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USP9X as a Candidate Mediator of Prenatal Aspirin-Induced Ovarian Reserve Reduction in Offspring Mice
Yating Li1,2, Caiyun Ge3,4, Wai Yen Yim5
1Department of Obstetrics and Gynaecology, Zhongnan Hospital of Wuhan University, Wuhan, China.
Insights
Prenatal aspirin exposure (PAE) in mice reduced ovarian reserve by epigenetically silencing Usp9x, impacting the HIF1α/NOBOX pathway. This highlights potential risks of gestational aspirin use for female offspring
Area of Science:
- Reproductive Biology
- Developmental Toxicology
- Epigenetics
Background:
- Aspirin is commonly used during pregnancy.
- Potential adverse effects of prenatal aspirin exposure (PAE) on fetal development are a concern.
- The impact of PAE on ovarian reserve in female offspring requires investigation.
Purpose of the Study:
- To investigate the effects of PAE on ovarian reserve in female offspring.
- To elucidate the molecular mechanisms underlying PAE-induced ovarian dysfunction.
- To identify potential therapeutic targets for mitigating PAE's effects.
Main Methods:
- Pregnant mice were administered varying doses of aspirin.
- Ovarian morphology and function were assessed across developmental stages.
- Transcriptomic analysis identified key molecular pathways involved.
- In vitro studies confirmed the role of the USP9X-HIF1α-NOBOX pathway.
- HDAC1 activity and epigenetic modifications were examined.
Main Results:
- PAE (specifically at 20 mg/kg·d) significantly reduced follicle counts and impaired ovulation in adult female offspring.
- Usp9x was consistently downregulated in response to PAE, correlating with suppressed HIF1α/NOBOX signaling.
- Aspirin exposure increased HDAC1 activity, leading to epigenetic silencing of Usp9x via reduced H3K27ac marks at its promoter.
- HDAC1 inhibition or knockdown restored Usp9x expression and rescued ovarian development.
Conclusions:
- PAE reduces ovarian reserve in female offspring through HDAC1-mediated epigenetic silencing of Usp9x.
- The disruption of the USP9X-HIF1α-NOBOX pathway is a key mechanism underlying PAE's adverse effects on ovarian reserve.
- Findings inform the gestational safety of aspirin and suggest therapeutic strategies for fetal-origin ovarian disorders.
Abstract:
Aspirin, widely used during pregnancy to prevent complications, may adversely affect fetal development. This study investigates prenatal aspirin exposure (PAE) on ovarian reserve in female offspring. Pregnant mice received aspirin (5, 10, and 20 mg/kg·d) from gestational days 918. Morphological and functional analyses of ovaries across prenatal to postnatal stages revealed PAE (20 mg/kg·d) reduced primordial and antral follicle counts, increased follicular atresia, and impaired ovulation in adulthood. Transcriptomics identified sustained downregulation of Usp9x as a potential mediator, which correlated with suppression of the HIF1α/NOBOX signaling axis. Mechanistically, our data suggest that aspirin exposure is associated with increased HDAC1 activity and enrichment of HDAC1 at the Usp9x promoter, accompanied by a reduction of H3K27ac marks, thereby potentially epigenetically silencing Usp9x expression. This enhanced HIF1α ubiquitination and degradation, ultimately attenuating NOBOX-mediated transcriptional regulation of downstream follicular genes. Using in vitro fetal ovarian cultures and NIH3T3 cells, we confirmed aspirin's disruption of primordial follicle assembly via the USP9X-HIF1α-NOBOX pathway. Crucially, HDAC1 knockdown or pharmacological inhibition rescued USP9X expression and restored follicular development. Our findings indicate that PAE reduces ovarian reserve through HDAC1-linked epigenetic silencing of Usp9x, exacerbating HIF1α/NOBOX pathway dysfunction, thereby informing aspirin's gestational safety and future interventions for fetal-origin ovarian disorders.
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