation may also generate fluorescence (2). Despite these features, this marker is stable and relatively reproducible within persons over time (10, 12). Plasma fluorescent oxidation products independently predicted risk of subsequent coronary heart disease (CHD) in a nested case-control study (12) and in a small prospective study (13).

In clinical practice and epidemiologic studies, an ideal method of measuring oxidative stress is not currently available and may not exist. Nevertheless, a marker that reflects oxidative stress and is stable could be valuable for epidemiologic research even if it were not completely specific for oxidation.

A causal relation between smoking and oxidative stress is well established in human studies (14–17); thus, documentation of an association of fluorescent oxidation products with smoking can provide a measure of internal validity. Furthermore, evidence from animal and human studies suggests that oxidative stress is associated with hypertension (18–24), renal vascular hypertension (20, 21), and chronic renal failure (25–29).

In this study, we assessed the relation of a plasma fluorescent oxidation marker with a well-established cause of oxidative stress—smoking—and with factors believed to be associated with systemic oxidative stress, including hypertension and reduced renal function.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Study population
The Health Professionals Follow-up Study, established in 1986, consists of 51,529 male health professionals 40–75 years of age who completed a mailed questionnaire and provided medical history and lifestyle information at baseline. Health information, including newly diagnosed heart disease, is assessed biennially. In 1993–1994, we sent venipuncture kits to participants; 18,140 men returned specimens on ice by overnight courier. Aliquots of plasma were stored in liquid nitrogen freezers for future nested case-control analyses. We selected 524 men who were controls in a nested case-control study of myocardial infarction from this population (12). None had previously diagnosed cancer or cardiovascular diseases at blood draw. The Institutional Review Board of Harvard School of Public Health in Boston, Massachusetts, approved the study, which concluded in 2006.

Assessment of smoking
In the Health Professionals Follow-up Study, current smoking status (cigarettes/day) was assessed on each biennial questionnaire. At baseline, participants were asked whether they had ever smoked 20 packs of cigarettes or more in their lifetime and, if they had, whether they were current or past smokers. The participants who ever smoked were also asked about the mean number of cigarettes smoked per day.

Assessment of hypertension
Hypertension assessed from biennial questionnaires has been confirmed to be highly valid (30). Among Health Professionals Follow-up Study participants, 100 percent of a subset who reported hypertension also had the diagnosis confirmed by medical record review. For our analysis, any men who self-reported hypertension in 1994 or in previous questionnaires were considered hypertensive.

Assessment of renal function
We calculated glomerular filtration rate (GFR) as an estimate of renal function with the equation from the simplified Modification of Diet in Renal Diseases study (31): GFR (ml/minute per 1.73 m2) = 186 x plasma creatinine (mg/dl)–1.154 x age–0.203 x [1.212 if Black]. We used the Cockcroft-Gault equation to calculate creatinine clearance: ([140 – age (years) x weight (kg)]/plasma creatinine x 72) (32).

Measurement of other nondietary factors
Height, current weight, and smoking history were reported at baseline, and weight and smoking status were updated biennially. We calculated body mass index (kg/m2) as the ratio of body weight (reported in 1994) to body height (reported in 1986) squared. Waist/hip ratio was assessed on the 1996 questionnaire. The correlation coefficient between self-reported weight and weight measured by trained personnel was 0.96 (33). Physical activity was derived from the 1994 questionnaire. Reproducibility and validity of the physical activity questionnaire have been described elsewhere (34).

Measurement of fluorescent oxidation products, other lipids, and inflammatory markers
Measurement of fluorescent oxidation products was developed by Dillard and Tappel in the 1970s (9) and was later modified by Shimasaki (7). The procedures have been described in detail previously (10). Briefly, plasma was extracted with ethanol-ether (3/1, v/v) and was measured by spectrofluorometer at wavelength 360/430 (excitation/emission wavelength). Fluorescence was determined as relative fluorescent intensity (FI) units per milliliter (FI/ml) of plasma.

Total cholesterol (35), high density lipoprotein cholesterol (36), and triglycerides (37, 38) were measured by standard methods on the Hitachi 911 analyzer with reagents and calibrators from Roche Diagnostics (Indianapolis, Indiana). Concentrations of low density lipoprotein cholesterol were measured by a homogenous direct method from Genzyme (Cambridge, Massachusetts) (39). Plasma creatinine was measured by modified Jaffe method using an autoanalyzer (Hitachi Ltd., Tokyo, Japan) (40). C-reactive protein was measured by immunoturbimetric high-sensitivity assay with reagents and calibrators from Denka Seiken Co., Ltd. (Tokyo, Japan) (41). Soluble tumor necrosis factor-{alpha} receptors types 1 and 2 (42) and interleukin-6 (43) were measured by enzyme-linked immunosorbent assays (ELISAs; R&D Systems, Minneapolis, Minnesota). Hemoglobin A1c was measured by turbidimetric immunoinhibition with packed red blood cells (Hitachi 911 analyzer; San Jose, California and Roche Diagnostics, Indianapolis, Indiana) (44).

Statistical analysis
Lipid biomarkers, particularly triglycerides, are influenced by fasting status. Similarly, postprandial oxidation of food may influence this fluorescent marker and reduce its ability to distinguish predictors of chronically elevated systemic levels of oxidation. Indeed, the levels of oxidation were 44 FI/ml (29 percent) lower among men who fasted more than 14 hours than among those who fasted less than 3 hours. The greatest risk of CHD was for men who fasted for 10 or more hours before blood draw (12). Therefore, we restricted the main analysis to men who fasted more than 10 hours at blood draw (n = 286). We used linear regression models with log transformation of the dependent variable, fluorescent oxidation products, because the distribution of fluorescent marker was skewed.

In the multivariate analyses, we included low density lipoprotein cholesterol (quartiles), high density lipoprotein cholesterol (quartiles), triglycerides (quartiles), serum creatinine (quartiles), C-reactive protein, hemoglobin A1c, age (<55, 55–64.9, 65–74.9, ≥75 years), body mass index (quartiles), physical activity (quartiles), history of smoking (never, past, current), history of hypertension, high cholesterol, family history of myocardial infarction, hours since the last meal, and alcohol consumption (0, 0.1–4.9, 5–14.9, ≥15 g/day). We used the median of each quartile as a single continuous variable to control for C-reactive protein and hemoglobin A1c because they had no significant relation with the fluorescent oxidation marker and the overall association did not change whether we controlled for them as continuous variables or as quartiles.

To obtain p values for trends, we used the median of each quartile as a single continuous variable for creatinine, total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, triglycerides, body mass index, waist/hip ratio, and physical activity. For other continuous variables, such as age and alcohol intake, we used the median value of each category and entered it as a single continuous variable to test for trend.

In addition, we used three approaches to explore the impact of separate modeling techniques to examine continuous predictors of the oxidation marker: 1) predictors entered as continuous variables, the most powerful approach for a truly linear relation but sensitive to influential points and may produce bias for a nonlinear relation; 2) predictors entered as indicator variables such as quartiles or by a priori categories mentioned above, which has the advantage of its insensitivity to the shape of the dose-response curve and extreme influential points even though power can be lost if the dose-response curve is truly linear; and 3) the nonparametric smoothing method, most flexible for capturing a dose-response relation of any shape, although it can also be sensitive to influential points or to the choice of the smoothing parameter. We used stepwise restricted cubic splines (45). This method automatically selects optimal knot locations within the range of exposure and gives levels of the fluorescent oxidation marker as a smooth function of exposure variables. For the test for nonlinearity, we used the likelihood ratio test comparing the model with only the linear term with the model with the linear and cubic spline term (45).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Among these healthy men 47–81 years of age, the mean level of fluorescent oxidation marker was 197 FI/ml (standard deviation, 337), and the median level was 124 FI/ml (interquartile range, 125–193 FI/ml). Approximately 12 percent of the men were current smokers, 49 percent were past smokers, and 35 percent were never smokers, and about 46 percent were hypertensive.

In the multivariate-adjusted analysis, the levels of fluorescent oxidation products were positively and significantly associated with creatinine and total cholesterol (table 1). Levels of triglycerides, high density lipoprotein cholesterol, and low density lipoprotein cholesterol increased with levels of fluorescent oxidation products, but the association was not statistically significant. No significant associations or particular patterns were observed with hemoglobin A1c or any inflammatory markers including C-reactive protein, soluble tumor necrosis factor-{alpha} receptors types 1 and 2, and interleukin-6. For other cardiovascular risk factors, the fluorescent oxidation marker was strongly associated with smoking and hypertension. Among smokers, the fluorescent marker increased linearly with number of cigarettes smoked per day (p = 0.02). The level of oxidation for past smokers was 158 FI/ml in both crude- and multivariate-adjusted models, not statistically different from that for never smokers. Age was marginally associated with levels of fluorescent oxidation products in multivariate-adjusted models (p for trend = 0.07). The levels of oxidation tended to increase at higher levels of alcohol intake (p for trend = 0.03). No significant associations were observed with other risk factors including physical activity, body mass index, and diabetes, although only 26 men had diabetes.


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  		TABLE 1. Age- and multivariate-adjusted plasma levels of fluorescent oxidation products (fluorescent intensity (FI) units/ml) in relation to cardiovascular risk factors among 286 healthy US men in the Health Professionals Follow-up Study who had fasted for more than 10 hours before blood draw (present study conclusion date, 2006)

 
Because GFR and creatinine clearance are often used as better indicators of renal function than creatinine, we replaced creatinine with the two variables in the multivariate-adjusted model; the associations with fluorescent oxidation products did not change substantially (table 2). However, the levels of oxidation were significantly elevated among only those men with moderate kidney damage, in the lowest quartile of GFR or creatinine clearance (25 percent of men had a GFR of <80 ml/minute per 1.73 m2).


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  		TABLE 2. Age- and multivariate-adjusted* plasma levels of fluorescent oxidation products (fluorescent intensity (FI) units/ml) in relation to renal function among 286 healthy US men in the Health Professionals Follow-up Study who had fasted for more than 10 hours before blood draw (present study conclusion date, 2006)

 
Table 3 shows the results when predictors were entered as continuous variables. Similar to the results shown in tables 1 and 2, creatinine, GFR, and total cholesterol all had a significant relation with oxidation. Age had a positive, but only marginally significant association with oxidation (p = 0.09). In contrast to table 1, the association between physical activity and oxidation was significant, driven primarily by the positive association between extremely high levels of physical activity and oxidation, as shown in the spline graph. Overall, spline graph results were similar to our indicator approach (listed in tables 1 and 2) but gave a better picture of the overall shape of the relation of these variables to oxidation (most graphs not shown). In this paper, we have presented the graph for GFR only (figure 1) because reduced renal function was one of our main exposures of interest. GFR was nonlinearly related to log-transformed fluorescent oxidation products; the result of the test for nonlinearity relation was 0.02, and the p value for overall significance of the curve was 0.0004. Oxidation levels were significantly increased for a GFR below 90 ml/minute per 1.73 m2, remained flat for a GFR of 90–105 ml/minute per 1.73 m2, and slightly increased for a GFR of ≥105 ml/minute per 1.73 m2, but the magnitude was small (figure 1).


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  		TABLE 3. Levels of fluorescent oxidation products (fluorescent intensity (FI) units/ml) associated with a one-standard-deviation increase in each variable among 286 US men in the Health Professionals Follow-up Study (present study conclusion date, 2006)

 

Figure 1
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  		FIGURE 1. Multivariate-adjusted log-transformed fluorescent oxidation products (fluorescent intensity (FI) units/ml) by glomerular filtration rate (GFR) (ml/minute per 1.73 m2). The multivariate model was adjusted for low density lipoprotein cholesterol; high density lipoprotein cholesterol; triglycerides; glycated hemoglobin A1c; C-reactive protein; age; body mass index; physical activity; alcohol intake; number of hours of fasting; smoking status (never, past, current); history of diabetes, hypertension, and high cholesterol; and family history of myocardial infarction. Dashed lines, 95% confidence intervals. This US study concluded in 2006.

 
To assess the cumulative impact of multiple risk factors on plasma concentrations of fluorescent oxidation marker, we evaluated levels of fluorescent oxidation products according to age younger or older than 66 years, the presence or absence of smoking, hypertension, GFR <80.73 ml/minute per 1.73 m2 (quartile 1), and total cholesterol in quartile 4. Fluorescent oxidation products progressively increased as the prevalence of these risk factors increased. Specifically, the levels of this marker were 144, 150, 164, 196, and 361 FI/liter for those with none, one, two, three, and four or five risk factors, respectively (p for trend < 0.001).

To evaluate further the association of hypertension and reduced renal function with oxidation, we created a joint classification of hypertension and GFR. Levels of fluorescent oxidation products were 235 FI/ml in men with both reduced renal function (GFR < 80.73 ml/minute per 1.73 m2) and hypertension compared with 150 FI/ml in men with neither (p < 0.001).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
Levels of fluorescent oxidation products were significantly, positively associated with variables linked with systemic oxidative stress, including smoking, hypertension, and reduced renal function. This marker increased significantly with number of cigarettes smoked per day. The oxidation products were also associated with lipid-cardiovascular risk factors such as total cholesterol and were marginally associated with age in crude-adjusted and multivariate-adjusted analyses. The strong association between smoking and fluorescent oxidation products provides evidence of validity for this fluorescent marker as a marker of oxidation.

There are many methods for measuring oxidative stress, and none has proven useful or reliable (46). Several oxidative markers are not stable in plasma specimens from population studies (10), and measuring F2-isoprostanes, the most established marker, is complicated and expensive. Furthermore, F2-isoprostanes are end products of oxidation of lipids only, not of protein and DNA. Thus, until now, a stable and easily measured oxidation marker that reflects systemic oxidative stress, predictive of chronic diseases and applicable in large-scale human studies, has not been available.

The causal relation between oxidation and smoking is well established (14–17, 47). The gaseous phase of cigarette smoke contains many oxidants that can induce lipid oxidation in vitro (15). Smoking can cause oxidative damage in vivo; plasma levels of F2-isoprostanes significantly decreased in smokers who abstained for 2 weeks (14) and significantly increased after smoking was resumed (17). Other investigators have also documented the causal link between smoking and oxidation in free-living populations (16, 47). Although our cross-sectional data cannot demonstrate a causal relation, after controlling for several confounding factors we still found a strong association between smoking and the fluorescent oxidation marker. These data provided evidence of the validity of the fluorescent oxidation products as a marker of oxidation.

Hypertension and reduced renal function are thought to be associated with oxidative stress (18–29), although human studies of these conditions and biomarkers of oxidative stress are not entirely consistent. Our finding of an association of the fluorescent oxidation marker with hypertension is consistent with animal and in vitro studies (18, 19, 48–51). Some small (20–22) and two relatively large (23, 24) cross-sectional studies (n = 415 and n = 569, respectively) found a positive association with hypertension, but one study (52) (n = 2,828) did not. The reason for the null association in the latter study is not clear; perhaps the limited oxidation products assessed by the determination of F2-isoprostanes do not capture damage related to hypertension. Nevertheless, we demonstrated that plasma fluorescent oxidation is associated with hypertension. Oxidation is more likely to be an outcome of hypertension, because mechanical forces such as stretch (49, 50) and shear stress (51), and angiotensin II caused by hypertension, can stimulate generation of oxidation products (18, 53).

Experimental evidence has also linked oxidative stress to renal damage. Tubular cells increase the production of hydrogen peroxide during myoglobinuria (54), and a decrease in antioxidant activity and an increase in oxidative damage were found in patients with obstructive kidney damage (55). Several plasma oxidation products, including F2-isoprostanes (25), protein carbonyl (26), and advanced glycation end products (27, 28), have been associated with renal failure. However, these studies were small, and the levels of oxidation were higher only in those patients with advanced renal failure, not in those with moderate renal insufficiency. The fluorescent marker is more sensitive than F2-isoprostanes, protein carbonyl, and advanced glycation end products because we found that it was associated with reduced renal function among men without overt renal failure—GFR levels were >60 ml/minute per 1.73 m2 in 95 percent of our participants (a GFR of 60–89 is considered to indicate mild kidney damage).

Although in vitro (56, 57) and animal (58) studies show an association of aging with oxidative stress, two cross-sectional studies that used the measurement of F2-isoprostanes failed to find this association (52, 59). The null results could be explained if F2-isoprostanes in humans do not reflect oxidation products related to aging. Nevertheless, we still found a marginally significant association between fluorescent oxidation products and age even after accounting for age-related risk factors.

We found an association of fluorescent oxidation products with plasma levels of total cholesterol. Although cholesterol can be oxidized to a mixture of oxidation products during lipid oxidation, human cross-sectional studies are inconclusive with regard to markers of oxidative stress and hypercholesterolemia. F2-isoprostanes were elevated in hypercholesterolemic patients in some studies (60, 61) but not others (52, 62). The reason for the discrepancies between studies is not clear, and more studies are needed.

Our cross-sectional analysis corroborates and complements findings from our nested case-control study of CHD in the same cohort (12). In that analysis, the fluorescent marker was an independent risk factor for CHD after controlling for known CHD risk factors. In this cross-sectional analysis, we found several associations between CHD risk factors and the measure of fluorescent oxidation. Thus, the association between several known risk factors and CHD risk may be also mediated through pathways that involve oxidation processes.

In conclusion, the fluorescent assay potentially measures oxidation products from several sources including lipid, protein, and DNA and thus may reflect a more global oxidative stress than a single lipid oxidation product. We have demonstrated that fluorescent oxidation products in plasma are associated with several indicators of oxidative stress: smoking, hypertension, and reduced renal function. Oxidative stress has been hypothesized to play an important role in many diseases; thus, this marker may be a useful global marker of oxidative stress for epidemiologic studies.


   ACKNOWLEDGMENTS
 
This study is supported by grants from the National Institutes of Health (HL35464, CA55075), the American Heart Association (0430202N), and the National Colorectal Cancer Research Alliance.

The authors are indebted to Ellen Hertzmark and Alan Paciorek for their assistance.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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R. Meerwaldt, T. Links, C. Zeebregts, and A. Smit
RE: "PLASMA FLUORESCENT OXIDATION PRODUCTS AS POTENTIAL MARKERS OF OXIDATIVE STRESS FOR EPIDEMIOLOGIC STUDIES"
Am. J. Epidemiol., March 15, 2008; 167(6): 756 - 757.
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