Research Relation between Methylmercury Exposure and Plasma Paraoxonase Activity in Inuit Adults from Nunavik Pierre Ayotte,1,2 Antoine Carrier,1 Nathalie Ouellet,1,2 Véronique Boiteau,1 Belkacem Abdous,1 Elhadji Anassour Laouan Sidi,1 Marie-Ludivine Château-Degat,1 and Éric Dewailly1 1Axe de Recherche en Santé des Populations et Environnementale, Centre de Recherche du Centre Hospitalier Universitaire de Québec, Québec, QC, Canada; 2Laboratoire de Toxicologie, Institut National de Santé Publique du Québec, Québec, QC, Canada Background : Methylmercury (MeHg) exposure has been linked to an increased risk of coronary heart disease (CHD). Paraoxonase 1 (PON1), an enzyme located in the high-density–lipoprotein (HDL) fraction of blood lipids, may protect against CHD by metabolizing toxic oxidized lipids associated with low-density liproprotein and HDL. MeHg has been shown to inhibit PON1 activ- ity in vitro, but this effect has not been studied in human populations. o Bjectivs : This study was conducted to determine whether blood mercury levels are linked to decreased plasma PON1 activities in Inuit people who are highly exposed to MeHg through their seafood-based diet. Methods : We measured plasma PON1 activity using a fluorogenic substrate and blood concen- trations of mercury and selenium by inductively coupled plasma mass spectrometry in 896 Inuit adults. Sociodemographic, anthropometric, clinical, dietary, and lifestyle variables as well as PON1 gene variants (rs705379, rs662, rs854560) were considered as possible confounders or modifiers of the mercury–PON1 relation in multivariate analyses. r esult : In a multiple regression model adjusted for age, HDL cholesterol levels, omega-3 fatty acid content of erythrocyte membranes, and PON1 variants, blood mercury concentrations were inversely associated with PON1 activities [β-coefficient = –0.063; 95% confidence interval (CI), –0.091 to –0.035; p < 0.001], whereas blood selenium concentrations were positively associated with PON1 activities (β-coefficient = 0.067; 95% CI, 0.045–0.088; p < 0.001). We found no inter- action between blood mercury levels and PON1 genotypes. c onclusi : Our results suggest that MeHg exposure exerts an inhibitory effect on PON1 activ- ity, which seems to be offset by selenium intake. k ey words : Inuit, methylmercury, Nunavik, omega-3 polyunsaturated fatty acids, paraoxonase, PON1, selenium. Environ Health Perspect 119:1077–1083 (2011). doi:10.1289/ehp.1003296 [Online 4 May 2011] Exposure to methylmercury (MeHg) from fish consumption may be associated with an increased risk of heart diseases, particularly myocardial infarction (Stern 2005). The main evidence supporting this relationship was pro- vided by Finnish studies conducted among non-fatty-fish eaters (Salonen et al. 1995). Other populations consume different species of fish and in some cases marine mammals, and their risk of cardiovascular effects may be related not only to MeHg exposure but also to nutrients that may counteract the toxic effects of MeHg, such as omega-3 polyunsaturated fatty acids (n-3 PUFAs) and selenium, that are high in some marine foods. Inuit populations living in circumpolar countries have had lower incidences of coronary heart disease (CHD), particularly ischemic diseases, than those of more southern populations living in indus- trialized areas (Bang et al. 1971; Corcoran and Rabinowitch 1937; Kjaergaard et al. 2009). However, changes in some aspects of their diet and lifestyle that have occurred over the last decades have been associated with increased risk of CHD (Château-Degat et al. 2010; Counil et al. 2009; Jorgensen et al. 2008; Young et al. 2007). In particular, a decreased intake of food items that are rich in n-3 PUFAs or selenium (sea mammal fat and skin) could exacerbate the toxic effects of MeHg on the cardiovascular system. The mechanism of action through which MeHg increases the risk of CHD remains to be identified. Oxidative damage generated by MeHg has been suggested as a possible early biological effect resulting from MeHg expo- sure, in turn causing lipid peroxidation, inflam- mation, and endothelial cell damage (Grotto et al. 2009). Animal studies have shown that MeHg can induce oxidative stress directly by catalyzing reactions that produce reactive oxy- gen species (Grotto et al. 2009; Lin et al. 2006). Alternatively, oxidative stress may indirectly result from the interaction of MeHg with thiol or selenol groups in antioxidant molecules such as glutathione and enzymes such as glutathione peroxidase and thioredoxin reductase (Carvalho et al. 2008; Khan and Wang 2009). Human paraoxonase (PON1) is an enzyme associated with the high-density lipo- protein (HDL) particle that inhibits oxidation of low-density lipoprotein (LDL) and HDL through hydrolysis of lipid peroxides (Aviram 2000; Mackness et al. 1998). Knockout mice lacking the PON1 gene develop atherosclero- sis more rapidly than do wild-type mice (Shih et al. 2000). Hence, it has been suggested that PON1 inhibits the atherosclerotic process by Environmental Health Perspectives • volume 119 | number 8 | August 2011 preventing LDL oxidation in the arterial wall. The involvement of PON1 in the pathogenic sequence is further supported by the fact that decreased PON1 activity is associated with an increased prevalence of atherosclerosis (Jarvik et al. 2000; Mackness et al. 2001) and incidence of cardiovascular disease (Mackness et al. 2003). Three common single-nucleotide poly- morphisms (SNPs) within the PON1 gene appear to be the strongest determinants of serum PON1 activity (Costa et al. 2005; Ferré et al. 2003). Two SNPs occur in the coding region: the first involves a change of methionine (M allele) for leucine (L allele) at position 55 (L55M; rs854560); the second involves the substitution of arginine (R allele) for glutamine (Q allele) at position 192 (Q192R; rs662). The latter has been shown to significantly modulate the activity of PON1 toward its various substrates. The third SNP, –108C/T (rs705379), is located in the pro- moter region and has a major influence on PON1 expression (Brophy et al. 2001). Despite the predominance of genetic influences, several other factors can modu- late serum PON1 activity, such as age, drugs, diseases, smoking, alcohol, diet, and envi- ronmental chemicals (Costa et al. 2005). Because of the known capacity of toxic metals Address correspondence to P. Ayotte, Laboratoire de Toxicologie, Institut National de Santé publique du Québec, 945 Ave. Wolfe, 4e étage, Québec, QC, Canada G1V 5B3. Telephone: (418) 650-5115 ext. 4654. Fax: (418) 654-2148. E-mail: pierre.ayotte@ inspq.qc.ca Supplemental Material is available online (doi:10. 1289/ehp.1003296 via http://dx.doi.org/). We thank L. Rochette and D. Hamel (Institut National de Santé Publique du Québec) for managing the database and writing the programs for bootstrap esti- mation of statistical parameters. We are also grateful to J. Hansen, who provided the initial ideas for this work. We gratefully acknowledge the support of the Natural Sciences and Engineering Research Council of Canada’s Metals in the Human Environment Strategic Network. A complete list of sponsors is available at www.mithe-sn.org. We also acknowledge the support of Fonds de la recherche en santé du Québec Environmental Health Research Network. Funding for the Nunavik Health Survey was pro- vided by the Northern Contaminants Program (Indian Affairs and Northern Development Canada), Nunavik Regional Board of Health, Quebec’s Ministry of Health and Social Services, and ArcticNet Network of Centres of Excellence of Canada. The authors declare they have no actual or poten- tial competing financial interests. Received 3 December 2010; accepted 4 May 2011. 1077