Chronic prenatal stress epigenetically modifies spinal cordBDNFexpression to induce sex‐specific visceral hypersensitivity in offspring

Abstract

Background Irritable bowel syndrome (IBS) is a heterogeneous disorder with abdomen 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 events. 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 CPS 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. CPS 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. Conclusion & Inferences The development of visceral hypersensitivity, 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.

Prenatal stress induces spatial memory deficits and epigenetic changes in the hippocampus indicative of heterochromatin formation and reduced gene expression

“…This effect is notable in that previous studies have not examined the effects of PNS on histone acetylation in the brains of adult offspring. However, these data are consistent with one study showing that PNS increased histone H3 acetylation in a specific Bdnf promoter in the spinal cord dorsal horn of female, but not male, rat offspring [51]. The larger decrease in histone acetylation in PNS females is consistent with our other finding that levels of the maintenance methyltransferase DNMT1 are increased by PNS in females only.…”

Sex- and corticotropin-releasing factor receptor 2- dependent actions of urocortin 1 during inflammation

“…Males and females have different stress responses, which, among other reasons, are due to sex steroids or differences in corticosteroid-binding globulin levels, which can modulate activation of the hypothalamic-pituitary-adrenal axis (36). Chronic prenatal stress has been shown to exacerbate visceral hypersensitivity and upregulates brain-derived neurotrophic factor in female, but not male, offspring (62). Our findings provide strong evidence for involvement of the CRF system in mediating sex-specific responses.…”

Repeated Water Avoidance Stress Alters Mucosal Mast Cell Counts, Interleukin-1β Levels with Sex Differences in the Distal Colon of Wistar Rats

“…20 So far, several studies have focused on sex-specific stress response and visceral hypersensitivity. [21][22][23][24][25][26] To our knowledge, the sex-related differences between all kinds of parameters have not been fully described in a single report. Therefore, we aimed to elucidate differences in colonic movement, mucosal mast cell counts, cytokine levels, and visceral sensitivities between the 2 sexes in a stress rat model.…”