Plasma Levels of Selenium, Selenoprotein P and Glutathione

Plasma levels of selenium, selenoprotein P and glutathione peroxidase and their correlations to ®sh intake and serum levels of thyrotropin and thyroid hormones: A study on Latvian ®sh consumers

L Hagmar1, M Persson-Moschos2,BAÊkesson2 and A SchuÈtz1

1Department of Occupational and Environmental Medicine, University Hospital, Lund; and 2Department of Applied Nutrition and Food Chemistry, University of Lund, Lund, Sweden

Objective: To study the relationships between ®sh intake and different markers of selenium status and thyroid hormone function. Design: Cross-sectional study. Setting and subjects: Sixty-eight men (age 24±79 years) were recruited among coastal ®shermen and inland subjects from Latvia. None of the subjects was on selenium medication or had any known endocrine disease. Main outcome measures: Correlations between ®sh intake, plasma levels of selenium, selenoprotein P, glutathione peroxidase, organic mercury in erythrocytes and TSH in serum. Results: Selenium in plasma ranged from 0.30 to 1.56 mmol=1, selenoprotein P from 0.54 to 2.21 arbitrary units relative to pooled plasma, and glutathione peroxidase from 1.20 to 5.73 mg=1. The number of ®sh meals per month was correlated with plasma selenium, selenoprotein P and glutathione peroxidase (r 0.63, r 0.62 and r 0.50, respectively; P < 0.001). Plasma selenium was correlated with selenoprotein P and glutathione peroxidase (r 0.88 and r 0.67, respectively; P < 0.001), and also selenoprotein P and glutathione peroxidase were correlated (r 0.63, P < 0.001). The mean plasma selenium level in those with a high ®sh intake (21±50 ®sh meals=month), was 81% higher than in those with lowest ®sh intake. TSH in serum was inversely correlated with plasma selenium and selenoprotein P. Thyroid hormone levels were not correlated with plasma selenium, selenoproteins or ®sh intake. Conclusions: In this study group, selenium from ®sh intake had a marked impact on all variables studied on selenium status. No impact of selenium status on T3 and T4 levels was observed. The slightly negative correlation of selenium status with TSH levels might indicate a higher TSH secretion at low selenium status. Sponsorship: The study was supported by grants from the Swedish Environmental Protection Agency, the Medical Faculty, Lund University, and the PaÊhlsson Foundation. B.AÊ . was supported by FAIR CT95.0771. Descriptors: ®sh intake; selenium; selenoprotein P; glutathione peroxidase; thyrotropin; thyroid hormones; bioavailability

Introduction the three iodothyronine deiodinases are selenoproteins. The functional effects of low selenium status on thyroid func- The bioavailability and metabolic fate of selenium from tion in humans have so far not been fully characterized dietary ®sh in humans have not been studied extensively. (Beech et al, 1993; Terwolbek et al, 1993; Arthur & Svensson et al (1992) found that Swedish healthy subjects Beckett, 1994). In addition to the relationship between with a high consumption of ®sh had slightly higher con- selenium and deiodinases, it was recently hypothesized centrations of selenium in plasma than those with low ®sh that extracellular glutathione peroxidase may be a regulator consumption. Moreover, a change to a diet rich in ®sh of thyroid hormone synthesis (Howie et al, 1995). These increased plasma selenium of healthy subjects (Robinson et ®ndings prompted the study of thyroid function in indivi- al, 1978; Thorngren & AÊ kesson, 1987. However, in Swed- duals with large variations in selenium intake. ish ®sh consumers with slightly higher plasma selenium The aim of the present study was ®rstly to assess the levels compared with nonconsumers, no increase could be importance of the dietary contribution of selenium from observed in the plasma levels of the selenoproteins, sele- ®sh for the levels of selenoproteins in plasma in subjects noprotein P and glutathione peroxidase (Huang et al, 1995), with a larger variation in selenium status than in previously a ®nding that may have several explanations. studied cohorts. Latvian ®shermen at the Gulf of Riga, a Pronounced changes in thyroid hormone metabolism part of the Baltic Sea, with a high consumption of locally occur in experimental selenium de®ciency, mainly because caught ®sh, and subjects living in the inland of Latvia, with a low ®sh consumption, were considered as appropriate study populations. Secondly, the goal was to assess correla- Correspondence: Dr L Hagmar, Department of Occupational and Environmental Medicine, University Hospital, S-221 85 Lund, Sweden. tions between plasma levels of selenium and selenopro- Received 3 May 1998; revised 23 June 1998; accepted 30 June 1998 teins, and thyroid hormones in serum. Fish intake, selenium and thyroid hormones L Hagman et al 797 Lars Hagmar was responsible for the study design, mercury was used as a proxy for the levels of organic obtained fundings and performed the statistical analysis. mercury in the erythrocytes. Andrejs SchuÈtz was responsible for the ®eld study in Latvia, and for the analyses of organic mercury in erythro- Selenoprotein P and glutathione peroxidase cytes and selenium in plasma. Marie Persson-Moschos and Selenoprotein P and extracellular glutathione peroxidase BjoÈrn AÊ kesson performed the analyses of selenoprotein P were measured by radioimmunoassays as described else- and glutathione peroxidase in plasma. The latter also where (Huang & AÊ kesson, 1993; Persson-Moschos et al, obtained fundings. All four investigators contributed to 1995). The concentration of selenoprotein P was expressed the writing of the paper. Lars Hagmar is the guarantor for in arbitrary units (au) relative to a standard of pooled the integrity of the article as a whole. plasma. For selenoprotein P analysis the imprecision expressed as CV was 5.4% for intra-assay and 6.7% for Methods inter-assay variation. For the measurement of extracellular glutathione peroxidase the imprecision was 7.0% for intra- Study groups and assessment of ®sh intake assay and 3.5% for inter-assay variation. Sixty-eight men were recruited among coastal ®shermen from ®ve ®shing villages around the Gulf of Riga, and from Assay of thyroid hormones and creatinine Riga and four small villages in the Latvian inland. Each Serum thyrotropin (TSH) was analyzed with a ¯uoroimmuno- subject was interviewed about his average consumption of assay technique (Del®a, LKB, Finland), with an intra-assay different species of ®sh using a food frequency method. CV of 5% and an inter-assay CV of 2.6%. Serum free Information on present health status and intake of medical triiodothyronine (T3) and free thyroxine (T4) were assayed drugs was obtained as described previously (Hagmar et al, by a radioimmunoassay (Amersham International, Amer- 1995). The estimated monthly intake of ®sh ranged from 0 sham, UK, with intra- and inter-assay CVs of 2.9% and to 50 meals per month (median 11.8). In terms of ®sh 4.7%, and 3.7% and 6.9%, respectively, and total serum T3 species, the median intake of salmon from the Baltic Sea and T4 were analyzed by radioligand assays. Creatinine was 0.8 meals per month (range 0±18), that of herring from was measured by an enzymatic method using creatininase. the Baltic Sea was 4 meals per month (range 0±30), and These analyses were performed at the Laboratory of Clin- that of pike 2 was meals per month (range 0±18). For some ical Chemistry, Lund University Hospital. calculations the subjects were divided into three groups according to ®sh consumption (0±3, 4±20 and 21±50 meals Statistical methods per month). The median age in the study group was 48 Pearson's test was used to assess correlations. years (range 24±79). Forty-eight per cent of the subjects The study design was approved by the Ethics committee were smokers. None of the subjects was on selenium of Lund University. medication or had any known endocrine disease. Results Blood sampling and transport Venous blood sampling was made in the morning before The concentration of selenium in plasma varied from 0.30 the subjects had performed any major physical activity. to 1.56 mmol=1 (Table 1), and it was signi®cantly corre- Blood was collected in tubes containing heparin, and lated with the estimated number of ®sh meals per month plasma was stored frozen until analysis. The samples (r 0.63, P < 0.0001; Figure 1). Selenoprotein P ranged received by the analytical laboratories were coded with from 0.54 to 2.21 au and the concentration of glutathione respect to ®sh consumption. peroxidase varied from 1.20 to 5.73 mg=1 (Table 1); they were also signi®cantly correlated with the number of ®sh meals (r 0.62, P < 0.0001 and r 0.50, P < 0.001, Selenium in plasma respectively, Figures 2 and 3). The mean plasma selenium Selenium was determined ¯uorometrically (Lalonde et al, among those 31 subjects with the highest estimated ®sh 1982). The detection limit was 0.04 mmol=l (3 mg=l). All intake (21±50 ®sh meals=month) was 81% higher than for samples were analyzed in duplicate, and the coef®cient of those 21 subjects with a low ®sh consumption (0±3 ®sh variation (CV) was 6%. The average value for a serum meals=month) (Table 1). The corresponding values for reference sample (Seronorm Trace Elements, batch 10017, selenoprotein P and glutathione peroxidase were 68% and Nycomed AS, Oslo) was 1.2 (s.d. 0.08) mmol=l (n 10), and 45%, respectively. Organic mercury ranged from 0.4 to coincided with the recommended 1.2 (1.12±1.25) mmol=l. 218.1 nmol=1, and was associated with ®sh consumption (Table 1). The level of inorganic mercury did not exceed Mercury in erythrocytes 13 nmol=1 in any of the subjects. Total and inorganic mercury were determined in acid- Strong correlations were also observed between plasma digested samples (0.5 g) by an automated cold vapour selenium and selenoprotein P (r 0.88, P < 0.001; Figure 4), atomic absorption (CV-AA) technique, as described in and between selenium and glutathione peroxidase (r 0.67, detail previously (Svensson et al, 1994; Bergdahl et al, P < 0.001). Consequently, the plasma levels of selenoprotein 1995). All samples were analyzed in duplicate. The preci- P and glutathione peroxidase were also highly correlated sion calculated as the CV for the duplicate analysis was 5% (r 0.63, P < 0.001). Organic mercury in erythrocytes also for both methods, and was independent of the concentration correlated with both selenium in plasma (r 0.76, range. The results for a reference sample (Seronorm Trace P < 0.0001), selenoprotein P (r 0.66, P < 0.0001) and Elements, lyophilized blood, batch 904, Nycomed, Oslo) glutathione peroxidase (r 0.66, P < 0.0001). averaged 17 nmol=l (range 15.4±17.5; n 4), as compared Since especially extracellular glutathione peroxidase to the 19 nmol=l (range 10±30) obtained by other labora- may be related to kidney function, selenium status in tories. The difference between total mercury and inorganic relation to the serum creatinine level was examined. Fish intake, selenium and thyroid hormones L Hagman et al 798 Table 1 Selenium, selenoprotein P and glutathione peroxidase levels in plasma, and organic mercury in erythrocytes in 68 Latvian males in relation to ®sh consumptiona

Fish intake (meals per month)

0±3 (n 21) 4±20 (n 16) 21±50 (n 31) Median Median Median (Range) (Range) (Range)

Selenium (mmol=l) 0.69 0.91 1.18 (0.30±1.14) (0.46±1.47) (0.66±1.56) Selenoprotein P (au) 0.83 1.00 1.38 (0.54±1.15) (0.63±1.83) 0.75±2.21) Glutathione peroxidase (mg=l) 2.78 3.38 3.95 (1.20±4.32) (2.31±4.65) (2.69±5.73) Organic mercury (nmol=l) 6.6 41.1 87.5 (0.4±34.8) (5.1±115.6) (43.5±218.1)

aThe subjects were divided into three groups according to ®sh consumption (0±3, 4±20 or 21±50 ®sh meals per month).

Figure 1 The correlation between the estimated number of ®sh meals per Figure 3 The correlation between the estimated number of ®sh meals per month and selenium in plasma (r 0.63, P < 0.0001). month and glutathione peroxidase in plasma (r 0.50, P < 0.0001).

Figure 2 The correlation between the estimated number of ®sh meals per month and selenoprotein P in plasma (r 0.62, P < 0.0001). The concen- Figure 4 The correlation between selenium and selenoprotein P in tration of selenoprotein P was expressed in arbitrary units (au) relative to a plasma (r 0.88, P < 0.0001). The concentration of selenoprotein P was standard of pooled plasma. expressed in arbitrary units (au) relative to a standard of pooled plasma. Fish intake, selenium and thyroid hormones L Hagman et al 799 low-molecular-mass selenium compounds, the bioavailability of which is not known (AÊ kesson & Srikumar, 1994). Much less is known about the bioavailability of selenium from ®sh in humans, although a change to a diet rich in ®sh increased the selenium concentrations in plasma of healthy subjects (Robinson et al, 1978; Thorngren & AÊ kesson, 1987). On the other hand, Meltzer et al (1993) found that a diet rich in ®sh containing 50% more selenium than a control diet did not signi®cantly affect serum and platelet selenium in healthy subjects. In the present study high correlations were found between ®sh intake and plasma selenium and selenoproteins, indicating that ®sh in this study group had a considerable impact on the selenium status. Also a previous study of men living close to the Swedish Baltic coast indicated a positive correlation of ®sh intake with plasma selenium levels (Svensson et al, 1992) but not with the plasma levels of selenoprotein P and glutathione peroxidase, although the two selenoprotein levels were highly Figure 5 The correlation between selenium and TSH in plasma intercorrelated (Huang et al, 1995). There are at least two (r 7 0.30, P 0.01). possible reasons for this discrepancy. First, the relatively small variation in plasma selenium between the Swedish Plasma selenium was signi®cantly correlated with serum high and low consumers of ®sh might have prevented the creatinine (r 0.38, P 0.001), even more strongly with detection of relationships between selenoproteins and other seleno-protein P (r 0.50, P < 0.001), but not signi®cantly variables. Second, the biosynthesis of plasma seleno- with glutathione peroxidase (r 0.19; P 0.12). proteins may have approached saturation at the higher The median TSH level among the 68 male subjects was plasma selenium level in the low-®sh-intake group of the 1.3 IU=l (range 0.1±3.7). The median level for free T3 was previous study, 0.99 mmol=1 (Huang et al, 1995), compared 5.1 pmol=1 (range 4.0±6.8); for total T3 it was 1.9 nmol=1 to that observed in the present one, 0.66 mmol=1, which (range 1.4±2.7); for free T4 it was 13 pmol=1 (range 7.8± would decrease the correlation (Alfthan et al, 1991; March- 18); and for total T4 it was 82 nmol=1 (range 57±124). Both aluk et al, 1995). plasma selenium and selenoprotein P were signi®cantly There were several other differences between the Swed- negatively correlated with TSH (r 7 0.30, P 0.01 and ish and Latvian study groups. The mean selenoprotein P r 7 0.23, P 0.03, respectively; Figure 5), but not at all levels in the Swedish groups were 1.49±1.61 au, in close correlated with the total or free T3 and T4 levels (data not agreement with ®ndings in another group of healthy Swed- shown). The weak correlation between glutathione perox- ish adults (Marchaluk et al, 1995), whereas the three idase and TSH was not statistically signi®cant (r 7 0.19, Latvian groups had means ranging from 0.82 to 1.38 au P 0.11), and was similar to that found between TSH and Similarly, the mean level of glutathione peroxidase in the the erythrocyte level of organic mercury. The estimated ®sh low-consumption group of the present study, 2.73 mg=1, intake was not correlated with TSH and thyroid hormone was generally lower than that found previously, 3.51± levels. 3.67 mg=1 (Huang et al, 1995). Glutathione peroxidase, the ®rst speci®c selenoprotein identi®ed, forms part of the defense system against oxida- Discussion tive stress and may also have other functions (FloheÂ, 1989). A low selenium status has been implicated as a risk factor The glutathione peroxidase family has at least four member for several chronic diseases (Salonen et al, 1982; Fex et al, enzymes, but little is known about their physiological 1987; FloheÂ, 1989). Accordingly it is necessary to study the function. Extracellular glutathione peroxidase is the pre- in¯uence of selenium intake from major food groups on dominant form in plasma and is mainly produced in the selenium status in different populations. Fish is rich in kidney (Avissar et al, 1989; Huang & AÊ kesson, 1993; selenium. Herring, salmon and pike collected in Finnish Avissar et al, 1994; Huang, 1996), and it is also found in waters contained 0.18±0.26 mg Se=kg (Koivistoinen, 1980), milk (Avissar et al, 1991) and aqueous humor (Huang et al, whereas herring and salmon collected west of Norway 1997). It is also the major 75Se-substituted protein secreted contained 0.5 mg Se=kg (Lie et al, 1994). According to by human thyrocytes incubated with (75Se)selenite, and it the Finnish data, 100 g of ®sh would thus provide 20 mg was hypothesized that it may be a regulator of thyroid of selenium. hormone synthesis (Howie et al, 1995). Furthermore, the Studies in several animal species have indicated that the other major selenoprotein in human plasma, selenoprotein bioavailability of selenium from ®sh is 50% of that for P (AÊ kesson et al, 1994) may also act as an extracellular selenite (Miller et al, 1972; Cantor et al, 1975; Alexander antioxidant (Burk et al, 1995). et al, 1983), but in other studies values between 50% and Selenium status also plays a role in thyroid function 100% were obtained (Ringdal et al, 1985; Mutanen et al, because the three iodothyronine deiodinases that catalyze 1986; Hassan et al, 1987). The divergent results probably conversions of thyroxine to triiodo- and diiodothyronines re¯ect the use of different animals and ®sh feeds, and have been identi®ed as selenoproteins (Arthur et al, 1990; variations in the methods for assessment of bioavailability Behne et al, 1990; Salvatore et al, 1996). Pronounced (Mutanen, 1986). It is also intriguing that ®sh species changes in thyroid hormone metabolism occur in experi- contain varying proportions of high-molecular-mass and mental selenium de®ciency, but the functional effects of Fish intake, selenium and thyroid hormones L Hagman et al 800 low selenium status on thyroid function in humans have not Fex G, Pettersson B & AÊ kesson B (1987): Low plasma selenium as a risk been fully investigated (Beech et al, 1993; Terwolbek et al, factor for cancer death in middle-aged men. Nutr. Cancer 10, 221±229. FloheÂ L (1989): The selenoprotein glutathione peroxidase. In Glutathione 1993; Arthur & Beckett 1994). In the present study, no Ð Chemical, Biochemical, and Medical Aspects, eds D Dolphin, O relation between T3 or T4 and the selenium status variables Avramovic, R Poulson, pp 643±731 New York: Wiley-Interscience. or ®sh intake was observed. The weak negative correlations Hagmar L, Hallberg T, Leja M, Nilsson A & SchuÈtz (1995): High between TSH and selenium status might indicate a higher consumption of fatty ®sh from the Baltic Sea is associated with changes TSH secretion at low selenium status. In contrast, in in human lymphocyte subset levels. Toxicol. Lett. 77, 335±342. Hassan S, Hakkarainen J & Lindberg PO (1987): Bioavailability to chicks children with low selenium status, a high T4 but no of selenium in wheat and ®sh meal. J. Vet. Med. A, 34, 353±363. change in T3 and TSH was observed (Terwolbek et al, Howie AF, Walker SW, AÊ kesson B, Arthur JR & Beckett GJ (1995): 1993). 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