title: Chronic prenatal stress epigenetically modifies spinal cord BDNF expression to induce sex-specific visceral hypersensitivity in offspring.
abstract: BACKGROUND
  Irritable bowel syndrome (IBS) is a heterogeneous disorder with abdominal pain as one of the primary symptoms. The etiology of IBS remains unknown. Epidemiological studies found that a subset of these patients have a history of adverse early-life experiences. We tested the hypothesis that chronic prenatal stress (CPS) epigenetically enhances brain-derived neurotrophic factor (BDNF) in spinal cord to aggravate colon sensitivity to colorectal distension (CRD) differentially in male and female offspring.
  
  
  METHODS
  We used heterotypic intermittent chronic stress (HeICS) protocols in pregnant dams from E11 until delivery.
  
  
  RESULTS
  Chronic prenatal stress induced significant visceral hypersensitivity (VHS) to CRD in male and female offspring. A second exposure to HeICS in adult offspring exacerbated VHS greater in female offspring that persisted longer than in male offspring. Chronic prenatal stress upregulated BDNF expression in the lumbar-sacral dorsal horn that correlated with the exacerbation of VHS in female, but not in male offspring. The upregulation of BDNF was due to a significant increase in RNA Pol II binding, histone H3 acetylation, and significant decrease in histone deacetylase 1 association with the core promoter of BDNF in female offspring. Other chronic prenatal and neonatal stress protocols were less effective than HeICS.
  
  
  CONCLUSIONS
  The development of VHS, which contributes to the symptom of intermittent abdominal pain, is a two-step process, chronic in utero stress followed by chronic stress in adult-life. This two-step process induces aggravated and persistent colon hypersensitivity in female than in male offspring. Our preclinical model explains several clinical features in IBS patients.
authors.affiliation: Enteric Neuromuscular Disorders and Visceral Pain Center, Division of Gastroenterology, Department of Internal Medicine, The University of Texas Medical Branch at Galveston, Galveston, TX, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Winston
authors.forename: Q
authors.initials: Q
authors.lastname: Li
authors.forename: S K
authors.initials: SK
authors.lastname: Sarna
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D003106:Colon / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D006930:Hyperalgesia / Q000235:genetics / Q000378:metabolism*; D008297:Male; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D013116:Spinal Cord / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology*; D013315:Stress, Psychological / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D059265:Visceral Pain / Q000235:genetics / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor
keywords: BDNF; chronic stress; functional bowel disorders; iritable bowel syndrome; visceral hypersnsitivity