Biomarkers and Fatty Fish Intake: A Randomized Controlled Trial in Norwegian Preschool Children

Beate S Solvik, Jannike Øyen, Ingrid Kvestad, Maria W Markhus, Per M Ueland, Adrian McCann, Tor A Strand, Beate S Solvik, Jannike Øyen, Ingrid Kvestad, Maria W Markhus, Per M Ueland, Adrian McCann, Tor A Strand

Abstract

Background: Biomarkers such as omega-3 (n-3) PUFAs, urinary iodine concentration (UIC), 1-methylhistidine (1-MH), and trimethylamine N-oxide (TMAO) have been associated with fish intake in observational studies, but data from children in randomized controlled trials are limited.

Objectives: The objective of this exploratory analysis was to investigate the effects of fatty fish intake compared with meat intake on various biomarkers in preschool children.

Methods: We randomly allocated (1:1) 232 children, aged 4 to 6 y, from 13 kindergartens. The children received lunch meals of either fatty fish (herring/mackerel) or meat (chicken/lamb/beef) 3 times a week for 16 wk. We analyzed 86 biomarkers in plasma (n = 207), serum (n = 195), RBCs (n = 211), urine (n = 200), and hair samples (n = 210). We measured the effects of the intervention on the normalized biomarker concentrations in linear mixed-effect regression models taking the clustering within the kindergartens into account. The results are presented as standardized effect sizes.

Results: We found significant effects of the intervention on the following biomarkers: RBC EPA (20:5n-3), 0.61 (95% CI: 0.36, 0.86); DHA (22:6n-3), 0.43 (95% CI: 0.21, 0.66); total n-3 PUFAs, 0.41 (95% CI: 0.20, 0.64); n-3/n-6 ratio, 0.48 (95% CI: 0.24, 0.71); adrenic acid (22:4n-6, -0.65 (95% CI: -0.91, -0.40), arachidonic acid (20:4n-6), -0.54 (95% CI: -0.79, -0.28); total n-6 PUFAs, -0.31 (95% CI: -0.56, -0.06); UIC, 0.32 (95% CI: 0.052, 0.59); hair mercury, 0.83 (95% CI: 0.05, 1.05); and plasma 1-MH, -0.35 (95% CI: -0.61, -0.094).

Conclusions: Of the 86 biomarkers, the strongest effect of fatty fish intake was on n-3 PUFAs, UIC, hair mercury, and plasma 1-MH. We observed no or limited effects on biomarkers related to micronutrient status, inflammation, or essential amino acid, choline oxidation, and tryptophan pathways.The trial was registered at clinicaltrials.gov (NCT02331667).

Keywords: 1-methylhistidine; biomarkers; fatty fish; mercury; omega-3; polyunsaturated fatty acids; preschool children; targeted metabolomics.

© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.

Figures

FIGURE 1
FIGURE 1
Flow chart of the study participants in a randomized controlled trial of fatty fish intake.
FIGURE 2
FIGURE 2
Standardized mean difference in RBC fatty acids, serum ferritin, serum vitamin D, urinary iodine concentration, and hair mercury concentration in the preschool children postintervention. The graph shows effect sizes and 95% CIs of the transformed concentrations of the different biomarkers calculated by mixed-effect linear models with random intercepts for kindergartens, without adjustments for covariates and multiple comparisons. Estimates on the right side of the vertical line indicate a higher postintervention concentration of the biomarkers in the fish group compared with the control. n = 139–210; see Supplemental Table 3 for exact n for each individual biomarker. AA, arachidonic acid; AdA, adrenic acid; DPA, docosapentaenoic acid; ETE, eicosatrienoic acid; LA, linoleic acid; s-25(OH)D3, serum 25-hydroxycholecalciferol; UIC, urinary iodine concentration.
FIGURE 3
FIGURE 3
Standardized mean difference in plasma biomarker concentration in the preschool children postintervention. The graph shows effect sizes and 95% CIs of the transformed plasma concentrations of the different biomarkers, calculated by mixed-effect linear models with random intercepts for kindergartens, without adjustments for covariates and multiple comparisons. Estimates on the right side of the vertical line indicate a higher postintervention concentration of the biomarkers in the fish group compared with the control. n = 205–207; see Supplemental Table 4 for exact n for each individual biomarker. ADMA, asymmetric dimethylarginine; aKG, α-ketoglutarate; HCC index: 10,000 × [homocysteine (Hcy) divided by cysteine and (by) creatinine]; HK-ratio, 3-hydroxykynurenine divided by the sum of kynurenic acid, anthranilic acid, xanthurenic acid plus 3-hydroxyanthranilic acid; MMA, methylmalonic acid; PA, 4-pyridoxic acid; PAr index, 4-pyridoxic acid divided by the sum of pyridoxal 5´-phosphate plus pyridoxal; PL, pyridoxal; PLP, pyridoxal 5´-phosphate; SDMA, symmetric dimethylarginine; TMAO, trimethylamine N-oxide; XA, xanthurenic acid; 1-MH, 1-methylhistidine; 3-MH, 3-methylhistidine.

References

    1. Nordic Council of Ministers.. Nordic nutrition recommendations 2012: integrating nutrition and physical activity, 5th ed. Copenhagen: Nordic Council of Ministers; 2014.
    1. Eckel RH, Jakicic JM, Ard JD, de Jesus JM, Houston Miller N, Hubbard VS, Lee IM, Lichtenstein AH, Loria CM, Millen BEet al. . 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25):2960–84.
    1. McGuire S. Scientific report of the 2015 Dietary Guidelines Advisory Committee. Washington (DC): US Departments of Agriculture and Health and Human Services, 2015. Adv Nutr. 2016;7(1):202–4.
    1. Herforth A, Arimond M, Álvarez-Sánchez C, Coates J, Christianson K, Muehlhoff E. A global review of food-based dietary guidelines. Adv Nutr. 2019;10(4):590–605.
    1. FAO/WHO.. Report of the Joint FAO/WHO Expert Consultation on the Risks and Benefits of Fish Consumption. Rome: FAO; 2011.
    1. VKM.. Benefit-risk assessment of fish and fish products in the Norwegian diet—an update. Scientific Opinion of the Scientific Steering Committee. Oslo (Norway): VKM; 2014. [Internet]. [Cited 1 Sep 2020]. Available from:
    1. Zeisel SH, Mar MH, Howe JC, Holden JM. Concentrations of choline-containing compounds and betaine in common foods. J Nutr. 2003;133(5):1302–7.
    1. Lund EK. Health benefits of seafood; is it just the fatty acids?. Food Chem. 2013;140(3):413–20.
    1. Turunen AW, Mannisto S, Kiviranta H, Marniemi J, Jula A, Tiittanen P, Suominen-Taipale L, Vartiainen T, Verkasalo PK. Dioxins, polychlorinated biphenyls, methyl mercury and omega-3 polyunsaturated fatty acids as biomarkers of fish consumption. Eur J Clin Nutr. 2010;64(3):313–23.
    1. Thompson FE, Subar AF. Dietary assessment methodologyIn: Coulston AM, Boushey CJ, Ferruzzi MG, Delahanty LM, editors. Nutrition in the prevention and treatment of disease, 4th ed. Academic Press; 2017. p.; 5–48.
    1. Picó C, Serra F, Rodríguez AM, Keijer J, Palou A. Biomarkers of nutrition and health: new tools for new approaches. Nutrients. 2019;11(5):1092.
    1. Serra-Majem L, Nissensohn M, Øverby NC, Fekete K. Dietary methods and biomarkers of omega 3 fatty acids: a systematic review. Br J Nutr. 2012;107(S2):S64–76.
    1. Neveu V, Moussy A, Rouaix H, Wedekind R, Pon A, Knox C, Wishart DS, Scalbert A. Exposome-Explorer: a manually-curated database on biomarkers of exposure to dietary and environmental factors. Nucleic Acids Res. 2017;45(D1):D979–84.
    1. Hanhineva K, Lankinen MA, Pedret A, Schwab U, Kolehmainen M, Paananen J, de Mello V, Sola R, Lehtonen M, Poutanen Ket al. . Nontargeted metabolite profiling discriminates diet-specific biomarkers for consumption of whole grains, fatty fish, and bilberries in a randomized controlled trial. J Nutr. 2015;145(1):7–17.
    1. Pallister T, Jennings A, Mohney RP, Yarand D, Mangino M, Cassidy A, MacGregor A, Spector TD, Menni C. Characterizing blood metabolomics profiles associated with self-reported food intakes in female twins. PLoS One. 2016;11(6):e0158568.
    1. Boldyrev AA, Aldini G, Derave W. Physiology and pathophysiology of carnosine. Physiol Rev. 2013;93(4):1803–45.
    1. Wu G. Important roles of dietary taurine, creatine, carnosine, anserine and 4-hydroxyproline in human nutrition and health. Amino Acids. 2020;52(3):329–60.
    1. Cuparencu C, Praticó G, Hemeryck LY, Sri Harsha PSC, Noerman S, Rombouts C, Xi M, Vanhaecke L, Hanhineva K, Brennan Let al. . Biomarkers of meat and seafood intake: an extensive literature review. Genes Nutr. 2019;14:35.
    1. Oyen J, Kvestad I, Midtbo LK, Graff IE, Hysing M, Stormark KM, Markhus MW, Baste V, Froyland L, Koletzko Bet al. . Fatty fish intake and cognitive function: FINS-KIDS, a randomized controlled trial in preschool children. BMC Med. 2018;16(1):41.
    1. Dahl L, Maeland CA, Bjorkkjaer T. A short food frequency questionnaire to assess intake of seafood and n-3 supplements: validation with biomarkers. Nutr J. 2011;10:127.
    1. Markhus MW, Graff IE, Dahl L, Seldal CF, Skotheim S, Braarud HC, Stormark KM, Malde MK. Establishment of a seafood index to assess the seafood consumption in pregnant women. Food Nutr Res. 2013;57:19272.
    1. Araujo P, Nguyen T-T, Frøyland L, Wang J, Kang JX. Evaluation of a rapid method for the quantitative analysis of fatty acids in various matrices. J Chromatogr A. 2008;1212(1):106–13.
    1. Araujo P, Kjellevold M, Nerhus I, Dahl L, Aakre I, Moe V, Smith L, Markhus MW. Fatty acid reference intervals in red blood cells among pregnant women in Norway-cross sectional data from the ‘Little in Norway’ cohort. Nutrients. 2020;12(10):2950.
    1. Kvestad I, Vabo S, Kjellevold M, Nostbakken OJ, Midtbo LK, Hysing M, Markhus MW, Madsen L, Handeland K, Graff IEet al. . Fatty fish, hair mercury and cognitive function in Norwegian preschool children: results from the randomized controlled trial FINS-KIDS. Environ Int. 2018;121(Pt 2):1098–105.
    1. Nerhus I, Odland M, Kjellevold M, Midtbø LK, Markhus MW, Graff IE, Lie Ø, Kvestad I, Frøyland L, Dahl Let al. . Iodine status in Norwegian preschool children and associations with dietary iodine sources: the FINS-KIDS study. Eur J Nutr. 2019;58(6):2219–27.
    1. Midtbø LK, Nygaard LB, Markhus MW, Kjellevold M, Lie Ø, Dahl L, Kvestad I, Frøyland L, Graff IE, Øyen J. Vitamin D status in preschool children and its relations to vitamin D sources and body mass index – the FINS-KIDS study. Nutrition. 2020;70:110595.
    1. Molloy AM, Scott JM. Microbiological assay for serum, plasma, and red cell folate using cryopreserved, microtiter plate method. Methods Enzymol. 1997;281:43–53.
    1. Kelleher BP, Broin SD. Microbiological assay for vitamin B12 performed in 96-well microtitre plates. J Clin Pathol. 1991;44(7):592–5.
    1. Midttun Ø, Kvalheim G, Ueland PM. High-throughput, low-volume, multianalyte quantification of plasma metabolites related to one-carbon metabolism using HPLC-MS/MS. Anal Bioanal Chem. 2013;405(6):2009–17.
    1. Midttun Ø, Hustad S, Ueland PM. Quantitative profiling of biomarkers related to B-vitamin status, tryptophan metabolism and inflammation in human plasma by liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom. 2009;23(9):1371–9.
    1. Midttun Ø, McCann A, Aarseth O, Krokeide M, Kvalheim G, Meyer K, Ueland PM. Combined measurement of 6 fat-soluble vitamins and 26 water-soluble functional vitamin markers and amino acids in 50 μl of serum or plasma by high-throughput mass spectrometry. Anal Chem. 2016;88(21):10427–36.
    1. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B Methodol. 1995;57(1):289–300.
    1. Institute of Marine Research [Havforskningsinstituttet].. Seafood data [Sjømatdata]. [Internet]. [Cited 1 Sep 2020]. Available from:
    1. Handeland K, Skotheim S, Baste V, Graff IE, Frøyland L, Lie Ø, Kjellevold M, Markhus MW, Stormark KM, Øyen Jet al. . The effects of fatty fish intake on adolescents' nutritional status and associations with attention performance: results from the FINS-TEENS randomized controlled trial. Nutr J. 2018;17(1):30.
    1. Vuholm S, Teisen MN, Buch NG, Stark KD, Jakobsen J, Mølgaard C, Lauritzen L, Damsgaard CT. Is high oily fish intake achievable and how does it affect nutrient status in 8-9-year-old children? The FiSK Junior trial. Eur J Nutr. 2020;59(3):1205–18.
    1. Demmelmair H, Øyen J, Pickert T, Rauh-Pfeiffer A, Stormark KM, Graff IE, Lie Ø, Kjellevold M, Koletzko B. The effect of Atlantic salmon consumption on the cognitive performance of preschool children – a randomized controlled trial. Clin Nutr. 2019;38(6):2558–68.
    1. Dahl L, Johansson L, Julshamn K, Meltzer HM. The iodine content of Norwegian foods and diets. Public Health Nutr. 2004;7(4):569–76.
    1. Zimmermann MB. Methods to assess iron and iodine status. Br J Nutr. 2008;99(S3):S2–S9.
    1. Rohner F, Zimmermann M, Jooste P, Pandav C, Caldwell K, Raghavan R, Raiten DJ. Biomarkers of nutrition for development—iodine review. J Nutr. 2014;144(8):1322S–42S.
    1. Mozaffarian D, Rimm EB. Fish intake, contaminants, and human health: evaluating the risks and the benefits. JAMA. 2006;296(15):1885–99.
    1. Hagen IV, Helland A, Bratlie M, Midttun O, McCann A, Sveier H, Rosenlund G, Mellgren G, Ueland PM, Gudbrandsen OA. TMAO, creatine and 1-methylhistidine in serum and urine are potential biomarkers of cod and salmon intake: a randomised clinical trial in adults with overweight or obesity. Eur J Nutr. 2020;59(5):2249–59.
    1. Cheung W, Keski-Rahkonen P, Assi N, Ferrari P, Freisling H, Rinaldi S, Slimani N, Zamora-Ros R, Rundle M, Frost Get al. . A metabolomic study of biomarkers of meat and fish intake. Am J Clin Nutr. 2017;105(3):600–8.
    1. Norwegian Food Safety Authority.. Norwegian food composition database. 2019. [Internet]. [Cited 1 Sep 2020]. Available from:
    1. Schönfeldt HC, Hall NG. Determining iron bio-availability with a constant heme iron value. J Food Compos Anal. 2011;24(4-5):738–40.
    1. Pizarro F, Olivares M, Valenzuela C, Brito A, Weinborn V, Flores S, Arredondo M. The effect of proteins from animal source foods on heme iron bioavailability in humans. Food Chem. 2016;196:733–8.
    1. Lloyd AJ, Favé G, Beckmann M, Lin W, Tailliart K, Xie L, Mathers JC, Draper J. Use of mass spectrometry fingerprinting to identify urinary metabolites after consumption of specific foods. Am J Clin Nutr. 2011;94(4):981–91.
    1. Andersen M-BS, Reinbach HC, Rinnan Å, Barri T, Mithril C, Dragsted LO. Discovery of exposure markers in urine for Brassica-containing meals served with different protein sources by UPLC-qTOF-MS untargeted metabolomics. Metabolomics. 2013;9(5):984–97.
    1. Taesuwan S, Cho CE, Malysheva OV, Bender E, King JH, Yan J, Thalacker-Mercer AE, Caudill MA. The metabolic fate of isotopically labeled trimethylamine-N-oxide (TMAO) in humans. J Nutr Biochem. 2017;45:77–82.
    1. Solvik BS, Strand TA, Kvestad I, Markhus MW, Ueland PM, McCann A, Øyen J. Dietary Intake and biomarkers of folate and cobalamin status in Norwegian preschool children: the FINS-KIDS study. J Nutr. 2020;150(7):1852–8.
    1. Antonucci R, Locci C, Clemente MG, Chicconi E, Antonucci L. Vitamin D deficiency in childhood: old lessons and current challenges. J Pediatr Endocrinol Metab. 2018;31(3):247–60.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner