title: Maternal smoking during pregnancy and infant stress response: test of a prenatal programming hypothesis.
abstract: BACKGROUND
  Maternal smoking during pregnancy (MSDP) is associated with early and long-term neurobehavioral deficits; however mechanisms remain unknown. We tested the hypothesis that MSDP programs the hypothalamic pituitary adrenocortical (HPA) axis of the offspring leading to adverse outcomes. In an intensive, prospective study, we investigated associations between MSDP and infant cortisol stress response and explored whether alterations in cortisol response were mediated by epigenetic modulation of the placental glucocorticoid receptor gene (NR3C1).
  
  
  METHODS
  Participants were 100 healthy mother-infant pairs (53% MSDP-exposed; 42% female) from a low income, racially/ethnically diverse sample (55% minorities). MSDP was assessed by timeline followback interview verified by saliva and meconium cotinine. Infant cortisol responses to a neurobehavioral exam were assessed seven times over the first postnatal month. Methylation of placental NR3C1 promoter exon 1F was assessed using bisulfite pyrosequencing in a subsample (n=45).
  
  
  RESULTS
  MSDP-exposed infants showed significantly and persistently attenuated basal and reactive cortisol levels over the first postnatal month vs. unexposed infants. Exploratory analyses revealed that MSDP was associated with altered methylation of the placental NR3C1 promoter; degree of methylation of the placental NR3C1 was associated with infant basal and reactive cortisol over the first postnatal month and mediated effects of MSDP on infant basal cortisol.
  
  
  CONCLUSIONS
  Results provide initial support for our hypothesis that MSDP programs offspring HPA (dys)regulation. Epigenetic regulation of placental GR may serve as a novel underlying mechanism. Results may have implications for delineating pathways to adverse outcomes from MSDP.
authors.affiliation: Department of Psychiatry and Human Behavior, Warren Alpert Medical School, Brown University, Providence, RI 02906, United States; Centers for Behavioral and Preventive Medicine, The Miriam Hospital, Providence, RI 02906, United States. Electronic address: Laura_Stroud@brown.edu.
authors.forename: Laura R
authors.initials: LR
authors.lastname: Stroud
authors.affiliation: Department of Biostatistics, School of Public Health, Brown University, Providence, RI 02903, United States.
authors.forename: George D
authors.initials: GD
authors.lastname: Papandonatos
authors.affiliation: Department of Public Health and Nutrition, School of Nursing and Health Sciences, La Salle University, Philadelphia, PA 19141, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rodriguez
authors.affiliation: Department of Psychology, Emory University, Atlanta, GA 30322, United States.
authors.forename: Meaghan
authors.initials: M
authors.lastname: McCallum
authors.affiliation: Department of Psychiatry and Human Behavior, Warren Alpert Medical School, Brown University, Providence, RI 02906, United States; Department of Pediatrics, Warren Alpert Medical School, Brown University, Providence, RI 02903, United States; Women & Infants' Hospital of Rhode Island, Providence, RI 02905, United States.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Salisbury
authors.affiliation: Women & Infants' Hospital of Rhode Island, Providence, RI 02905, United States; Department of Obstetrics and Gynecology, Warren Alpert Medical School, Brown University, Providence, RI 02905, United States.
authors.forename: Maureen G
authors.initials: MG
authors.lastname: Phipps
authors.affiliation: Department of Psychiatry and Human Behavior, Warren Alpert Medical School, Brown University, Providence, RI 02906, United States; Department of Pediatrics, Warren Alpert Medical School, Brown University, Providence, RI 02903, United States; Women & Infants' Hospital of Rhode Island, Providence, RI 02905, United States.
authors.forename: Barry
authors.initials: B
authors.lastname: Lester
authors.affiliation: Chemistry and Drug Metabolism, Intramural Research Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, United States.
authors.forename: Marilyn A
authors.initials: MA
authors.lastname: Huestis
authors.affiliation: Schroeder Institute for Tobacco Research and Policy Studies, American Legacy Foundation, Washington, DC 20036, United States.
authors.forename: Raymond
authors.initials: R
authors.lastname: Niaura
authors.affiliation: Department of Pediatrics, Warren Alpert Medical School, Brown University, Providence, RI 02903, United States; Women & Infants' Hospital of Rhode Island, Providence, RI 02905, United States.
authors.forename: James F
authors.initials: JF
authors.lastname: Padbury
authors.affiliation: Department of Pharmacology and Toxicology, Dartmouth University, Hanover, NH 03755, United States.
authors.forename: Carmen J
authors.initials: CJ
authors.lastname: Marsit
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D019175:DNA Methylation; D047108:Embryonic Development / Q000235:genetics; D044127:Epigenesis, Genetic / Q000502:physiology; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007231:Infant, Newborn; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011248:Pregnancy Complications / Q000378:metabolism / Q000503:physiopathology* / Q000523:psychology; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism / Q000503:physiopathology* / Q000523:psychology; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects* / Q000378:metabolism / Q000503:physiopathology; D013312:Stress, Physiological / Q000235:genetics; D055815:Young Adult
chemical_list: C497713:NR3C1 protein, human; D011965:Receptors, Glucocorticoid; D006854:Hydrocortisone
keywords: Cortisol; Epigenetic; Infant; NR3C1; Placenta; Pregnancy; Programming; Smoking; Stress; Tobacco