Exposure to Progestin 17-OHPC Induces Gastrointestinal Dysfunction through Claudin-1 Suppression in Female Mice with Increased Anxiety-Like Behaviors

Abstract

Plain Language SummaryProgestin is commonly used in oral contraceptives and for preventing preterm birth, but it exhibits various off-target side effects on brain and gastrointestinal (GI) function, the full extent of which remains largely unclear. In this study, we investigate the potential impact of progestin on the GI function in female mice with anxiety-like behaviors. Our findings reveal that exposure to the progestin 17-hydroxyprogesterone caproate (17-OHPC) suppresses the expression of claudin-1 (CLDN1) through epigenetic modifications and the dissociation of the vitamin D receptor (VDR) from the CLDN1 promoter. Additionally, 17-OHPC exposure exacerbates oxidative stress and the release of pro-inflammatory cytokines. Partial VDR deficiency in the intestine partly replicates the enhanced intestinal permeability and altered gut microbiota induced by 17-OHPC, though it has minimal effect on the anxiety-like behaviors triggered by 17-OHPC in female mice. In summary, progestin 17-OHPC suppresses CLDN1 expression via epigenetic alterations, contributing to GI dysfunction, distinct from progestin-induced anxiety-like behaviors. This sheds light on a novel mechanism and potential side effect of progestin exposure on GI system, alongside eliciting anxiety-like behaviors in female mice.