Department of Biological Sciences, University of Calgary, 2500 University Drive NW, Calgary, Alberta, Canada T2N 1N4.
Laboratório de Processamento de Tecidos, Universidade Federal de São João Del Rei, Avenida Sebastião Gonçalves Coelho, 400 - Chanadour, CEP: 35.501-296 - Divinópolis/MG, Brazil.
Proc Biol Sci. 2020 Dec 9;287(1940):20202190. doi: 10.1098/rspb.2020.2190. Epub 2020 Dec 2.
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 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.
中年女性生殖能力下降是衰老过程中的一个既定表型。压力和糖皮质激素 (GCs) 的增加加速了生殖衰老，但涉及的机制知之甚少。在压力下，GCs 激活糖皮质激素受体 (GR)，一种广泛表达的配体结合转录因子，引发生理变化以恢复体内平衡。在这里，我们测试了 GC-GR 信号对于加速生殖衰老至关重要的假设。为了验证这一点，我们使用了一种普遍存在的 GR 敲除 (GRKO) 斑马鱼，这种斑马鱼固有的皮质醇水平升高，以阐明高皮质醇和 GR 信号对生殖衰老的作用。GR 的缺失导致卵巢过早衰老，包括卵黄发生卵母细胞中典型和非典型卵泡闭锁的高频、卵黄液化和大的炎症浸润。与早期成年 GRKO 和成年野生型斑马鱼相比，成年 GRKO 鱼卵巢中的表达减少也与卵母细胞质量下降有关。加速的卵巢衰老也影响后代，包括成年 GRKO 鱼的繁殖成功率、繁殖力、卵受精率以及体节形成和胚胎存活延迟降低。我们推断，GR 信号对于延长斑马鱼的生殖寿命以及提高卵子质量和胚胎活力是必不可少的。
