Exposure to Progestin 17-OHPC Induces Gastrointestinal Dysfunction through Claudin-1 Suppression in Female Mice with...

Area of Science:

• Endocrinology
• Gastroenterology
• Neuroscience

Background:

• Progestins are widely used in contraception and preventing preterm birth.
• Off-target effects on brain and gastrointestinal (GI) functions are known but poorly understood.
• Precise mechanisms of progestin's impact on GI function and anxiety remain elusive.

Purpose of the Study:

• To investigate the impact of progestin 17-hydroxyprogesterone caproate (17-OHPC) on GI function and anxiety-like behaviors in female mice.
• To elucidate the molecular mechanisms underlying 17-OHPC's effects on the gut epithelium and brain.
• To explore the roles of vitamin D receptor (VDR) and estrogen receptor β (ERβ) in mediating these effects.

Main Methods:

• Utilized colon stem cells to study 17-OHPC's effect on claudin-1 (CLDN1) expression.
• Performed chromatin immunoprecipitation and luciferase assays to identify progestin-response elements on the CLDN1 promoter.
• Generated intestine-specific VDR deficient mice to assess GI dysfunction and anxiety-like behaviors.
• Analyzed gene expression in brain regions including the amygdala, hypothalamus, and hippocampus.

Main Results:

• 17-OHPC suppressed CLDN1 expression via epigenetic modifications and VDR dissociation from the CLDN1 promoter.
• 17-OHPC intensified oxidative stress and pro-inflammatory cytokine release.
• Intestinal VDR deficiency partly mimicked 17-OHPC-induced GI dysfunction but had minimal impact on anxiety-like behaviors.

Conclusions:

• 17-OHPC suppresses CLDN1 expression through VDR, contributing to GI dysfunction in female mice.
• The mechanism for GI dysfunction is distinct from that of 17-OHPC-induced anxiety-like behaviors.
• Revealed a novel mechanism of progestin's negative impact on the GI tract and its role in inducing anxiety-like behaviors.