PMID- 24588943 OWN - NLM STAT- MEDLINE DCOM- 20141216 LR - 20220318 IS - 1365-2982 (Electronic) IS - 1350-1925 (Print) IS - 1350-1925 (Linking) VI - 26 IP - 5 DP - 2014 May TI - Chronic prenatal stress epigenetically modifies spinal cord BDNF expression to induce sex-specific visceral hypersensitivity in offspring. PG - 715-30 LID - 10.1111/nmo.12326 [doi] AB - 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. KEY 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 & INFERENCES: 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. CI - (c) 2014 John Wiley & Sons Ltd. FAU - Winston, J H AU - Winston JH AD - 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. FAU - Li, Q AU - Li Q FAU - Sarna, S K AU - Sarna SK LA - eng GR - R01 DK088796/DK/NIDDK NIH HHS/United States GR - 5R01DK088796/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20140304 PL - England TA - Neurogastroenterol Motil JT - Neurogastroenterology and motility JID - 9432572 RN - 0 (Brain-Derived Neurotrophic Factor) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/genetics/*metabolism MH - Colon/metabolism MH - *Epigenesis, Genetic MH - Female MH - Hyperalgesia/genetics/*metabolism MH - Male MH - Pregnancy MH - Rats MH - Rats, Sprague-Dawley MH - Sex Characteristics MH - Spinal Cord/*metabolism MH - Stress, Physiological/*physiology MH - Stress, Psychological/genetics/*metabolism MH - Up-Regulation MH - Visceral Pain/genetics/*metabolism PMC - PMC3997587 MID - NIHMS566432 OTO - NOTNLM OT - BDNF OT - chronic stress OT - functional bowel disorders OT - iritable bowel syndrome OT - visceral hypersnsitivity COIS- Each author has read the final manuscript and approved it. No author has any conflict of interest. EDAT- 2014/03/05 06:00 MHDA- 2014/12/17 06:00 PMCR- 2015/05/01 CRDT- 2014/03/05 06:00 PHST- 2013/09/24 00:00 [received] PHST- 2014/02/01 00:00 [accepted] PHST- 2014/03/05 06:00 [entrez] PHST- 2014/03/05 06:00 [pubmed] PHST- 2014/12/17 06:00 [medline] PHST- 2015/05/01 00:00 [pmc-release] AID - 10.1111/nmo.12326 [doi] PST - ppublish SO - Neurogastroenterol Motil. 2014 May;26(5):715-30. doi: 10.1111/nmo.12326. Epub 2014 Mar 4.