Fertility impairment by maternal stress: impact of cortisol on oviduct epithelium functions | Beeinträchtigung der Fruchtbarkeit durch maternalen Stress: Auswirkungen von Cortisol auf die Funktionen des Eileiterepithels

In both humans and animals, severe maternal stress and elevation of the stress hormone cortisol have been linked to reduced fertility. As a pivotal reproductive organ, the oviduct provides a suitable microenvironment for the maturation of gametes and early embryonic development. The early embryo is especially vulnerable to maternal health problems, including stress. Although many studies have demonstrated that reproductive function is impaired at multiple levels due to severe or prolonged maternal stress-activated HPA axis, the direct and local actions of the stress hormone cortisol on the oviduct epithelium are not yet fully understood. The aim of this study was to explore the potential effects of cortisol on the oviduct epithelium. First, porcine primary oviduct epithelial cells were cultured and differentiated using the ALI culture model to replicate the native oviduct epithelium in vivo. To investigate the effect of long-term stress on the oviduct epithelium, physiological levels of cortisol representing moderate and severe stress in pigs were administered basolaterally for long-term (21 d). The expression of GR pathway-related genes in POEC was activated in response to cortisol treatment. Even though long-term exposure to cortisol had no effect on the overall morphology of the oviduct epithelium, the barrier function and mRNA expression of genes regulating oviduct function and immune response were modified by cortisol. Additionally, the in vitro oviduct epithelium constantly metabolized cortisol to biologically inactive cortisone, suggesting that the oviduct epithelium is able to modulate the hormonal environment of the oviduct even under the condition of chronic repeated stress. Second, individual (cortisol, E2, P4) or combined (cortisol/E2, cortisol/P4) hormone stimulation was applied for 12 h and 72 h, and the morphological, bioelectrical, and transcriptional profile of the cultures were assessed to explore the specific effects of ovarian steroid hormones (i.e., E2 and P4) and the hormonal interactions between cortisol and ovarian steroid hormones. The results suggest that individual E2 and P4 have primary and complex effects on the function of the oviduct epithelium, and P4 is one of the driving force to regulate the morphological modification. In addition, E2 and P4 induced transcriptional regulation of genes involved in cortisol signaling (NR3C1, FKBP5, and TSC22D3), implying that ovarian steroid hormones affect cortisol action on oviduct epithelial cells. Cortisol, in turn, not only directly induces changes in the bioelectrical properties and gene expression of oviduct epithelial cells, but also appears to affect the response of cells to ovarian steroid hormones at the morphological, functional, and gene expression levels by altering the corresponding receptor-dependent signal transduction. In summary, the results of the present study in pigs suggest that the oviduct epithelium is capable of regulating the hormonal environment of the oviduct and limiting the luminal accumulation of stress hormone cortisol under stressed conditions. The cortisol exposure not only affected the function of the oviduct epithelium directly but also modified the E2- and P4-induced regulation of oviduct epithelium functions. This implies indirect effects on the dynamic control of the oviductal microenvironment, which is essential for proper gamete maturation and especially early embryonic development. Thus, perturbation of the fine-tuned interplay between cortisol and sex steroids in the regulation of oviduct epithelium functions may be one of the mechanism by which an elevated maternal cortisol level contributes to the stress-induced impairment of fertility in pigs.