Placental epigenetic patterning of glucocorticoid response genes is associated with infant neurodevelopment.
OBJECTIVE
To determine associations between methylation of NR3C1, HSD11B2, FKBP5 and ADCYAP1R1 and newborn neurobehavioral outcomes.


METHODS
In 537 newborns, placental methylation was quantified using bisulfite pyrosequencing. Profiles of neurobehavior were derived via the Neonatal Intensive Care Unit Network Neurobehavioral Scales. Using exploratory factor analysis, the relationships between methylation factor scores and neurobehavioral profiles were examined.


RESULTS
Increased scores of the factor characterized by NR3C1 methylation were associated with membership in a reactive, poorly regulated profile (odds ratio: 1.47; 95% CI: 1.00-2.18), while increased scores of the factor characterized by HSD11B2 methylation reduced this risk.


CONCLUSIONS
These results suggest that coordinated regulation of these genes influences neurobehavior and demonstrates the importance of examining these alterations in a harmonized fashion.
Department of Pharmacology & Toxicology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
Alison G
AG
Paquette
Department of Pediatrics, Center for the Study of Children at Risk, Women & Infants Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA.
Barry M
BM
Lester
Department of Pharmacology & Toxicology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
Corina
C
Lesseur
Department of Pharmacology & Toxicology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
David A
DA
Armstrong
Department of Pharmacology & Toxicology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
Dylan J
DJ
Guerin
Department of Epidemiology & Biostatistics, University at Albany School of Public Health, Rensselaer, NY, USA.
Allison A
AA
Appleton
Department of Pharmacology & Toxicology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.|Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
Carmen J
CJ
Marsit
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics; D000293:Adolescent; D000328:Adult; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics*; D057890:Epigenomics / Q000379:methods*; D005260:Female; D005865:Gestational Age; D005938:Glucocorticoids / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D018730:Infant Behavior / Q000187:drug effects / Q000502:physiology; D007231:Infant, Newborn; D008297:Male; D008423:Maternal Age; D009420:Nervous System / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011965:Receptors, Glucocorticoid / Q000235:genetics; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000235:genetics; D012044:Regression Analysis; D022021:Tacrolimus Binding Proteins / Q000235:genetics; D055815:Young Adult; D000099159:Tacrolimus Binding Protein 5
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C495503:ADCYAP1R1 protein, human; C497713:NR3C1 protein, human; C468387:HSD11B2 protein, human
ADCYAP1R1; FKBP5; HSD11B2; NR3C1; fetal basis of adult disease; glucocorticoids; neurobehavior; placenta