DOI: 10.1002/ame2.70102
Disruption of ovarian function and induction of apoptosis in female mice by Brefeldin A:Mechanistic insights into reproductive toxicity
Yao Jiang1
Meng Lv2
Haidan Fan3
Yonghua Shi4
Tao Wang5
Penghao Wang6
Xiaolong Yuan7
Fei Gao8
Bin Ma1
1.Cancer Center,The Kids Research Institute Australi2.School of Medical,Molecular and Forensic Sciences,3.School of Medical,Molecular and Forensic Sciences,4.Shenzhen Branch,Guangdong Laboratory for Lingnan M5.School of Medical,Molecular and Forensic Sciences,6.State Key Laboratory of Swine and Poultry Breeding7.State Key Laboratory of Swine and Poultry Breeding8.State Key Laboratory of Swine and Poultry Breeding
摘要：Background:The investigation of ovarian development,dysfunction,and aging is essential for female reproductive health.Despite extensive research on the cellular functions of Brefeldin A(BFA)as an intracellular transport inhibitor,its specific effects and mechanisms on ovarian development/aging remain inadequately understood.
Methods:Mice and porcine oocytes/granulosa cells(GCs)were treated with BFA.Morphological and omics analyses(including Western blot,real-time polymerase chain reaction(RT-PCR),transcriptomics,and metabolomics)were conducted.
Results:In 3-week-old female mice,BFA treatment significantly suppressed oocyte maturation,induced apoptosis,and increased estradiol and LH levels.This treatment upregulated apoptosis-related genes while downregulating proliferation-associated genes.Additionally,BFA elevated senescence markers(p21 and p26)and decreased the activity of the longevity gene SIRT6.In porcine oocytes,BFA reduced the maturation rate and lowered mRNA levels of key maturation-related genes,LHX8 and GDF9.In porcine GCs,BFA increased apoptosis and upregulated genes such as Caspase-3,BAX,and P21,while downregulating genes associated with proliferation and longevity.Similar effects were observed in 12-month-old female mice,indicating consistency across age groups.Metabolomic analysis in these mice revealed that BFA primarily impacted pathways related to steroid biosynthesis,ovarian steroidogenesis,and estrogen signaling.Transcriptomic analysis in 12-month-old female mice further demonstrated that BFA disrupted ovarian function through multiple mechanisms,including modulation of the GnRH signaling pathway,activation of the FOXO pathway,and interference with meiosis-related gene expression.
Conclusion:Our findings are pivotal for advancing the understanding of ovarian aging,dysfunctions,and diseases,and ultimately facilitate addressing BFA's potential adverse effects on reproductive health/aging.
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论文发表日期：2025-11-30
在线出版日期：2026-01-09（本平台首次上网日期，不代表文献的发表时间）
页数：16( 2053-2068 )
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