Loss of the glucocorticoid receptor causes accelerated ovarian ageing in zebrafish: Cortisol resistance and ovarian aging

Abstract

Reproductive decline in mid-adult females is an established phenotype of the ageing process. Stress and the rise in glucocorticoids (GCs) accelerate reproductive ageing, but little is known about the mechanisms involved. During stress, GCs activate the glucocorticoid receptor (GR), a ubiquitously expressed, ligand-bound transcription factor, to elicit physiological changes for restoring homeostasis. Here, we tested the hypothesis that GC-GR signalling is essential for accelerating reproductive ageing. To test this, we used a ubiquitous GR knockout (GRKO) zebrafish, which is inherently hypercortisolemic, to delineate the role of high cortisol and GR signalling on reproductive ageing. The loss of GR led to premature ovarian ageing, including high frequency of typical and atypical follicular atresia in vitellogenic oocytes, yolk liquefaction and large inflammatory infiltrates. The reduction in oocyte quality was also associated with a decline in ovarian tert expression in the adult GRKO fish compared to the early adult GRKO and adult wild-type zebrafish. Accelerated ovarian ageing also impacted the progeny, including lower breeding success, fecundity, egg fertilization rate and delayed somitogenesis and embryo survival in the adult GRKO fish. We adduce that GR signalling is essential for prolonging the reproductive lifespan and improving the egg quality and embryo viability in zebrafish.