2. Academic Validation
  3. Disruption of ovarian function and induction of apoptosis in female mice by Brefeldin A: Mechanistic insights into reproductive toxicity

Disruption of ovarian function and induction of apoptosis in female mice by Brefeldin A: Mechanistic insights into reproductive toxicity

  • Animal Model Exp Med. 2025 Nov 11. doi: 10.1002/ame2.70102.
Yao Jiang 1 2,  Meng Lv 3 4,  Haidan Fan 3,  Yonghua Shi 3 5,  Tao Wang 6,  Penghao Wang 1,  Xiaolong Yuan 1 2 3,  Fei Gao 5,  Bin Ma 1 2
Affiliations

Affiliations

  • 1 School of Medical, Molecular and Forensic Sciences, Murdoch University, Murdoch, Western Australia, Australia.
  • 2 Centre for Healthy Ageing, Health Futures Institute, Murdoch University, Murdoch, Western Australia, Australia.
  • 3 State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Laboratory of Lingnan Modern Agriculture, National Engineering Research Center for Breeding Swine Industry, Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China.
  • 4 Sun Yat-sen University Cancer Center, Sun Yat-sen University, Zhongshan, Guangdong, China.
  • 5 Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, Guangdong, China.
  • 6 Cancer Center, The Kids Research Institute Australia, Nedlands, Western Australia, Australia.
PMID: 41216763 DOI: 10.1002/ame2.70102
Abstract

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.

Keywords

Brefeldin A; SIRT1/SIRT6; follicular development; oocyte maturation; ovary; reproductive toxicity.

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