Skip to main content
SpringerLink
Log in

A meta-analysis of glucocorticoids as modulators of oxidative stress in vertebrates

  • Review
  • Published:
Journal of Comparative Physiology B Aims and scope Submit manuscript

Abstract

Prolonged high secretion of glucocorticoids normally reflects a state of chronic stress, which has been associated with an increase in disease susceptibility and reduction in Darwinian fitness. Here, we hypothesize that an increase in oxidative stress accounts for the detrimental effects of prolonged high secretion of glucocorticoids. We performed a meta-analysis on studies where physiological stress was induced by administration of glucocorticoids to evaluate the magnitude of their effects on oxidative stress. Glucocorticoids have a significant effect on oxidative stress (Pearson r = 0.552), although this effect depends on the duration of treatment, and is larger in long-term experiments. Importantly, there was a significant effect on tissue, with brain and heart being the most and the least susceptible to GC-induced oxidative stress, respectively. Furthermore, effect size was larger (1) in studies using both sexes compared to males only, (2) when corticosterone rather than dexamethasone was administered and (3) in juveniles than in adults. These effects were not confounded by species, biochemical biomarker, or whether wild or laboratory animals were studied. In conclusion, our meta-analysis suggests that GC-induced oxidative stress could be a further mechanism underlying increases in disease susceptibility and decreases in Darwinian fitness observed under chronic stress.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Agostinho P, Cunha RA, Oliveira C (2010) Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer’s disease. Curr Pharm Design 16:2766–2778

    CAS  Google Scholar 

  • Arguelles S, Garcia S, Maldonado M, Machado A, Ayala A (2004) Do the serum oxidative stress biomarkers provide a reasonable index of the general oxidative stress status? Biochim Biophys Acta 1674:251–259

    PubMed  Google Scholar 

  • Atanasova S, Wieland E, Schlumbohm C, Korecka M, Shaw L, von Ahsen N, Fuchs E, Oellerich M, Armstrong V (2009) Prenatal dexamethasone exposure in the common marmoset monkey enhances gene expression of antioxidant enzymes in the aorta of adult offspring. Stress 12:215–224

    Article  PubMed  CAS  Google Scholar 

  • Barja G (2004) Free radicals and aging. Trends Neurosc 27:595–600

    Article  CAS  Google Scholar 

  • Begg CB (1994) Publication bias. In: Cooper H, Hedges LV (eds) The handbook of research synthesis. Russel Sage Foundation, New York, pp 399–409

    Google Scholar 

  • Behl C, Lezoualch F, Trapp T, Widmann M, Skutella T, Holsboer F (1997) Glucocorticoids enhance oxidative stress-induced cell death in hippocampal neurons in vitro. Endocrin 138:101–106

    Article  CAS  Google Scholar 

  • Bjelakovic G, Stojanovic I, Stoimenov TJ, Pavlovic D, Kocic G, Rossi S, Tabolacci C, Nikolic J, Sokolovic D, Bjelakovic L (2010) Metabolic correlations of glucocorticoids and polyamines in inflammation and apoptosis. Amino Acids 39:29–43

    Article  PubMed  CAS  Google Scholar 

  • Bonier F, Martin PR, Moore IT, Wingfield JC (2009) Do baseline glucocorticoids predict fitness? Trends Ecol Evol 24:634–642

    Article  PubMed  Google Scholar 

  • Breuner CW, Patterson SH, Hahn TP (2008) In search of relationships between the acute adrenocortical response and fitness. Gen Comp Endocr 157:288–295

    Article  PubMed  CAS  Google Scholar 

  • Caro P, Gomez J, Sanz A, Portero-Otin M, Pamplona R, Barja G (2007) Effect of graded corticosterone treatment on aging-related markers of oxidative stress in rat liver mitochondria. Biogerontol 8:1–11

    Article  CAS  Google Scholar 

  • Cohen J (1988) Power analysis for the behavioural sciences. Erlbaum, Hillsdale

    Google Scholar 

  • Cohen RM, Szczepanik J, McManus M, Mirza N, Putnam K, Levy J, Sunderland T (2006) Hippocampal atrophy in the healthy is initially linear and independent of age. Neurobiol Aging 27:1385–1394

    Article  PubMed  CAS  Google Scholar 

  • Costantini D (2008) Oxidative stress in ecology and evolution: lessons from avian studies. Ecol Lett 11:1238–1251

    PubMed  Google Scholar 

  • Costantini D (2010) Effects of diet quality on growth pattern, serum oxidative status, and corticosterone in pigeons (Columba livia). Can J Zool 88:795–802

    Article  Google Scholar 

  • Costantini D, Møller AP (2008) Carotenoids are minor antioxidants for birds. Funct Ecol 22:367–370

    Article  Google Scholar 

  • Costantini D, Møller AP (2009) Does immune response cause oxidative stress in birds? A meta-analysis. Comp Biochem Physiol Part A 153:339–344

    Article  Google Scholar 

  • Costantini D, Verhulst S (2009) Does high antioxidant capacity indicate low oxidative stress? Funct Ecol 23:506–509

    Article  Google Scholar 

  • Costantini D, Fanfani A, Dell’Omo G (2008) Effects of corticosteroids on oxidative damage and circulating carotenoids in captive adult kestrels (Falco tinnunculus). J Comp Physiol B 178:829–835

    Article  PubMed  CAS  Google Scholar 

  • Costantini D, Rowe M, Butler MW, McGraw KJ (2010) From molecules to living systems: historical and contemporary issues in oxidative stress and antioxidant ecology. Funct Ecol 24:950–959

    Article  Google Scholar 

  • Cote J, Meylan S, Clobert J, Voituron Y (2010) Carotenoid-based coloration, oxidative stress and corticosterone in common lizards. J Exp Biol 213:2116–2124

    Article  PubMed  CAS  Google Scholar 

  • Dallman MF, Akana SF, Levin N, Walker CD, Bradbury MJ, Suemaru S, Scribner KS (1994) Corticosteroids and the control of function in the hypothalamo–pituitary–adrenal (HPA) axis. Ann New York Acad Sci 746:22–32

    Article  CAS  Google Scholar 

  • Dhanabalan S, Mathur PP (2009) Low dose of 2,3,7,8 tetrachlorodibenzo-p-dioxin induces testicular oxidative stress in adult rats under the influence of corticosterone. Exp Toxic Pathol 61:415–423

    Article  CAS  Google Scholar 

  • Dickens M, Romero LM, Cyr NE, Dunn IC, Meddle SL (2009) Chronic stress alters glucocorticoid receptor and mineralocorticoid receptor mRNA expression in the European starling (Sturnus vulgaris) brain. J Neuroendocr 21:832–840

    Article  CAS  Google Scholar 

  • Felszeghy K, Bagdy G, Nyakas C (2000) Blunted pituitary-adrenocortical stress response in adult rats following neonatal dexamethasone treatment. J Neuroendocr 12:1014–1021

    Article  CAS  Google Scholar 

  • Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408:239–247

    Article  PubMed  CAS  Google Scholar 

  • Gredilla R, Sanz A, Lopez-Torres M, Barja G (2001) Caloric restriction decreases mitochondrial free radical generation at complex I and lowers oxidative damage to mitochondrial DNA in the rat heart. FASEB J 15:1589–1591

    PubMed  CAS  Google Scholar 

  • Halliwell BH, Gutteridge JMC (2007) Free radicals in biology and medicine. Oxford University Press, Oxford

    Google Scholar 

  • Hatamoto LK, Baptista Sobrinho CA, Nichi M, Barnabe VH, Barnabe RC, Cortada CNM (2006) Effects of dexamethasone treatment (to mimic stress) and vitamin E oral supplementation on the spermiogram and on seminal plasma spontaneous lipid peroxidation and antioxidant enzyme activities in dogs. Theriogenol 66:1610–1614

    Article  CAS  Google Scholar 

  • Haussmann MF, Marchetto NM (2010) Telomeres: linking stress and survival, ecology and evolution. Curr Zool 56:703–713

    Google Scholar 

  • Herrera EA, Verkerk MM, Derks JB, Giussani DA (2010) Antioxidant treatment alters peripheral vascular dysfunction induced by postnatal glucocorticoid therapy in rats. Plos One 5:8

    Google Scholar 

  • Hulbert AJ, Pamplona R, Buffenstein R, Buttemer WA (2007) Life and death: metabolic rate, membrane composition, and life span of animals. Physiol Rev 87:1175–1213

    Article  PubMed  CAS  Google Scholar 

  • Joels M, Karst H, Krugers HJ, Lucassen PJ (2007) Chronic stress: implications for neuronal morphology, function and neurogenesis. Front Neuroendocrin 28:72–96

    Article  Google Scholar 

  • Kobayashi N, Machida T, Takahashi T, Takatsu H, Shinkai T, Abe K, Urano S (2009) Elevation by oxidative stress and aging of hypothalamic–pituitary–adrenal activity in rats and its prevention by vitamin E. J Clin Biochem Nutr 45:207–213

    Article  PubMed  CAS  Google Scholar 

  • Lawrence MS, Sapolsky RM (1994) Glucocorticoids accelerate ATP loss following metabolic insults in cultured hippocampal-neurons. Brain Res 646:303–306

    Article  PubMed  CAS  Google Scholar 

  • Light RJ, Pillemer DB (1984) Summing up: the science of reviewing research. Harvard University Press, Cambridge

    Google Scholar 

  • Lin H, Deculypere E, Buyse J (2004a) Oxidative stress induced by corticosterone administration in broiler chickens (Gallus gallus domesticus)––2. Short-term effect. Comp Biochem Physiol Part B 139:745–751

    Article  CAS  Google Scholar 

  • Lin H, Decuypere E, Buyse J (2004b) Oxidative stress induced by corticosterone administration in broiler chickens (Gallus gallus domesticus)––1. Chronic exposure. Comp Biochem Physiol Part B 139:737–744

    Article  CAS  Google Scholar 

  • Lin H, Gao J, Song ZG, Jiao HC (2009) Corticosterone administration induces oxidative injury in skeletal muscle of broiler chickens. Poult Sci 88:1044–1051

    Article  PubMed  CAS  Google Scholar 

  • Long F, Wang YX, Liu L, Zhou J, Cui RY, Jiang CL (2005) Rapid nongenomic inhibitory effects of glucocorticoids on phagocytosis and superoxide anion production by macrophages. Steroids 70:55–61

    Article  PubMed  CAS  Google Scholar 

  • Long F, Wang Y, Qi H-H, Zhou X, Jin X-Q (2008) Rapid non-genomic effects of glucocorticoids on oxidative stress in a guinea pig model of asthma. Respirology 13:227–232

    Article  PubMed  Google Scholar 

  • Lopez Torres M, Perez Campo R, Cadenas S, Rojas C, Barja G (1993) A comparative study of free-radicals in vertebrates. 2. Nonenzymatic antioxidants and oxidative stress. Comp Biochem Physiol Part B 105:757–763

    Article  CAS  Google Scholar 

  • Love OP, Bird DM, Shutt LJ (2003) Corticosterone levels during post-natal development in captive American kestrels (Falco sparverius). Gen Comp Endocrin 130:135–141

    Article  CAS  Google Scholar 

  • Masoro EJ, Austad SN (1996) The evolution of the antiaging action of dietary restriction: a hypothesis. J Gerontol A Biol Sci Med Sci 51:B387–391

    PubMed  CAS  Google Scholar 

  • McEwen BS, Stellar E (1993) Stress and the individual–mechanisms leading to disease. Arch Inter Med 153:2093–2101

    Article  CAS  Google Scholar 

  • McIntosh LJ, Cortopassi KM, Sapolsky RM (1998a) Glucocorticoids may alter antioxidant enzyme capacity in the brain: kainic acid studies. Brain Res 791:215–222

    Article  PubMed  CAS  Google Scholar 

  • McIntosh LJ, Hong KE, Sapolsky RM (1998b) Glucocorticoids may alter antioxidant enzyme capacity in the brain: baseline studies. Brain Res 791:209–214

    Article  PubMed  CAS  Google Scholar 

  • Mendez-Armenta M, Villeda-Hernandez J, Barroso-Moguel R, Nava-Ruiz C, Jimenez-Capdeville ME, Rios C (2003) Brain regional lipid peroxidation and metallothionein levels of developing rats exposed to cadmium and dexamethasone. Toxicol Lett 144:151–157

    Article  PubMed  CAS  Google Scholar 

  • Metcalfe NB, Alonso-Alvarez C (2010) Oxidative stress as a life-history constraint: the role of reactive oxygen species in shaping phenotypes from conception to death. Funct Ecol 24:984–996

    Article  Google Scholar 

  • Monaghan P (2008) Early growth conditions, phenotypic development and environmental change. Phil Trans R Soc B 363:1635–1645

    Article  PubMed  Google Scholar 

  • Munck A, Guyre PM, Holbrook NJ (1984) Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocr Rev 5:25–44

    Article  PubMed  CAS  Google Scholar 

  • Negre-Salvayre A, Auge N, Ayala V, Basaga H, Boada J, Brenke R, Chapple S, Cohen G, Feher J, Grune T, Lengyel G, Mann GE, Pamplona R, Poli G, Portero-Otin M, Riahi Y, Salvayre R, Sasson S, Serrano J, Shamni O, Siems W, Siow RCM, Wiswedel I, Zarkovic K, Zarkovic N (2010) Pathological aspects of lipid peroxidation. Free Rad Res 44:1125–1171

    Article  CAS  Google Scholar 

  • Nikolaidis MG, Jamurtas AZ (2009) Blood as a reactive species generator and redox status regulator during exercise. Arch Biochem Biophys 490:77–84

    Article  PubMed  CAS  Google Scholar 

  • Odedra BR, Bates PC, Millward DJ (1983) Time course of the effect of catabolic doses of corticosterone in protein turnover in rat skeletal muscle and liver. Biochem J 214:617–628

    PubMed  CAS  Google Scholar 

  • Oitzl MS, Champagne DL, van der Veen R, de Kloet ER (2010) Brain development under stress: hypotheses of glucocorticoid actions revisited. Neurosc Biobehav Rev 34:853–866

    Article  CAS  Google Scholar 

  • Pamplona R, Portero-Otin M, Sanz A, Requena J, Barja G (2004) Modification of the longevity-related degree of fatty acid unsaturation modulates oxidative damage to proteins and mitochondrial DNA in liver and brain. Exp Geront 39:725–733

    Article  CAS  Google Scholar 

  • Patel NV, Finch CE (2002) The glucocorticoid paradox of caloric restriction in slowing brain aging. Neurobiol Aging 23:707–717

    Article  PubMed  CAS  Google Scholar 

  • Pereira B, Bechara EJH, Mendoca JR, Curi R (1999) Superoxide dismutase, catalase and glutathione peroxidase activities in the lymphoid organs and skeletal muscles of rats treated with dexamethasone. Cell Biochem Funct 17:15–19

    Article  PubMed  CAS  Google Scholar 

  • Pérez-Campo R, Lopez-Torres M, Cadenas S, Rojas C, Barja G (1998) The rate of free radical production as a determinant of the rate of aging: evidence from the comparative approach. J Comp Physiol B 168:149–158

    Article  PubMed  Google Scholar 

  • Reul JMHM, De Kloet ER (1985) Two receptor systems for corticosterone in rat brain microdistribution and differential occupation. Endocrinol 117:2505–2511

    Article  CAS  Google Scholar 

  • Ricklefs RE (1984) The optimization of growth rate in altricial birds. Ecology 65:1602–1616

    Article  Google Scholar 

  • Romero LM (2004) Physiological stress in ecology: lessons from biomedical research. Trends Ecol Evol 19:249–255

    Article  PubMed  Google Scholar 

  • Romero LM, Wikelski M (2001) Corticosterone levels predict survival probabilities of Galapagos marine iguanas during El Niño events. Proc Nat Acad Sci USA 98:7366–7370

    Article  PubMed  CAS  Google Scholar 

  • Romero LM, Dickens MJ, Cyr NE (2009) The reactive scope model––a new model integrating homeostasis, allostasis, and stress. Horm Behav 55:375–389

    Article  PubMed  Google Scholar 

  • Rosenthal R (1991) Meta-analytic procedures for social research. Sage, New York

    Google Scholar 

  • Rosenthal R (1994) Parametric measures of effect size. In: Cooper H, Hedges LV (eds) The handbook of research synthesis. Russel Sage Foundation, New York, pp 231–244

    Google Scholar 

  • Roussel D, Dumas JF, Simard G, Malthiery Y, Ritz P (2004) Kinetics and control of oxidative phosphorylation in rat liver mitochondria after dexamethasone treatment. Biochem J 382:491–499

    Article  PubMed  CAS  Google Scholar 

  • Santana de Vasconcellos AP, Battistela Nieto F, Machado Crema L, Diehl LA, de Almeida LM, Prediger ME, Rocha da Rocha E, Dalmaz C (2006) Chronic lithium treatment has antioxidant properties but does not prevent oxidative damage induced by chronic variate stress. Neurochem Res 31:1141–1151

    Article  Google Scholar 

  • Sapolsky RM, Romero LM, Munck AU (2000) How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev 21:55–89

    Article  PubMed  CAS  Google Scholar 

  • Sies H (1991) Oxidative stress: oxidants and antioxidants. Academic Press, London

    Google Scholar 

  • Sohal RS, Weindruch R (1996) Oxidative stress, caloric restriction, and aging. Science 273:59–63

    Article  PubMed  CAS  Google Scholar 

  • Sørensen J (2010) Application of heat shock protein expression for detecting natural adaptation and exposure to stress in natural populations. Curr Zool 56:703–716

    Google Scholar 

  • Stier KS, Almasi B, Gasparini J, Piault R, Roulin A, Jenni L (2009) Effects of corticosterone on innate and humoral immune functions and oxidative stress in barn owl nestlings. J Exp Biol 212:2084–2090

    Article  Google Scholar 

  • Surai P (2002) Natural antioxidants in avian nutrition and reproduction. Nottingham University Press, Nottingham

    Google Scholar 

  • Taniguchi Y, Iwasaki Y, Tsugita M, Nishiyama M, Taguchi T, Okazaki M, Nakayama S, Kambayashi M, Hashimoto K, Terada Y (2010) Glucocorticoid receptor-beta and receptor-gamma exert dominant negative effect on gene repression but not on gene induction. Endocrinol 151:3204–3213

    Article  CAS  Google Scholar 

  • Tuo JS, Deng XS, Loft S, Poulsen HE (1999) Dexamethasone ameliorates oxidative DNA damage induced by benzene and LPS in mouse bone marrow. Free Rad Res 30:29–36

    Article  CAS  Google Scholar 

  • Veskoukis AS, Nikolaidis MG, Kyparos A, Kouretas D (2009) Blood reflects tissue oxidative stress depending on biomarker and tissue studied. Free Rad Biol Med 47:1371–1374

    Article  PubMed  CAS  Google Scholar 

  • Wada H, Salvante KG, Stables C, Wagner E, Williams TD, Breuner CW (2008) Adrenocortical responses in zebra finches (Taeniopygia guttata): individual variation, repeatability, and relationship to phenotypic quality. Horm Behav 53:472–480

    Article  PubMed  CAS  Google Scholar 

  • Walther UI, Stets R (2009) Glucocorticoid pretreatment increases toxicity due to peroxides in alveolar epithelial-like cell lines. Toxicol 256:48–52

    Article  CAS  Google Scholar 

  • West-Eberhard MJ (2003) Developmental plasticity and evolution. Oxford University Press, Oxford

    Google Scholar 

  • Wilckens T (1995) Glucocorticoids and immune function––physiological relevance and pathogenic potential of hormonal dysfunction. Trends Pharmacol Sci 16:193–197

    Article  PubMed  CAS  Google Scholar 

  • Wingfield JC, Maney DL, Breuner CW, Jacobs JD, Lynn S, Ramenofsky M, Richardson RD (1998) Ecological bases of hormone–behavior interactions: the “emergency life history stage”. Am Zool 38:191–206

    CAS  Google Scholar 

  • Yoshioka T, Kawamura T, Meyrick BO, Beckman JK, Hoover RL, Yoshida H, Ichikawa I (1994) Induction of manganese superoxide-dismutase by glucocorticoids in glomerular cells. Kidney Int 45:211–219

    Article  PubMed  CAS  Google Scholar 

  • Zatsepina OG, Evgen’ev MB, Liashchko VN (1990) Changes in the transcription activity of c-myc genes and heat shock proteins (HSP 70) after incubation of mouse plasmacytoma cells with dexamethasone. Mol Biol 24:391–395

    CAS  Google Scholar 

Download references

Acknowledgments

We thank J. Cote for kindly providing sample sizes and three anonymous reviewers for valuable comments on the manuscript. DC was supported by a postdoctoral NERC research fellowship (NE/G013888/1); VM was supported by a Lord Kelvin/Adam Smith PhD scholarship from the University of Glasgow.

Author information

Authors and Affiliations

  1. Institute for Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Graham Kerr Building, Glasgow, G12 8QQ, UK

    David Costantini & Valeria Marasco

  2. Laboratoire d’Ecologie Systématique et Evolution, CNRS UMR 8079, Université Paris-Sud, Bâtiment 362, 91405, Orsay Cedex, France

    Anders Pape Møller

Authors
  1. David Costantini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Valeria Marasco
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anders Pape Møller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David Costantini.

Additional information

Communicated by G. Heldmaier.

Electronic supplementary material

Below is the link to the electronic supplementary material.

(PDF 54 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Costantini, D., Marasco, V. & Møller, A.P. A meta-analysis of glucocorticoids as modulators of oxidative stress in vertebrates. J Comp Physiol B 181, 447–456 (2011). https://doi.org/10.1007/s00360-011-0566-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00360-011-0566-2

Keywords

Search

Navigation