Fertility impairment by maternal stress: Using a novel 3D in vitro system to decipher the impact of cortisol on oviduct epithelium physiology, oviduct-derived extracellular vesicles and early embryonic development

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The preimplantation period is considered to be a highly "sensitive window" during embryo development in mammals. Maternal exposure to stress, particularly during the transit phase of the embryo in the oviduct, exerts negative consequences on fertility and early embryonic development, most likely mediated by the oviduct epithelium. However, until now it remains unclear how stress hormones, i.e. glucocorticoids, locally regulate oviduct physiology, thereby altering the early embryonic environment. Extracellular vesicles (EVs) have recently been suggested as important mediators in the embryo-maternal crosstalk. Polarized cells e.g. oviduct epithelia, directionally release distinct EV populations on their luminal and basolateral cell surface, which cannot be mimicked using traditional 2D cell culture methods. We recently established a compartmentalized air-liquid interface (ALI) culture system for oviduct epithelial cells (OEC) from different species (mouse, pig and cattle). This system maintains the polarized differentiation of the epithelial cells, enables formation and acquisition of apical “oviductal fluid” and even embryonic development on the apical cell surface. In compliance with the 3R principle, in this project we will employ porcine and bovine ALI-OEC established from slaughterhouse by-products to study: 1) direct cortisol action on oviduct epithelium physiology; 2) the interplay of cortisol with ovarian steroid hormones regulating oviduct epithelium function throughout the estrous cycle; 3) the modification of oviduct-derived EVs in response to cortisol; 4) the effect of cortisol on the composition of the oviductal secretome and (as a consequence) on developing embryos. We will apply high-throughput “-omics” and integrative analyses at OEC, EV and embryo level to unveil the complex biological networks impacted by maternal cortisol excess. This project elucidates mechanisms of cortisol action on the early embryonic micro-environment, thereby offering profound insights into the connection between stress and infertility in mammals.