Lead exposure, B vitamins, and plasma homocysteine in men 55 years of age and older: the VA normative aging study

Abstract

Background: Lead (Pb) exposure may influence the plasma concentration of homocysteine, a one-carbon metabolite associated with cardiovascular and neurodegenerative diseases. Little is known about the associations between Pb and homocysteine over time, or the potential influence of dietary factors.

Objectives: We examined the longitudinal association of recent and cumulative Pb exposure with homocysteine concentrations and the potential modifying effect of dietary nutrients involved in one-carbon metabolism.

Methods: In a subcohort of the Veterans Affairs (VA) Normative Aging Study (1,056 men with 2,301 total observations between 1993 and 2011), we used mixed-effects models to estimate differences in repeated measures of total plasma homocysteine across concentrations of Pb in blood and tibia bone, assessing recent and cumulative Pb exposure, respectively. We also assessed effect modification by dietary intake and plasma concentrations of folate, vitamin B6, and vitamin B12.

Results: An interquartile range (IQR) increment in blood Pb (3 μg/dL) was associated with a 6.3% higher homocysteine concentration (95% CI: 4.8, 7.8%). An IQR increment in tibia bone Pb (14 μg/g) was associated with a 3.7% higher homocysteine (95% CI: 1.6, 5.6%), which was attenuated to 1.5% (95% CI: -0.5, 3.6%) after adjusting for blood Pb. For comparison, a 5-year increase in time from baseline was associated with a 5.7% increase in homocysteine (95% CI: 4.3, 7.1%). The association between blood Pb and homocysteine was significantly stronger among participants with estimated dietary intakes of vitamin B6 and folate below (vs. above) the study population medians, which were similar to the U.S. recommended dietary allowance intakes.

Conclusions: Pb exposure was positively associated with plasma homocysteine concentration. This association was stronger among men with below-median dietary intakes of vitamins B6 and folate. These findings suggest that increasing intake of folate and B6 might reduce Pb-associated increases in homocysteine, a risk factor for cardiovascular disease and neurodegeneration.

Figure 1

One-carbon metabolism pathway. Homocysteine can be elevated in conditions of low folate, low vitamin B₆, or low vitamin B₁₂. The sulfhydryl groups on several proteins, including cystathionine β-synthase, in the one-carbon metabolism pathway are potential sites for interferences by Pb. Abbreviations: Ado, adenosine; BHMT, betaine-homocysteine S-methyltransferase; CBS, cystathionine β-synthase; DHF, dihydrofolate; DMG, dimethylglycine; Glu, glutamate; Gly, glycine; GSH, glutathione; MS, methionine synthase; MT, methyltransferase; MTHFR, methylenetetrahydrofolate reductase; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; THF, tetrahydrofolate; Zn, zinc. Adapted from Bistulfi et al. (2010). *Indicates putative locations for interference by Pb.

Figure 2

Adjusted percentage difference in homocysteine per IQR increment in blood Pb concentration by nutrient status level. All analyses were adjusted for age, education, alcohol consumption, smoking status, and BMI.