Longitudinal lead exposure impairs HDL-associated paraoxonase-1 activities independently of PON1 polymorphisms: Evidence from a three-year occupational cohort.

Chronic lead (Pb) exposure is a recognized cardiovascular toxicant, however its long-term impact on HDL-associated antioxidant defenses and genetic susceptibility remains unclear. Paraoxonase-1 (PON1), an HDL-bound enzyme, limits lipid peroxidation and atherogenic modification. We conducted a 3-year longitudinal study of 141 Pb workers with repeated measures of blood lead (B-Pb), serum lipids, and PON1 activities (arylesterase, paraoxonase, diazoxonase). PON1 Q192R, L55M, and C108T polymorphisms were genotyped. Generalized estimating equation models adjusted for demographic, occupational, and behavioral factors. Higher B-Pb levels were consistently associated with reduced HDL-C-adjusted arylesterase, diazoxonase and paraoxonase activities. Each 1 µg/dL increase in B-Pb corresponded to a 0.0093 µmol/min/mL× [HDL] decrease in arylesterase activity (p < 0.001). Although genotypes influenced baseline enzyme levels, no significant gene-lead interaction was observed. These findings indicate that chronic Pb exposure suppresses PON1 antioxidant function independently of these genetic variants, supporting HDL dysfunction as a mechanistic link between Pb exposure and cardiovascular toxicity.