Fetal hypoxia exposure induced Hif1a activation and autophagy in adult ovary granulosa cells

生物 HIF1A型 自噬 缺氧(环境) 胎儿 卵巢 细胞生物学 男科 内科学 内分泌学 癌症研究 细胞凋亡 怀孕 氧气 血管生成 医学 生物化学 遗传学 化学 有机化学
作者
Luyao Zhang,Ke Zhang,Xi Zhao,Hai-Ping Tao,Gongxue Jia,You-Gui Fang,Yunpeng Hou,Qi‐En Yang
出处
期刊:Biology of Reproduction [Oxford University Press]
卷期号:111 (6): 1220-1234 被引量:1
标识
DOI:10.1093/biolre/ioae141
摘要

Abstract Environmental hypoxia adversely impacts the reproduction of humans and animals. Previously, we showed that fetal hypoxia exposure led to granulosa cell (GC) autophagic cell death via the Foxo1/Pi3k/Akt pathway. However, the upstream regulatory mechanisms underlying GC dysfunction remain largely unexplored. Here, we tested the hypothesis that fetal hypoxia exposure altered gene expression programs in adult GCs and impaired ovarian function. We established a fetal hypoxia model in which pregnant mice were maintained in a high-plateau hypoxic environment from gestation day (E) 0–16.5 to study the impact of hypoxia exposure on the ovarian development and subsequent fertility of offspring. Compared with the unexposed control, fetal hypoxia impaired fertility by disordering ovarian function. Specifically, fetal hypoxia caused mitochondrial dysfunction, oxidant stress, and autophagy in GCs in the adult ovary. RNA sequencing analysis revealed that 437 genes were differentially expressed in the adult GCs of exposed animals. Western blotting results also revealed that fetal exposure induced high levels of hypoxia-inducible factor 1-alpha (Hif1a) expression in adult GCs. We then treated granulosa cells isolated from exposed mice with PX-478, a specific pharmacological inhibitor of Hif1a, and found that autophagy and apoptosis were effectively alleviated. Finally, by using a human ovarian granulosa-like tumor cell line (KGN) to simulate hypoxia in vitro, we showed that Hif1a regulated autophagic cell death in GCs through the Pi3k/Akt pathway. Together, these findings suggest that fetal hypoxia exposure induced persistent Hif1a expression, which impaired mitochondrial function and led to autophagic cell death in the GCs of the adult ovary.
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