Altered Serum Lipids and Paraoxonase Activity : A Step toward Atherosclerosis among Lead Exposed Egyptian Workers

A vast amount of evidence during the past decade, has confirmed that lead is associated with lipid and lipoprotein abnormalities which play a major role in the pathogenesis and progression of atherosclerosis and cardiovascular diseases. This study aimed: to investigate the relationship between chronic occupational lead exposure, lipid profile, and serum PON1 activity as one of the mechanisms of atherosclerosis. Male workers (n=100) in lead battery manufactory were recruited for this study. They were compared with 100 male age matched non-lead workers. Serum lipid profile and paraoxonase activity were done to their samples. Serum Lead was determined vsing atomic absorption spectroscopy. There was significant differences regarding triglycerides, total cholesterol, and HDLc (p=0.01, 0.05 and 0.04, respectively) between both groups. A cumulative effect of blood lead on lipid profile was significantly detected. Multiple linear regression analysis showed that blood lead level was the only negative significant predictors to serum paraoxonase activity (p=0.03) in lead workers. lead exposure is associated with increased triglycerides, total cholesterol and LDL-c and decrease HDL-c. Because of the protective role of PON1 in the development of atherosclerosis, decrease in serum PON1 activity due to lead exposure may render individuals more susceptible to atherosclerosis. INTRODUCTION Lead exposure is a well known occupational health hazard. The continuous lead over exposure and lead poisoning remains a serious problem in Egypt especially among workers of battery and recycling factories.(1) Multiple morphological and biochemical changes in the cardiovascular system, various organs and blood are documented with chronic lead exposure.(2) Also it is associated with altered lipid metabolism especially serum cholesterol and lipoprotein levels in 538 Bull High Inst Public Health Vol.39 No.3 [2009] both humans and animals. (3-6) Atherosclerosis is a chronic disease that is caused by damage to the arterial wall from inflammation and fibro-fatty deposits.(7) A vast amount of evidence during the past decade, has confirmed that lipid and lipoprotein abnormalities play a major role in the pathogenesis and progression of atherosclerosis and cardiovascular diseases.(8,9) Cholesterol is a key component in the development of atherosclerosis. An inverse correlation between the serum concentration of HDL-c (high density lipoprotein cholesterol) and the development of atherosclerosis has long been known.(10) Several laboratories have reported that HDL-c protects against LDL-c (low density lipoprotein cholesterol) oxidation.(11,12) which is the main step in initiation and progression of atherosclerosis.(13) The anti-atherogenic properties of HDL-c are partially due to the activity of HDL-associated enzymes, which prevent and/or reverse LDL oxidation. (14) One of those enzymes is the calciumdependent ester hydrolase paraoxonase (PON1) which is found tightly associated with the HDL particle.(15) Paraoxonase-1 (PON1) is a protein of 354 amino acids with a molecular mass of 43 kilo Dalton. Multiple factors can affect PON1 levels and thus interfering with its protective function.(16) Previous studies have shown that various metals, including lead even at low concentrations < 1 μg/dl, caused significant inhibition of PON1 activity in vitro.(17,18) and in vivo.(19) The aim of the present study was to investigate the relationship between chronic occupational lead exposure, lipid profile, and serum PON1 activity as one of the mechanisms of atherosclerosis SUBJECTS AND METHODS This cross sectional study was conducted from June 2008 till May 2009. Subjects 1. Occupational lead exposed group


INTRODUCTION
Lead exposure is a well known occupational health hazard.The continuous lead over exposure and lead poisoning remains a serious problem in Egypt especially among workers of battery and recycling factories. (1)ultiple morphological and biochemical changes in the cardiovascular system, various organs and blood are documented with chronic lead exposure. (2))(6) Atherosclerosis is a chronic disease that is caused by damage to the arterial wall from inflammation and fibro-fatty deposits. (7)A vast amount of evidence during the past decade, has confirmed that lipid and lipoprotein abnormalities play a major role in the pathogenesis and progression of atherosclerosis and cardiovascular diseases. (8,9)olesterol is a key component in the development of atherosclerosis.An inverse correlation between the serum concentration of HDL-c (high density lipoprotein cholesterol) and the development of atherosclerosis has long been known. (10)Several laboratories have reported that HDL-c protects against LDL-c (low density lipoprotein cholesterol) oxidation. (11,12)which is the main step in initiation and progression of atherosclerosis. (13)The anti-atherogenic properties of HDL-c are partially due to the activity of HDL-associated enzymes, which prevent and/or reverse LDL oxidation. (14)e of those enzymes is the calciumdependent ester hydrolase paraoxonase (PON1) which is found tightly associated with the HDL particle. (15)raoxonase-1 (PON1) is a protein of 354 amino acids with a molecular mass of 43 kilo Dalton.Multiple factors can affect PON1 levels and thus interfering with its protective function. (16)Previous studies have shown that various metals, including lead even at low concentrations < 1 μg/dl, caused significant inhibition of PON1 activity in vitro. (17,18)and in vivo. (19)e aim of the present study was to investigate the relationship between chronic occupational lead exposure, lipid

Statistical analysis:
Data obtained from the study was coded and entered using the software and blood lead and LDL cholesterol (r = 0.3; p = 0.04), while, non significant negative correlation was found between blood lead and HDL-c(r=-0.2;p=0.1) Paraoxonase activity: A significant difference was observed between the three groups regarding the paraoxonase activity.
Gradual decrease in the enzyme activity was obvious as the lead level increased.
The activity reached a minimum median value of 300 (100.6-1087umol/min/L) when lead level was ≥60ug/dl (Table 2).A negative significant correlation was detected between blood lead level and paraoxonase activity as shown in figure 1 (r=-0.2;p=0.03).
Table 3 represents the prediction of paraoxonase activity.Only the lead level was the significant predictors (p=0.03).An increase in the blood lead of 1ug/dl was found to be associated with 5.7 umol/min /L decrease in the paraoxonase activity (Table 3).

DISCUSSION
The present study showed that positive significant correlations existed between blood lead and both, total cholesterol and LDL cholesterol as well as a negative non significant correlation with HDL cholesterol among chronically lead exposed workers (Table 2).Also it illustrated the role of blood lead as the only significant predictor of PON1 activity (Table 3).
Bull High Inst Public Health Vol.39 No. 3 [2009]   The findings of the present study support the findings of others. (1,5,6)and indicate that exposure to lead alters significantly the lipid levels as demonstrated by comparing lead exposed (group A) and non lead exposed (group B) workers (Table1).
Plasma lipoprotein includes four groups (cholesterol, triglycerides, HDL and LDL).HDL and LDL are responsible for lipid metabolism and the exchange of cholesterol and triglycerides between tissues. (9,26)merous population studies have shown an inverse correlation between plasma HDL levels and risk of cardiovascular disease, implying that factors associated with HDL protect against atherosclerosis. (27,28)he cholesterol requirements of most extra-hepatic tissues are supplied by LDL.A major function of HDL cholesterol is to enhance removal of excess cholesterol from peripheral tissues followed by esterification and delivering it to the liver for eventual elimination from the body. (29,30)This role of HDL has been shown to be responsible for its atheroprotective properties.In this study, although all the values of lipid profile were within the reference range, the total cholesterol levels in group A were 1.4 times higher than group B (Table 1).Also a significant difference between both groups were detected in triglyceride level and HDL This study exhibited the cumulative effect of blood lead level and strengthened the dose response relationship between it and altered lipid profile.Increasing the duration of lead exposure and consequently gradual increase in the blood lead level was associated with a significant increase in cholesterol, LDL-c and a significant decrease in HDL-c.Although correlations do not imply causality, the observation of a significant positive relationship between lead and total cholesterol on one hand, and a significant positive correlation between lead and LDL cholesterol on the other hand (Table 3), seems to support these findings.These are in accordance with the results of other studies. (1,5,6,19,31)e of the most important mechanisms by which HDL can prevent atherosclerosis is inhibition of oxidation of LDL as well as the atherogenic effects of oxidised LDL. (30)The paraoxonase enzyme (PON1) resides on high-density lipoprotein (HDL, 'good cholesterol') and is involved in the prevention of atherosclerosis by protecting against LDL-c oxidation. (15)It is to be mentioned that a significant decrease in PON1 activity between lead exposed and non exposed workers was obvious in this study (Table 1).As the blood lead increased, a steady significant decrease in PON1 activity was observed.This represents a reduced protection against LDL oxidation, thereby increasing the accumulation of lipid peroxides and, eventually, promoting atherosclerosis.This was consistent with studies previously performed by Ito et al. (3 ) , Debord et al. (18) and Li et al. (19) The mechanism by which heavy metals including lead inhibit serum PON1 activity was discussed by Gonzalvo et al. (32) They suggested that metal ions, such as lead, copper and mercury, bind to the free sulfhydryl group of the enzyme and this will reduce not only the hydrolytic activity of PON1 but also its antioxidant function.

LeadFigure 1 :
Figure 1: Correlation between paraoxonase activity and blood lead level

Table 2 : companion between age, duration of work and blood profile of lead exposed workers.
BPb: blood lead level; DBP: diastolic blood pressure; SBP: systolic blood pressure † Median (25thpercentile-75th percentile