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CC BY-NC V4.0, Open Access
Journal article
Disruption of ovarian function and induction of apoptosis in female mice by Brefeldin A: Mechanistic insights into reproductive toxicity
Animal models and experimental medicine, Early View
2025
PMID: 41216763
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.
Details
- Title
- Disruption of ovarian function and induction of apoptosis in female mice by Brefeldin A: Mechanistic insights into reproductive toxicity
- Authors/Creators
- Yao Jiang - Murdoch UniversityMeng Lv - South China Agricultural UniversityHaidan Fan - South China Agricultural UniversityYonghua Shi - Agricultural Genomics Institute at ShenzhenTao Wang - Keogh Institute for Medical ResearchPenghao Wang - Murdoch UniversityXiaolong Yuan - South China Agricultural UniversityFei Gao - Agricultural Genomics Institute at ShenzhenBin Ma - Murdoch University
- Publication Details
- Animal models and experimental medicine, Early View
- Publisher
- WILEY
- Number of pages
- 16
- Grant note
- 2024B03J1305 / Science and Technology Project of Guangzhou 2024A1515012999 / Guangdong Basic and Applied Basic Research Foundation 2024B1515020112 / Guangdong Basic and Applied Basic Research Foundation 2023A1515030054 / Guangdong Basic and Applied Basic Research Foundation
- Identifiers
- 991005828906407891
- Copyright
- © 2025 The Author(s).
- Murdoch Affiliation
- Centre for Crop and Food Innovation; School of Medical, Molecular and Forensic Sciences
- Language
- English
- Resource Type
- Journal article
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