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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

Subject Area Animal Breeding, Animal Nutrition, Animal Husbandry
Reproductive Medicine, Urology
Term from 2018 to 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 417759456
 
Final Report Year 2025

Final Report Abstract

The oviduct is a crucial reproductive organ in which highly sensitive early reproductive processes such as gamete maturation, fertilization, and early embryonic development take place. Maternal stress during this critical period has been associated with reduced fertility and negative reproductive outcomes in mammals. In response to stress, the hypothalamic– pituitary–adrenal (HPA) axis is activated, leading to an increased release of glucocorticoids (GCs) from the adrenal cortex. However, the local impact of elevated GCs on the oviduct remains largely unclear, with limited studies mainly from rodent species. This project investigated the cortisol-mediated regulation of oviductal physiology and underlying molecular mechanisms using a highly differentiated air–liquid interface (ALI) culture model of oviductal epithelial cells (OEC) from two complementary species, pigs and cattle. We discovered that the porcine oviductal epithelium has a strong capacity to metabolize cortisol, thereby limiting its apical diffusion, which could represent a protective mechanism for the early embryonic environment. Elevated cortisol levels, however, altered the structure and bioelectrical properties of the epithelium, with acute and chronic cortisol exposure triggering distinct, time-specific transcriptional responses. Additionally, maternal cortisol indirectly influences oviduct function by interfering with ovarian hormone signaling. While estrogen (E2) and progesterone (P4) exert a dominant role in regulating oviduct physiology, cortisol modulates these effects, particularly by altering E2-driven transcriptional regulations. We also conducted the first study into the local effects of chronically elevated cortisol levels on the oviduct epithelium in cattle, a monoovulatory species. Comparative analysis between bovine and porcine models revealed potential species-specific responses towards cortisol, which is likely attributed to the differential regulation of cortisol-metabolizing enzymes. Our analysis of extracellular vesicles (EVs) from the ALI system revealed that polarized oviduct epithelial cells preferentially release EVs via the apical cell pole. The ALI system generated EVs more efficiently than 2D submerged culture approaches and contained miRNA signatures closely matching that of EVs in vivo. Collectively, the findings from this project establish a foundational understanding of the regulatory mechanisms by which elevated cortisol levels (as a proxy for maternal stress) shape the oviductal environment, providing a basis for future research into species-specific reproductive resilience. We have so far published 6 peer-reviewed articles, 1 book chapter, and 4 additional publications are currently in progress.

Link to the final report

https://doi.org/10.4126/FRL01-006526382

Publications

 
 

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