title: A measure of glucocorticoid load provided by DNA methylation of Fkbp5 in mice.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Lee
authors.forename: Kellie L K
authors.initials: KL
authors.lastname: Tamashiro
authors.forename: Xiaoju
authors.initials: X
authors.lastname: Yang
authors.forename: Ryan H
authors.initials: RH
authors.lastname: Purcell
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Huo
authors.forename: Michael
authors.initials: M
authors.lastname: Rongione
authors.forename: James B
authors.initials: JB
authors.lastname: Potash
authors.forename: Gary S
authors.initials: GS
authors.lastname: Wand
mesh_terms: D000818:Animals; D003345:Corticosterone / Q000008:administration & dosage* / Q000097:blood; D019175:DNA Methylation / Q000187:drug effects*; D050152:Intra-Abdominal Fat / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000235:genetics*; D000099159:Tacrolimus Binding Protein 5
chemical_list: D003345:Corticosterone; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5