MeHg and plasma paraoxonase activity in Inuit reported by others (Cherki et al. 2007; Jarvik et al. 2002; Seres et al. 2004). The negative effect of age on PON1 activity has been attrib- uted to a reduced number of sulfhydryl groups on the protein, because of an increase in oxida- tive stress in the elderly (Jaouad et al. 2006). The positive association between HDL-C and PON1 activity was expected because the enzyme circulates in the plasma associated with HDL. This relation has been reported in other studies pertaining to factors that influ- ence the activity of the enzyme in healthy subjects (Boesch-Saadatmandi et al. 2010; Ferré et al. 2003). We also noted a positive influence of EPA plus DHA content of eryth- rocyte membranes on PON1 activity. The fact that n-3 PUFA intake is significantly linked to PON1 activity in a multivariate model that Table 2. Geometric mean (GM) PON1 activity (kU/L) according to selected characteristics of participants. Table 3. Multiple linear regression modela of plasma PON1 activity (log kU/L) in Inuit adults, Nunavik, 2004. CI, confidence interval. aMultiple R2 = 0.314; n = 651. bLog-transformed variables. cInverse-transformed variable. dReference category is AT and AA. Environmental Health Perspectives • volume 119 | number 8 | August 2011 Characteristic Sex Men Women No. of cigarettes/day 0 1–10 11–24 ≥ 25 Frequency of alcohol consumption Daily Weekly Monthly Never of yearly Variant and genotype rs705379 (–108C/T) GG (CC) AG (CT) AA (TT) rs662 (Q192R) GG (QQ) AG (QR) AA (RR) rs854560 (L55M) TT (MM) AT and AA (LM and LL) Statin intake Yes No Cardiovascular disease Yes No Diabetes Yes No Dyslipidemia Yes No CI, confidence interval. Variable Age (years) Blood mercury (nmol/L)b Blood selenium (μmol/L)c HDL-C (mmol/L)b EPA + DHA (%) PON1 variants rs662 (Q192R) GG (CC) AG (CT) rs854560 (L55M)d TT (MM) rs705379 (–108C/T) GG (QQ) AG (QR) c > 110 1081 included HDL-C as a covariate suggests that these fatty acids may increase PON1 activ- ity independently of their known effect on HDL-C levels. Results from an experiment in which rats were fed a diet rich in n-3 PUFAs (13.8% of caloric intake) showed reduced serum PON1 activity compared with rats receiving a diet with a low n-3 PUFA content (2.8% of caloric intake) (Varatharajalu et al. 2010). Although these results suggest that a high intake of n-3 PUFAs can promote oxi- dation, this may not be the case for a lower intake such as that of the Inuit population. Three PON1 gene variants that were pre- viously shown to affect the arylesterase activ- ity of the enzyme (Brophy et al. 2001) were also found to influence the activity measured by the hydrolysis rate of the fluorogenic sub- strate in the present study (Table 3). Based on squared partial correlation coefficients (data not shown), the rs705379 polymorphism had the largest effect on PON1 activity, followed by rs662 and then rs854560. Brophy et al. (2001) reported that the rs854560 effect of lowered arylesterase activity was attributable largely to linkage disequilibrium with the rs705379 polymorphism. We specifically tested the interaction between blood mercury concentration and the rs662 (PON1192) polymorphism because of results from an in vitro study indicating that metals, including mercury, might be more effective in inhibiting the PON1R192 isozyme (Cole et al. 2002; Costa et al. 2005; Gençer and Arslan 2009). However, we did not find support for such an allele-specific susceptibil- ity to MeHg toxicity, because the mercury × rs662 interaction term was not statistically significant when entered in a multivariate model [see Supplemental Material, model 4 (doi:10.1289/ehp.1003296)]. Results from biochemical studies sug- gest that the free thiol group on the cysteine- 285 residue may be the molecular target of 12.0 )L 11.5 / (kU11.0 ity 10.5 v i tc10.0 a 1N 9.5 PO 9.0 8.5 a ≤ 30 a,b b 30–55 56–110 Quartiles of blood mercury concentrations (nmol/L) Figure 2. Relation between blood mercury con- centrations and PON1 activity in Inuit adults from Nunavik. Each bar represents the geometric mean ± 95% confidence interval. Mean values were adjusted for age, blood selenium levels, plasma HDL-C concentrations, and PON1 genotypes (rs662, rs854560, rs705379). Different letters above the bars indicate mean values that are significantly different from one another. n 405 491 196 257 235 100 60 157 177 388 419 214 26 224 322 108 615 41 70 826 164 732 32 864 71 825 β-Coefficient –0.047 –0.063 0.067 0.077 0.048 –0.189 –0.101 0.096 0.366 0.230 GM (95% CI) PON1 activity 10.2 (9.9–10.4) 11.1 (10.8–11.3) 10.7 (10.3–11.2) 10.4 (10.1–10.8) 10.8 (10.5–11.1) 10.7 (10.2–11.2) 11.5 (10.8–12.2) 10.6 (10.3–11.1) 10.7 (10.4–11.1) 10.5 (10.2–10.8) 11.4 (11.1–11.6) 9.8 (9.5–10.1) 7.5 (6.9–8.2) 9.9 (9.5–10.2) 10.9 (10.6–11.2) 11.8 (11.2–12.4) 10.8 (10.6–11.0) 9.3 (8.7–10.1) 10.4 (9.8–11.1) 10.6 (10.4–10.8) 10.5 (10.1–10.9) 10.6 (10.4–10.8) 9.5 (8.7–10.4) 10.6 (10.4–10.8) 10.5 (9.8–11.1) 10.6 (10.4–10.8) 95% CI –0.066 to –0.028 –0.091 to –0.035 0.045 to 0.088 0.061 to 0.094 0.023 to 0.074 –0.241 to –0.136 –0.147 to –0.055 0.038 to 0.153 0.279 to 0.452 0.142 to 0.317 p-Value < 0.001 0.531 0.046 < 0.001 < 0.001 < 0.001 0.572 0.663 0.017 0.694 p-Value < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 0.001 < 0.001 < 0.001