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Prenatal and childhood exposures are associated with thymulin concentrations in young adolescent children in rural Nepal

Part of: DOHaD on International Women's Day 2020

Published online by Cambridge University Press:  02 September 2019

Amanda C. Palmer Open the ORCID record for Amanda C. Palmer [Opens in a new window] ,
Kerry J. Schulze ,
Subarna K. Khatry  and
Keith P. West Jr.
Amanda C. Palmer*
Affiliation:
Department of International Health, Center for Human Nutrition, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
Kerry J. Schulze
Affiliation:
Department of International Health, Center for Human Nutrition, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
Subarna K. Khatry
Affiliation:
Department of International Health, Center for Human Nutrition, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA Nepal Nutrition Intervention Project-Sarlahi, Sarlahi, Nepal National Society for the Prevention of Blindness, Kathmandu, Nepal
Keith P. West Jr.
Affiliation:
Department of International Health, Center for Human Nutrition, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
*
Address for correspondence: Amanda C. Palmer, Department of International Health, Center for Human Nutrition, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, USA. Email: acpalmer@jhu.edu
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Abstract

The thymus undergoes a critical period of growth and development early in gestation and, by mid-gestation, immature thymocytes are subject to positive and negative selection. Exposure to undernutrition during these periods may permanently affect phenotype. We measured thymulin concentrations, as a proxy for thymic size and function, in children (n = 290; aged 9–13 years) born to participants in a cluster-randomized trial of maternal vitamin A or β-carotene supplementation in rural Nepal (1994–1997). The geometric mean (95% confidence interval) thymulin concentration was 1.37 ng/ml (1.27, 1.47). A multivariate model of early-life exposures revealed a positive association with gestational age at delivery (β = 0.02; P = 0.05) and higher concentrations among children born to β-carotene-supplemented mothers (β = 0.19; P < 0.05). At ∼9–12 years of age, thymulin was positively associated with all anthropometric measures, with height retained in our multivariate model (β = 0.02; P < 0.001). There was significant seasonal variation: concentrations tended to be lower pre-monsoon (β = −0.13; P = 0.15), during the monsoon (β = −0.22; P = 0.04), and pre-harvest (β = −0.34; P = 0.01), relative to the post-harvest season. All early-life associations, except supplementation, were mediated in part by nutritional status at follow-up. Our findings underscore the known sensitivity of the thymus to nutrition, including potentially lasting effects of early nutritional exposures. The relevance of these findings to later disease risk remains to be explored, particularly given the role of thymulin in the neuroendocrine regulation of inflammation.

Keywords

Thymusplasticityimmune developmentneuroendocrineseasonality
Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 11 , Issue 2 , April 2020 , pp. 127 - 135
Copyright
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2019

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References

Hanson, MA, Gluckman, PD.Early developmental conditioning of later health and disease: physiology or pathophysiology? Physiol Rev. 2014; 94, 1027–1076.CrossRefGoogle ScholarPubMed
Palmer, AC.Nutritionally mediated programming of the developing immune system. Adv Nutr. 2011; 2, 377–395.CrossRefGoogle ScholarPubMed
Kuper, CF, van Bilsen, J, Cnossen, H, Houben, G, Garthoff, J, Wolterbeek, A.Development of immune organs and functioning in humans and test animals: implications for immune intervention studies. Reprod Toxicol. 2016; 64, 180–190.CrossRefGoogle ScholarPubMed
Collinson, AC, Moore, SE, Cole, TJ, Prentice, AM.Birth season and environmental influences on patterns of thymic growth in rural Gambian infants. Acta Paediatr. 2003; 92, 1014–1020.CrossRefGoogle ScholarPubMed
Ngom, PT, Collinson, AC, Pido-Lopez, J, Henson, SM, Prentice, AM, Aspinall, R.Improved thymic function in exclusively breastfed infants is associated with higher interleukin 7 concentrations in their mothers’ breast milk. Am J Clin Nutr. 2004; 80, 722–728.10.1093/ajcn/80.3.722CrossRefGoogle ScholarPubMed
Moore, SE, Collinson, AC, Tamba N’gom, P, Aspinall, R, Prentice, AM.Early immunological development and mortality from infectious disease in later life. Proc Nutr Soc. 2006; 65, 311–318.10.1079/PNS2006503CrossRefGoogle ScholarPubMed
Fulford, AJ, Moore, SE, Arifeen, SE, et al.Disproportionate early fetal growth predicts postnatal thymic size in humans. J Dev Orig Health Dis. 2013; 4, 223–231.10.1017/S2040174413000044CrossRefGoogle ScholarPubMed
McDade, TW, Beck, MA, Kuzawa, CW, Adair, LS.Prenatal undernutrition and postnatal growth are associated with adolescent thymic function. J Nutr. 2001; 131, 1225–1231.CrossRefGoogle ScholarPubMed
McFarland, RD, Picker, LJ, Koup, RA, Douek, DC.Recently identified measures of human thymic function. Clin Appl Immunol Rev. 2001; 2, 65.CrossRefGoogle Scholar
Brelinska, R.Thymic epithelial cells in age-dependent involution. Microsc Res Tech. 2003; 62, 488–500.CrossRefGoogle ScholarPubMed
Hadden, JW.Thymic endocrinology. Ann N Y Acad Sci. 1998; 840, 352–358.CrossRefGoogle ScholarPubMed
Safieh-Garabedian, B, Kendall, MD, Khamashta, MA, Hughes, GR.Thymulin and its role in immunomodulation. J Autoimmun. 1992; 5, 547–555.10.1016/0896-8411(92)90152-GCrossRefGoogle ScholarPubMed
Reggiani, PC, Schwerdt, JI, Console, GM, Roggero, EA, Dardenne, M, Goya, RG.Physiology and therapeutic potential of the thymic peptide thymulin. Curr Pharm Des. 2014; 20, 4690–4696.CrossRefGoogle ScholarPubMed
West, KP, Jr., Katz, J., Khatry, SK, et al.Double blind, cluster randomised trial of low dose supplementation with vitamin A or beta carotene on mortality related to pregnancy in Nepal. The NNIPS-2 Study Group. BMJ. 1999; 318, 570–575.CrossRefGoogle ScholarPubMed
Central Bureau of Statistics [Nepal]. Report on the Situation of Women, Children and Households: Between Census Household Information, Monitoring and Evaluation System (March–May 2000), 2001. Central Bureau of Statistics, National Planning Commission, UNICEF Nepal, Kathmandu, Nepal.Google Scholar
Wu, L, Katz, J, Mullany, LC, et al.Association between nutritional status and positive childhood disability screening using the ten questions plus tool in Sarlahi, Nepal. J Health Popul Nutr. 2010; 28, 585–594.10.3329/jhpn.v28i6.6607CrossRefGoogle ScholarPubMed
Shrestha, S, Thorne-Lyman, AL, Manohar, S, et al.Pre-earthquake national patterns of preschool child undernutrition and household food insecurity in Nepal in 2013 and 2014. Asia Pac J Clin Nutr. 2018; 27, 624–637.Google ScholarPubMed
Christian, P, Katz, J, Wu, L, et al.Risk factors for pregnancy-related mortality: a prospective study in rural Nepal. Public Health. 2008; 122, 161–172.CrossRefGoogle ScholarPubMed
Jiang, T, Christian, P, Khatry, SK, Wu, L, West, KP, Jr.Micronutrient deficiencies in early pregnancy are common, concurrent, and vary by season among rural Nepali pregnant women. J Nutr. 2005; 135, 1106–1112.CrossRefGoogle ScholarPubMed
Christian, P, Khatry, SK, Katz, J, et al.Effects of alternative maternal micronutrient supplements on low birth weight in rural Nepal: double blind randomised community trial. BMJ. 2003; 326, 571.CrossRefGoogle ScholarPubMed
Institute of Medicine: Food and Nutrition Board. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc, 2001. National Academy Press, Washington, DC.Google Scholar
Gibson, RS.Principles of Nutritional Assessment, 2nd edn, 2005. Oxford University Press, New York.Google Scholar
World Health Organization. WHO Child Growth Standards: Length/Height-for-Age, Weight-for-Age, Weight-for-Length, Weight-for-Height and Body Mass Index-for-Age: Methods and Development, 2006. World Health Organization, Geneva.Google Scholar
Lunin, SM, Novoselova, EG.Thymus hormones as prospective anti-inflammatory agents. Expert Opin Ther Targets. 2010; 14, 775–786.CrossRefGoogle ScholarPubMed
Liang, KY, Zeger, SL.Regression analysis for correlated data. Annu Rev Public Health. 1993; 14, 43–68.CrossRefGoogle ScholarPubMed
Pejcic-Karapetrovic, B, Kosec, D, Leposavic, G.Differential effects of male and female gonadal hormones on the intrathymic T cell maturation. Dev Immunol. 2001; 8, 305–317.10.1155/2001/52789CrossRefGoogle ScholarPubMed
Leposavic, G, Perisic, M, Kosec, D, et al.Neonatal testosterone imprinting affects thymus development and leads to phenotypic rejuvenation and masculinization of the peripheral blood T-cell compartment in adult female rats. Brain Behav Immun. 2009; 23, 294–304.CrossRefGoogle ScholarPubMed
Consolini, R, Legitimo, A, Calleri, A, Milani, M.Distribution of age-related thymulin titres in normal subjects through the course of life. Clin Exp Immunol. 2000; 121, 444–447.CrossRefGoogle ScholarPubMed
Henriques-Coelho, T, Oliveira, SM, Moura, RS, et al.Thymulin inhibits monocrotaline-induced pulmonary hypertension modulating interleukin-6 expression and suppressing p38 pathway. Endocrinology. 2008; 149, 4367–4373.CrossRefGoogle ScholarPubMed
Moore, SE, Prentice, AM, Wagatsuma, Y, et al.Early-life nutritional and environmental determinants of thymic size in infants born in rural Bangladesh. Acta Paediatr. 2009; 98, 1168–1175.CrossRefGoogle ScholarPubMed
Waterland, RA, Kellermayer, R, Laritsky, E, et al.Season of conception in rural gambia affects DNA methylation at putative human metastable epialleles. PLoS genetics. 2010; 6, e1001252.CrossRefGoogle ScholarPubMed
Ngom, PT, Solon, J, Moore, SE, Morgan, G, Prentice, AM, Aspinall, R.Thymic function and T cell parameters in a natural human experimental model of seasonal infectious diseases and nutritional burden. J Biomed Sci. 2011; 18, 41.CrossRefGoogle Scholar
Niederreither, K, Vermot, J, Le Roux, I, Schuhbaur, B, Chambon, P, Dolle, P.The regional pattern of retinoic acid synthesis by RALDH2 is essential for the development of posterior pharyngeal arches and the enteric nervous system. Development. 2003; 130, 2525–2534.CrossRefGoogle ScholarPubMed
Vermot, J, Niederreither, K, Garnier, JM, Chambon, P, Dolle, P.Decreased embryonic retinoic acid synthesis results in a DiGeorge syndrome phenotype in newborn mice. Proc Natl Acad Sci USA. 2003; 100, 1763–1768.CrossRefGoogle Scholar
Ryckebusch, L, Bertrand, N, Mesbah, K, et al.Decreased levels of embryonic retinoic acid synthesis accelerate recovery from arterial growth delay in a mouse model of DiGeorge syndrome. Circ Res. 2010; 106, 686–694.CrossRefGoogle Scholar
Mendelsohn, C, Lohnes, D, Decimo, D, et al.Function of the retinoic acid receptors (RARs) during development (II). Multiple abnormalities at various stages of organogenesis in RAR double mutants. Development. 1994; 120, 2749–2771.Google ScholarPubMed
Wendling, O, Dennefeld, C, Chambon, P, Mark, M.Retinoid signaling is essential for patterning the endoderm of the third and fourth pharyngeal arches. Development. 2000; 127, 1553–1562.Google ScholarPubMed
Christian, P, West, KP, Jr., Khatry, SK, et al.Vitamin A or beta-carotene supplementation reduces symptoms of illness in pregnant and lactating Nepali women. J Nutr. 2000; 130, 2675–2682.CrossRefGoogle ScholarPubMed
Beloosesky, R, Maravi, N, Weiner, Z, et al.Maternal lipopolysaccharide-induced inflammation during pregnancy programs impaired offspring innate immune responses. Am J Obstet Gynecol. 2010; 203, 185.e1–185.e4. doi: 10.1016/j.ajog.2010.04.033.CrossRefGoogle ScholarPubMed
Breivik, T, Stephan, M, Brabant, GE, Straub, RH, Pabst, R, von Horsten, S.Postnatal lipopolysaccharide-induced illness predisposes to periodontal disease in adulthood. Brain Behav Immun. 2002; 16, 421–438.CrossRefGoogle ScholarPubMed
Ellis, S, Mouihate, A, Pittman, QJ.Early life immune challenge alters innate immune responses to lipopolysaccharide: implications for host defense as adults. Faseb J. 2005; 19, 1519–1521.CrossRefGoogle ScholarPubMed
Ellis, S, Mouihate, A, Pittman, QJ.Neonatal programming of the rat neuroimmune response: stimulus specific changes elicited by bacterial and viral mimetics. J Physiol. 2006; 571, 695–701.CrossRefGoogle ScholarPubMed
Hodyl, NA, Krivanek, KM, Lawrence, E, Clifton, VL, Hodgson, DM.Prenatal exposure to a pro-inflammatory stimulus causes delays in the development of the innate immune response to LPS in the offspring. J Neuroimmunol. 2007; 190, 61–71.CrossRefGoogle ScholarPubMed
Hodyl, NA, Krivanek, KM, Clifton, VL, Hodgson, DM.Innate immune dysfunction in the neonatal rat following prenatal endotoxin exposure. J Neuroimmunol. 2008; 204, 126–130.CrossRefGoogle ScholarPubMed
Kentner, AC, McLeod, SA, Field, EF, Pittman, QJ.Sex-dependent effects of neonatal inflammation on adult inflammatory markers and behavior. Endocrinology. 2010; 151, 2689–2699.CrossRefGoogle ScholarPubMed
Kohman, RA, Tarr, AJ, Sparkman, NL, Bogale, TM, Boehm, GW.Neonatal endotoxin exposure impairs avoidance learning and attenuates endotoxin-induced sickness behavior and central IL-1beta gene transcription in adulthood. Behav Brain Res. 2008; 194, 25–31.CrossRefGoogle ScholarPubMed
Spencer, SJ, Hyland, NP, Sharkey, KA, Pittman, QJ.Neonatal immune challenge exacerbates experimental colitis in adult rats: potential role for TNF-alpha. Am J Physiol Regul Integr Comp Physiol. 2007; 292, R308–315.CrossRefGoogle ScholarPubMed
Savino, W, Dardenne, M.Neuroendocrine control of thymus physiology. Endocr Rev. 2000; 21, 412–443.Google ScholarPubMed
Sakaguchi, S, Miyara, M, Costantino, CM, Hafler, DA.FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol. 2010; 10, 490–500.10.1038/nri2785CrossRefGoogle ScholarPubMed
Murphy, K, Weaver, CM.Janeway’s Immunobiology, 9th edn, 2012. Garland Science/Taylor & Francis Group, LLC, New York, NY.Google Scholar
West, LJ.Defining critical windows in the development of the human immune system. Hum Exp Toxicol. 2002; 21, 499–505.CrossRefGoogle ScholarPubMed
Phillips, DI, Cooper, C, Fall, C, et al.Fetal growth and autoimmune thyroid disease. Q J Med. 1993; 86, 247–253.Google ScholarPubMed
Phillips, DI, Osmond, C, Baird, J, Huckle, A, Rees-Smith, B.Is birthweight associated with thyroid autoimmunity? A study in twins. Thyroid. 2002; 12, 377–380.CrossRefGoogle ScholarPubMed
Kajantie, E, Phillips, DI, Osmond, C, Barker, DJ, Forsen, T, Eriksson, JG.Spontaneous hypothyroidism in adult women is predicted by small body size at birth and during childhood. J Clin Endocrinol Metab. 2006; 91, 4953–4956.CrossRefGoogle ScholarPubMed
Godfrey, KM, Barker, DJ, Osmond, C.Disproportionate fetal growth and raised IgE concentration in adult life. Clin Exp Allergy. 1994; 24, 641–648.CrossRefGoogle ScholarPubMed
McDade, TW, Kuzawa, CW, Adair, LS, Beck, MA.Prenatal and early postnatal environments are significant predictors of total immunoglobulin E concentration in Filipino adolescents. Clin Exp Allergy. 2004; 34, 44–50.CrossRefGoogle ScholarPubMed
Brix, TH, Kyvik, KO, Hegedus, L.Low birth weight is not associated with clinically overt thyroid disease: a population based twin case-control study. Clin Endocrinol (Oxf). 2000; 53, 171–176.CrossRefGoogle Scholar
Edwards, CJ, Cooper, C.Early environmental factors and rheumatoid arthritis. Clin Exp Immunol. 2006; 143, 1–5.CrossRefGoogle ScholarPubMed
Prentice, AM.The thymus: a barometer of malnutrition. Br J Nutr. 1999; 81, 345–347.CrossRefGoogle ScholarPubMed
Savino, W, Dardenne, M, Velloso, LA, Dayse Silva-Barbosa, S. The thymus is a common target in malnutrition and infection. Br J Nutr. 2007; 98, S11–S16.CrossRefGoogle ScholarPubMed
Lyra, JS, Madi, K, Maeda, CT, Savino, W.Thymic extracellular matrix in human malnutrition. J Pathol. 1993; 171, 231–236.CrossRefGoogle ScholarPubMed
Parent, G, Chevalier, P, Zalles, L, et al.In vitro lymphocyte-differentiating effects of thymulin (Zn-FTS) on lymphocyte subpopulations of severely malnourished children. Am J Clin Nutr. 1994; 60, 274–278.CrossRefGoogle ScholarPubMed
Kuvibidila, S, Dardenne, M, Savino, W, Lepault, F.Influence of iron-deficiency anemia on selected thymus functions in mice: thymulin biological activity, T-cell subsets, and thymocyte proliferation. Am J Clin Nutr. 1990; 51, 228–232.CrossRefGoogle ScholarPubMed
Dhur, A, Galan, P, Christides, JP, Polier de Courcy, G, Preziosi, P, Hercberg, S.Effect of folic acid deficiency upon lymphocyte subsets from lymphoid organs in mice. Comp Biochem Physiol A Comp Physiol. 1991; 98, 235–240.CrossRefGoogle ScholarPubMed
Malpuech-Brugere, C, Nowacki, W, Gueux, E, et al.Accelerated thymus involution in magnesium-deficient rats is related to enhanced apoptosis and sensitivity to oxidative stress. Br J Nutr. 1999; 81, 405–411.CrossRefGoogle ScholarPubMed
Nodera, M, Yanagisawa, H, Wada, O.Increased apoptosis in a variety of tissues of zinc-deficient rats. Life Sci. 2001; 69, 1639–1649.CrossRefGoogle Scholar
Mittal, A, Woodward, B.Thymic epithelial cells of severely undernourished mice: accumulation of cholesteryl esters and absence of cytoplasmic vacuoles. Proc Soc Exp Biol Med. 1985; 178, 385–391.CrossRefGoogle ScholarPubMed
Moore, SE, Collinson, AC, Fulford, AJ, et al.Effect of month of vaccine administration on antibody responses in The Gambia and Pakistan. Trop Med Int Health. 2006; 11, 1529–1541.CrossRefGoogle ScholarPubMed
Moore, SE, Collinson, AC, Prentice, AM.Immune function in rural Gambian children is not related to season of birth, birth size, or maternal supplementation status. Am J Clin Nutr. 2001; 74, 840–847.CrossRefGoogle ScholarPubMed
Kauppila, A, Kivela, A, Pakarinen, A, Vakkuri, O.Inverse seasonal relationship between melatonin and ovarian activity in humans in a region with a strong seasonal contrast in luminosity. J Clin Endocrinol Metab. 1987; 65, 823–828.CrossRefGoogle Scholar
Molinero, P, Soutto, M, Benot, S, Hmadcha, A, Guerrero, JM.Melatonin is responsible for the nocturnal increase observed in serum and thymus of thymosin alpha1 and thymulin concentrations: observations in rats and humans. J Neuroimmunol. 2000; 103, 180–188.CrossRefGoogle ScholarPubMed
Tielsch, JM, Khatry, SK, Stoltzfus, RJ, et al.Effect of daily zinc supplementation on child mortality in southern Nepal: a community-based, cluster randomised, placebo-controlled trial. Lancet. 2007; 370, 1230–1239.CrossRefGoogle ScholarPubMed
Brestoff, JR, Artis, D.Immune regulation of metabolic homeostasis in health and disease. Cell. 2015; 161, 146–160.CrossRefGoogle ScholarPubMed
Safieh-Garabedian, B, Mayasi, Y, Saade, NE.Targeting neuroinflammation for therapeutic intervention in neurodegenerative pathologies: a role for the peptide analogue of thymulin (PAT). Expert Opin Ther Targets. 2012; 16, 1065–1073.CrossRefGoogle Scholar
Geovanini, GR, Libby, P.Atherosclerosis and inflammation: overview and updates. Clin Sci (Lond). 2018; 132, 1243–1252.CrossRefGoogle ScholarPubMed
Ferguson, LR.Chronic inflammation and mutagenesis. Mutat Res. 2010; 690, 3–11.CrossRefGoogle ScholarPubMed
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