Psychopharmacology

, Volume 218, Issue 1, pp 303–312 | Cite as

A measure of glucocorticoid load provided by DNA methylation of Fkbp5 in mice

  • Richard S. Lee
  • Kellie L. K. Tamashiro
  • Xiaoju Yang
  • Ryan H. Purcell
  • Yuqing Huo
  • Michael Rongione
  • James B. Potash
  • Gary S. Wand
Original Investigation

Abstract

Rationale

Given the contribution of cortisol dysregulation to neuropsychiatric and metabolic disorders, it is important to be able to accurately compute glucocorticoid burden, a measure of allostatic load. One major problem in calculating cortisol burden is that existing measures reflect cortisol exposure over a short duration and have not been proven to reliably quantify cortisol burden over weeks or months.

Method

We treated two cohorts of mice with corticosterone in the drinking water and determined the relationship between serial plasma corticosterone levels drawn over 4 weeks and the whole-blood DNA methylation (DNAm) changes in a specific glucocorticoid-sensitive gene, Fkbp5, determined at the end of the treatment period.

Results

We observed that the percent reduction in DNAm in the intron 1 region of Fkbp5 determined from a single blood draw strongly reflected average glucocorticoid burden generated weekly during the prior month of glucocorticoid exposure. There were also strong correlations in DNAm with glucocorticoid-induced end organ changes in spleen weight and visceral fat. We tested a subset of these animals for anxiety-like behavior in the elevated plus maze and found that DNAm in the blood also has predictive value in determining the behavioral consequences of glucocorticoid exposure.

Conclusion

A whole-blood assessment of Fkbp5 gene methylation is a biomarker that integrates 4 weeks of glucocorticoid exposure and may be a useful measure in states of excess exposure. It will be important to determine if Fkbp5 DNAm changes can also be a biomarker of glucocorticoid burden during chronic social stress.

Keywords

DNA methylation Fkbp5 Glucocorticoid burden Corticosterone Epigenetics Allostasis 

Supplementary material

213_2011_2307_MOESM1_ESM.ppt (156 kb)
Suppl Fig. 1Regression analysis of mean plasma corticosterone levels vs. DNAm in Expt. 2. a A strong correlation was observed between blood DNAm of Fkbp5 intron 1, CpG position 1 from the second experiment and the mean corticosterone levels calculated from 25 daily blood draws. Similar results were obtained for CpG position 2 (b) (PPT 156 kb)
213_2011_2307_MOESM2_ESM.ppt (275 kb)
Suppl Fig. 2Organ weights and regression analysis of DNAm vs. spleen mass and percent visceral fat. a Thymus and adrenal glands were weighed for corticosterone-treated (varying shades of gray and black for 100, 75, 50, and 25 μg/ml) and vehicle-treated (white bars) mice. The absence of data for thymic mass of corticosterone-treated mice for doses >50 μg/ml reflects a complete atrophy of the organ after 4 week of treatment with corticosterone. Asterisks (*) indicate differences that are statistically significant (P < 0.05). A strong correlation was observed between the DNAm of Fkbp5 intron 1, CpG position 1 vs. spleen mass (b), and DNAm vs. percentage of visceral fat (c). Similar results were observed for CpG position 2 vs. spleen mass (d) and percentage of visceral fat (e). All of the organ weights are expressed as weight per gram total body weight of the mice (PPT 275 kb)

References

  1. Binder EB (2009) The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology 34(Suppl 1):S186–195PubMedCrossRefGoogle Scholar
  2. Clegg DJ, Brown LM, Woods SC, Benoit SC (2006) Gonadal hormones determine sensitivity to central leptin and insulin. Diabetes 55:978–987PubMedCrossRefGoogle Scholar
  3. Colella S, Shen L, Baggerly KA, Issa JP, Krahe R (2003) Sensitive and quantitative universal Pyrosequencing methylation analysis of CpG sites. Biotechniques 35:146–150PubMedGoogle Scholar
  4. Faggiano A, Pivonello R, Spiezia S, De Martino MC, Filippella M, Di Somma C, Lombardi G, Colao A (2003) Cardiovascular risk factors and common carotid artery caliber and stiffness in patients with Cushing's disease during active disease and 1 year after disease remission. J Clin Endocrinol Metab 88:2527–2533PubMedCrossRefGoogle Scholar
  5. Hansen AM, Garde AH, Skovgaard LT, Christensen JM (2001) Seasonal and biological variation of urinary epinephrine, norepinephrine, and cortisol in healthy women. Clin Chim Acta 309:25–35PubMedCrossRefGoogle Scholar
  6. Haskett RF (1985) Diagnostic categorization of psychiatric disturbances in Cushing's syndrome. Am J Psychiatry 142:911–916PubMedGoogle Scholar
  7. Karatsoreos IN, Bhagat SM, Bowles NP, Weil ZM, Pfaff DW, McEwen BS (2010) Endocrine and physiological changes in response to chronic corticosterone: a potential model of the metabolic syndrome in mouse. Endocrinology 151:2117–2127PubMedCrossRefGoogle Scholar
  8. Kelly JJ, Mangos G, Williamson PM, Whitworth JA (1998) Cortisol and hypertension. Clin Exp Pharmacol Physiol Suppl 25:S51–56PubMedCrossRefGoogle Scholar
  9. Kelly WF, Kelly MJ, Faragher B (1996) A prospective study of psychiatric and psychological aspects of Cushing's syndrome. Clin Endocrinol 45:715–720CrossRefGoogle Scholar
  10. Kunnecke B, Verry P, Benardeau A, von Kienlin M (2004) Quantitative body composition analysis in awake mice and rats by magnetic resonance relaxometry. Obes Res 12:1604–1615PubMedCrossRefGoogle Scholar
  11. Lee RS, Tamashiro KL, Yang X, Purcell RH, Harvey A, Willour VL, Huo Y, Rongione M, Wand GS, Potash JB (2010) Chronic corticosterone exposure increases expression and decreases deoxyribonucleic acid methylation of Fkbp5 in mice. Endocrinology 151:4332–4343PubMedCrossRefGoogle Scholar
  12. Ma DK, Jang MH, Guo JU, Kitabatake Y, Chang ML, Pow-Anpongkul N, Flavell RA, Lu B, Ming GL, Song H (2009) Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science 323:1074–1077PubMedCrossRefGoogle Scholar
  13. Magee JA, Chang LW, Stormo GD, Milbrandt J (2006) Direct, androgen receptor-mediated regulation of the FKBP5 gene via a distal enhancer element. Endocrinology 147:590–598PubMedCrossRefGoogle Scholar
  14. McEwen BS (2003) Interacting mediators of allostasis and allostatic load: towards an understanding of resilience in aging. Metabolism 52:10–16PubMedCrossRefGoogle Scholar
  15. McEwen BS (2004) Protection and damage from acute and chronic stress: allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders. Ann NY Acad Sci 1032:1–7PubMedCrossRefGoogle Scholar
  16. Nuber UA, Kriaucionis S, Roloff TC, Guy J, Selfridge J, Steinhoff C, Schulz R, Lipkowitz B, Ropers HH, Holmes MC, Bird A (2005) Up-regulation of glucocorticoid-regulated genes in a mouse model of Rett syndrome. Hum Mol Genet 14:2247–2256PubMedCrossRefGoogle Scholar
  17. Paakinaho V, Makkonen H, Jaaskelainen T, Palvimo JJ (2010) Glucocorticoid receptor activates poised FKBP51 locus through long-distance interactions. Mol Endocrinol 24:511–525PubMedCrossRefGoogle Scholar
  18. Pearce G, Tabensky DA, Delmas PD, Baker HW, Seeman E (1998) Corticosteroid-induced bone loss in men. J Clin Endocrinol Metab 83:801–806PubMedCrossRefGoogle Scholar
  19. Resmini E, Farkas C, Murillo B, Barahona MJ, Santos A, Martinez-Momblan MA, Roig O, Ybarra J, Geli C, Webb SM (2010) Body composition after endogenous (Cushing's syndrome) and exogenous (rheumatoid arthritis) exposure to glucocorticoids. Horm Metab Res 42:613–618PubMedCrossRefGoogle Scholar
  20. Sapolsky RM, Uno H, Rebert CS, Finch CE (1990) Hippocampal damage associated with prolonged glucocorticoid exposure in primates. J Neurosci 10:2897–2902PubMedGoogle Scholar
  21. Seeman TE, Singer BH, Rowe JW, Horwitz RI, McEwen BS (1997) Price of adaptation–allostatic load and its health consequences. MacArthur studies of successful aging. Arch Intern Med 157:2259–2268PubMedCrossRefGoogle Scholar
  22. Taicher GZ, Tinsley FC, Reiderman A, Heiman ML (2003) Quantitative magnetic resonance (QMR) method for bone and whole-body-composition analysis. Anal Bioanal Chem 377:990–1002PubMedCrossRefGoogle Scholar
  23. Tauchmanova L, Rossi R, Biondi B, Pulcrano M, Nuzzo V, Palmieri EA, Fazio S, Lombardi G (2002) Patients with subclinical Cushing's syndrome due to adrenal adenoma have increased cardiovascular risk. J Clin Endocrinol Metab 87:4872–4878PubMedCrossRefGoogle Scholar
  24. Vermeer H, Hendriks-Stegeman BI, van der Burg B, van Buul-Offers SC, Jansen M (2003) Glucocorticoid-induced increase in lymphocytic FKBP51 messenger ribonucleic acid expression: a potential marker for glucocorticoid sensitivity, potency, and bioavailability. J Clin Endocrinol Metab 88:277–284PubMedCrossRefGoogle Scholar
  25. Wochnik GM, Ruegg J, Abel GA, Schmidt U, Holsboer F, Rein T (2005) FK506-binding proteins 51 and 52 differentially regulate dynein interaction and nuclear translocation of the glucocorticoid receptor in mammalian cells. J Biol Chem 280:4609–4616PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Richard S. Lee
    • 1
  • Kellie L. K. Tamashiro
    • 1
  • Xiaoju Yang
    • 3
  • Ryan H. Purcell
    • 1
  • Yuqing Huo
    • 1
  • Michael Rongione
    • 1
  • James B. Potash
    • 1
    • 2
  • Gary S. Wand
    • 3
  1. 1.Department of Psychiatry and Behavioral SciencesJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Center for EpigeneticsJohns Hopkins University School of MedicineBaltimoreUSA
  3. 3.Department of MedicineJohns Hopkins University School of MedicineBaltimoreUSA

Personalised recommendations