We hypothesized that oxidative DNA damage is increased in persons with low cholesterol levels. In the present study of a healthy working population, we found a statistically significant inverse association between serum TC and urinary 8-OHdG concentrations even after adjustment of confounding factors. Subgroup analysis showed that the inverse association was more pronounced in smoking men and younger women. This is one of few epidemiological studies which examined the association between TC levels and oxidative DNA damage [12, 13].
Available data on associations between circulating cholesterol levels and markers of oxidative DNA damage are limited and conflicting. In a study of 677 middle-aged city officers, urinary 8-OHdG concentrations were statistically, positively associated with LDL-C, but not with TC . In another study among 90 non-smokers who participated in a health program, a weak non-significant inverse association was observed between TC and urinary 8-OHdG levels (r = −0.155) . In measuring urinary 8-OHdG, these studies used ELISA method, which is less accurate than HPLC method .
In the present study, a significant inverse association between TC and urinary 8-OHdG levels was found among smokers (β = −0.0017, p < 0.01) but not among non-smokers (β = −0.0015, p = 0.15) in men. However, the estimated slope (β) of smokers was similar to that of nonsmokers. In women, the association was more apparent among women aged less than 48 years (β = −0.0040, p < 0.01) than those aged 48 years or older (β = −0.0014, p = 0.47). This result may suggest that menopausal status may modify the association between circulating TC and oxidative stress. Such differential association has also been observed in epidemiological studies on cancer. For instance, low serum TC was associated with an increased risk of breast cancer among pre-menopausal women, but not among post-menopausal women .
Biological mechanism underlying the association between lower serum TC and higher oxidative DNA damage remains unclear. Cholesterol is an important structural lipid for maintaining cell functions. In addition, cholesterol plays an important role in the absorption of lipid-soluble vitamins including vitamin E, the major membrane-bound antioxidant, and controls the flow of these vitamins in and out of cell membranes [19, 20]. Persons with low cholesterol levels may thus have a decreased antioxidant capacity, leading to increased oxidative DNA damage.
In women aged less than 48 years, urinary 8-OHdG levels were significantly, inversely associated with LDL-C (β = −0.0041, p < 0.05), and marginally significantly associated with HDL-C levels (β = −0.0052, p = 0.08). Plausible mechanisms underlying these associations are unclear, but the following has been suggested. HDL-C can prevent oxidation of LDL-C . Thus, LDL-C derived oxidized stress might be increased among subjects with lower levels of HDL-C. Meanwhile, LDL-C level itself is not associated with oxidized LDL-C level . Although LDL-C might be partially oxidized, most of the remaining unoxidized LDL-C might play a protective role against oxidative stress.
Major strengths of the present study include high response rate (91%), control of known background and lifestyle factors associated with oxidative DNA damage, and use of reliable technique (HPLC) in measuring biomarker of oxidative DNA damage . Limitations of the study also warrant mention. The cross-sectional design of this study does not allow us to infer causality. Because study participants were employees of municipal offices in Japan, the present findings may not be applicable to populations with different background. Finally, the sample size of this study may not be sufficient to detect a modest association.
In conclusion, serum TC levels were inversely associated with urinary 8-OHdG concentrations in a healthy working population. This finding suggests that oxidative DNA damage is increased in persons with low cholesterol levels, and thus may support a link of low TC to carcinogenesis.