New insights regarding tissue Se and Hg interactions on oxidative stress from plasma IsoP and IsoF measures in the Canadian Inuit population

Despite animal and in vitro studies demonstrating pro-oxidative effects of Hg, previous human work showed no relationship between tissue Hg and plasma levels of F2-isoprostanes (IsoPs), a whole-body oxidative stress marker. We hypothesized that another IsoP species, isofurans (IsoFs), was a more sensitive indicator of Hg-mediated oxidative stress, which can be modified by tissue Se status. A cross-sectional study was carried out involving individuals from a random subset (n = 233) of Inuit adults from a population-based survey (n = 2,595) of 36 Canadian Arctic Inuit communities to assess the relationships of plasma IsoPs to Se and Hg status indicators. F2-IsoPs were inversely correlated with blood Se (r =−0.186, P = 0.005) and toenail Se (r =−0.146, P = 0.044), but not correlated with Hg. IsoFs were inversely correlated with blood Se (r =−0.164, P = 0.014) and positively correlated with Hg (r = 0.228, P < 0.001) and Hg:Se (r = 0.340, P < 0.001). The strength of the correlations remained unchanged after multivariate adjustments. Multivariate analysis showed that F2-IsoPs were not positively associated with Hg but with Hg:Se (β= 0.148, P = 0.021). We conclude that Se and Hg status and their interactions are important factors modulating F2-IsoP and IsoF levels such that the Inuit may be protected from Hg-induced oxidative stress because of their high Se status. Despite animal and in vitro studies demonstrating pro-oxidative effects of Hg, previous human work showed no relationship between tissue Hg and plasma levels of F2-isoprostanes (IsoPs), a whole-body oxidative stress marker. We hypothesized that another IsoP species, isofurans (IsoFs), was a more sensitive indicator of Hg-mediated oxidative stress, which can be modified by tissue Se status. A cross-sectional study was carried out involving individuals from a random subset (n = 233) of Inuit adults from a population-based survey (n = 2,595) of 36 Canadian Arctic Inuit communities to assess the relationships of plasma IsoPs to Se and Hg status indicators. F2-IsoPs were inversely correlated with blood Se (r =−0.186, P = 0.005) and toenail Se (r =−0.146, P = 0.044), but not correlated with Hg. IsoFs were inversely correlated with blood Se (r =−0.164, P = 0.014) and positively correlated with Hg (r = 0.228, P < 0.001) and Hg:Se (r = 0.340, P < 0.001). The strength of the correlations remained unchanged after multivariate adjustments. Multivariate analysis showed that F2-IsoPs were not positively associated with Hg but with Hg:Se (β= 0.148, P = 0.021). We conclude that Se and Hg status and their interactions are important factors modulating F2-IsoP and IsoF levels such that the Inuit may be protected from Hg-induced oxidative stress because of their high Se status. Methylmercury (MeHg) is postulated to increase cardiovascular risk via several pathways, including direct cardiovascular effects (such as decreased heart rate variability, increased blood pressure, and reduced myocardial contractile force) and systemic effects involving blood coagulation, inhibition of endothelial cell migration, and greater oxidative stress via the promotion of free radicals and reactive oxygen species, lipid peroxidation, and inhibition of antioxidant systems (1Mozaffarian D. Fish, mercury, selenium and cardiovascular risk: current evidence and unanswered questions.Int. J. Environ. Res. Public Health. 2009; 6: 1894-1916Crossref PubMed Scopus (155) Google Scholar, 2Huang Y.L. Cheng S.L. Lin T.H. Lipid peroxidation in rats administrated with mercuric chloride.Biol. Trace Elem. Res. 1996; 52: 193-206Crossref PubMed Scopus (103) Google Scholar, 3Chen C. Qu L. Li B. Xing L. Jia G. Wang T. Gao Y. Zhang P. Li M. Chen W. Chai Z. 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Direct antagonistic effects of MeHg on Se-dependent antioxidant enzymes have been noted (10Gailer J. George G.N. Pickering I.J. Madden S. Prince R.C. Yu E.Y. Denton M.B. Younis H.S. Aposhian H.V. Structural basis of the antagonism between inorganic mercury and selenium in mammals.Chem. Res. Toxicol. 2000; 13: 1135-1142Crossref PubMed Scopus (150) Google Scholar). Additionally, sequestration of Se caused by Hg-Se adducts can lead to a functional deficit of tissue Se caused by decreased availability of Se for incorporation into selenoproteins involved in antioxidant defense (11Tapiero H. Townsend D.M. Tew K.D. The antioxidant role of selenium and seleno-compounds.Biomed. Pharmacother. 2003; 57: 134-144Crossref PubMed Scopus (598) Google Scholar). MeHg-induced oxidative stress has also been associated with depressed tissue levels of sulfhydryl-dependent antioxidant proteins and the reduced form of glutathione (GSH) (12Jin X. Chan H.M. Lok E. Kapal K. Taylor M. Kubow S. Mehta R. Dietary fats modulate methylmercury-mediated systemic oxidative stress and oxidative DNA damage in rats.Food Chem. Toxicol. 2008; 46: 1706-1720Crossref PubMed Scopus (28) Google Scholar). Increased dietary Se, however, can counteract the sequestration of Se by Hg-Se adducts (13Ralston N.V. Blackwell 3rd, J.L. Raymond L.J. Importance of molar ratios in selenium-dependent protection against methylmercury toxicity.Biol. Trace Elem. Res. 2007; 119: 255-268Crossref PubMed Scopus (140) Google Scholar) and so maintain normal selenoenzyme activities (14Ralston N.V. Raymond L.J. Dietary selenium's protective effects against methylmercury toxicity.Toxicology. 2010; 278: 112-123Crossref PubMed Scopus (351) Google Scholar). Animal studies have generally indicated that Se intake mitigates against dietary MeHg toxicity, which appears to be related to both the absolute and relative amounts of MeHg and Se present in the diet (14Ralston N.V. Raymond L.J. Dietary selenium's protective effects against methylmercury toxicity.Toxicology. 2010; 278: 112-123Crossref PubMed Scopus (351) Google Scholar, 15Yoneda S. Suzuki K.T. Equimolar Hg-Se complex binds to selenoprotein P.Biochem. Biophys. Res. Commun. 1997; 231: 7-11Crossref PubMed Scopus (160) Google Scholar). The examination of the diets and tissues of MeHg-exposed animals has shown that Se:Hg molar ratios above one are protective against adverse effects associated with MeHg exposure (14Ralston N.V. Raymond L.J. Dietary selenium's protective effects against methylmercury toxicity.Toxicology. 2010; 278: 112-123Crossref PubMed Scopus (351) Google Scholar). Human studies, however, have shown mixed results regarding associations between tissue Se status and adverse outcomes from MeHg exposure and so their interactions remain (1Mozaffarian D. Fish, mercury, selenium and cardiovascular risk: current evidence and unanswered questions.Int. J. Environ. Res. 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L.J. et of oxidative stress study of the and on of oxidative of in Med. 2005; PubMed Scopus Google Scholar). between blood Se and F2-IsoPs has been noted in J. J. B. A. G. S. selenium levels of F2-isoprostanes and in a follow-up study of Res. 2005; PubMed Scopus Google Scholar), the relationship between tissue Se status and dietary MeHg exposure has not been with to F2-IsoP the of isofurans to F2-IsoPs to a more of oxidative IsoFs are of lipid peroxidation with a L.J. of lipid peroxidation that the of in of oxygen 2005; PubMed Scopus Google Scholar). The of F2-IsoPs and IsoFs is by oxygen the of F2-IsoPs is by oxygen the of IsoFs is by oxygen that can in of L.J. of lipid peroxidation that the of in of oxygen 2005; PubMed Scopus Google Scholar). a of the Inuit Health study showed that IsoFs and F2-IsoPs were positively associated with after for D. G. L.J. 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Scopus Google Scholar). a cross-sectional survey was in the and and for communities and for communities communities in the and the and and on dietary blood pressure, and blood were and for were and the of the of the was from to and blood were and were by a to a as Z. and Canadian the Inuit Health for PubMed Scopus Google Scholar). A of was and a of greater was serum high and were and was by high was with high in with in the for and for Hg and Se were the on blood were in a and which was by plasma was blood from a Se and may dietary intake the Stampfer M.J. Morris J.S. Spate C. M. Willett W.C. A of the of on selenium in blood and J. Nutr. 57: PubMed Scopus Google Scholar). Se analysis was the of and the of were in and in for were and in Se were a with a were from blood and of and analysis of F2-IsoPs and IsoFs by were as M.B. S. G.A. L.J. et of oxidative stress study of the and on of oxidative of in Med. 2005; PubMed Scopus Google Scholar). to a was with of The rate was the was to from to for was for for and for the are in The of the is and the is and for were as for as and from were as in and blood Hg, Se, and were and Hg:Se ratios were the for Hg, and Se The of was on with their and to for analysis was analysis to assess the relationship between plasma of of oxidative stress and of Hg, Hg:Se and toenail in to their relationship to study including and cardiovascular risk were between Se and a was P were and P < was for were to of plasma IsoPs for important including and of the and to the of multivariate analysis with was that were Se were in the to their to the in the IsoP were to the of were between in the was also assessed to correlated in the the of was to that no on the were in to assess results were after of individuals with with We also of individuals for hypertension the were A of and were from the Inuit Health from which were for and the in previous study plasma IsoPs in to risk factors in more D. G. L.J. Kubow S. and isofurans as risk factors for cardiovascular disease Canadian Res. 46: PubMed Scopus Google Scholar). to C.C. R.A. of PubMed Scopus Google Scholar), levels of greater evidence of and individuals were A of were of and were in one with F2-IsoP the was which decreased the to of the of was were for F2-IsoPs (n = IsoFs (n = (n = (n = blood Se (n = blood Hg (n = toenail Se (n = (n = and (n = individuals with < The of the was The levels of F2-IsoPs and IsoFs and their were the normal as D. G. L.J. Kubow S. and isofurans as risk factors for cardiovascular disease Canadian Res. 46: PubMed Scopus Google Scholar). of plasma F2-IsoP levels which is to be the in the for normal human plasma levels H. J.D. S. L.J. J.D. of F2-isoprostanes in and tissues as a of 2007; PubMed Scopus (150) Google Scholar). the was were and were on of a of myocardial and a of were current with of of in the of study (n = Se, intake for heart and blood for heart and in a blood and toenail Se were not correlated (r P = F2-IsoPs were correlated with both blood Se (r =−0.186, P < and toenail Se (r =−0.146, P = F2-IsoPs were not associated with blood Hg (r = P = Hg:Se (r = P = IsoFs were associated with blood Se (r =−0.164, P = 0.014) but were not associated with toenail Se (r P = however, were positively associated with blood Hg (r = P < 0.001) and with Hg:Se (r = 0.340, P < 0.001). The was not associated with blood Se (r P = toenail Se (r = P = however, the was positively associated with Hg (r = P < 0.001) and with Hg:Se (r = P < correlations between plasma tissue Se and Hg, and the the the the the the the the the the in a were into to the blood Se of the and and Hg by Se showed and but the for was with the Hg noted in the Se of both F2-IsoPs and IsoFs decreased with of Se in and of to of blood Se and P and P of Se, the the the Se, Hg, the the the the the the the the the the the the the the the the the the for including F2-IsoPs (n = IsoFs (n = (n = (n = blood Se (n = blood Hg (n = toenail Se (n = (n = and (n = the of for of in the as by with the is the blood the the P and P in a and of plasma IsoPs by blood Se from Se Se and Se of for and current of the the the the for current and of the the the the for F2-IsoPs (n = IsoFs (n = (n = (n = blood Se (n = blood Hg (n = (n = (n = and (n = the of for of in the as by with the is the the in a for including F2-IsoPs (n = IsoFs (n = (n = (n = blood Se (n = blood Hg (n = toenail Se (n = (n = and (n = the of for of in the as by with the is the blood for F2-IsoPs (n = IsoFs (n = (n = (n = blood Se (n = blood Hg (n = (n = (n = and (n = the of for of in the as by with the is Multivariate indicated that F2-IsoP were by blood Se = P = and toenail Se = P = in of Se for (β= = P < 0.001) and (β= = P = F2-IsoPs were not associated with Hg but were associated with the of Hg:Se (β= 0.148, = P = 0.021). in IsoF was by both Se = P = and Hg (β= = P < 0.001) and Hg:Se (β= = P < 0.001) in to (β= = P < 0.001) and = P = in the was by Hg (β= = P < Hg:Se (β= = P < and (β= = P = associations the of plasma IsoP the the the the the the the the the the the the the the the the the the the the the the the the the the the the the the the the the the the the the the the the hypertension on a not the the in a hypertension on a not study that a with blood of both Hg and Se, showed in plasma IsoPs in relationship to both tissue Se and Hg. Despite high Hg exposure levels in J. J. L. E. K. C. A. A. M. et and blood levels of mercury, and in Arctic Res. PubMed Scopus Google Scholar, A. T. L.J. Mercury in and blood associated with exposure in a Res. PubMed Scopus Google Scholar), the plasma of F2-IsoPs for the as a was the normal for H. J.D. S. L.J. J.D. of F2-isoprostanes in and tissues as a of 2007; PubMed Scopus (150) Google Scholar) and a of the levels the with previous regarding Inuit of E. L. M. J. P. Dietary and oxidative stress in Inuit of Full Text Full Text PDF PubMed Scopus Google Scholar), that Hg in the diet may not be of with to oxidative The of a of Hg with F2-IsoPs tissue Hg was in the form of the Hg:Se is because human studies have not the of tissue Hg and Se on plasma A of relationship between Hg and plasma F2-IsoPs and lipid peroxidation has been in a of with blood Hg of of but tissue Se was not S.L. M.S. J. of blood and mercury levels to of lipid peroxidation in J. PubMed Scopus Google Scholar). of the relationship of Hg and Se on oxidative stress, that Inuit in the of blood Se were protected from oxidative stress of that Se status including tissue Hg, risk and blood is the human study to protective effects of tissue Se status on oxidative stress status in to MeHg The above the of animal studies the of both Se and Hg the Hg-induced oxidative stress (13Ralston N.V. Blackwell 3rd, J.L. Raymond L.J. Importance of molar ratios in selenium-dependent protection against methylmercury toxicity.Biol. Trace Elem. Res. 2007; 119: 255-268Crossref PubMed Scopus (140) Google Scholar). The of Hg-mediated of F2-IsoPs by tissue Se is also with that Se the increase in urinary F2-IsoPs by dietary MeHg exposure in rats X. Lok E. Taylor M. Kapal K. K. A. A. Chan H. et selenium and methylmercury-mediated in of cardiovascular in Toxicol. 12: PubMed Scopus Google Scholar). MeHg has and been shown to be of (14Ralston N.V. Raymond L.J. 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Kubow S. and isofurans as risk factors for cardiovascular disease Canadian Res. 46: PubMed Scopus Google Scholar). current however, was not in the of IsoPs Hg, Se, toenail Se, the Hg:Se were with and The above results that the relationship of F2-IsoPs and IsoFs with in the Inuit is Se and Hg and is also of protective effects of Se on associated with We that the is related to the and of the G.A. The selenium and cardiovascular a of the 2003; Google Scholar) that be by the high tissue of Se in Se may the of by of selenoprotein C. a that and PubMed Scopus Google Scholar) in the of that Y. factor the 2003; PubMed Scopus Google Scholar). dietary Se may the of the of and that Y. Li M. A. K. C.C. The role of selenium-dependent and glutathione in the of Chem. Full Text PDF PubMed Google Scholar). results from and B. E. P. mercury exposure and blood Inuit 2009; PubMed Scopus Google Scholar) showed a between blood Hg and both and in Inuit adults from after the effects Se, n-3 and correlated blood Hg with the in with Se and n-3 concentrations, which have to adverse of Hg in the studies E. L. M. J. P. Dietary and oxidative stress in Inuit of Full Text Full Text PDF PubMed Scopus Google Scholar, B. E. P. mercury exposure and blood Inuit 2009; PubMed Scopus Google Scholar), Hg and Se were not correlated (r = P < which differences in the of in Se and Hg of shown to F2-IsoPs such as n-3 C. B. L. M. K. G. A. L. A. S. L. S. Dietary fatty acids plasma F2-isoprostanes but not in Nutr. PubMed Scopus Google Scholar) not with of the plasma IsoPs in study and was not in Hg exposure Inuit is to be to intake of MeHg from not of Hg which may effects on oxidative stress dietary factors that can F2-IsoP were not in including plasma such as and The associations between Hg and Se Se be to from not including important of the in and associations not be is the human study to a relationship between tissue Hg and plasma F2-IsoP that oxidative stress associated with Hg exposure was by tissue Se status the of tissue Se for the of Hg-mediated oxidative We have also shown that of Hg and Se can with to risk of oxidative stress as a to the progression to studies are to in to more complex with Hg and Se The the of of the study and of the also and for their and their for and cardiovascular disease glutathione high methylmercury blood

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