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Updated: Oct 1, 2025
Biochemical Measurement of Neonatal Hypoxia
Published on: August 24, 2011
Hypo-Hydroxymethylation of Nobox is Associated with Ovarian Dysfunction in Rat Offspring Exposed to Prenatal Hypoxia
Changfang Yao1,2, Likui Lu3, Yiting Ji1
1Reproductive Medicine Center of the First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, China.
Insights
Prenatal hypoxia impairs ovarian development in rat offspring by reducing Nobox gene hydroxymethylation. This epigenetic change leads to ovarian dysfunction, mimicking human conditions.
Area of Science:
- Reproductive Biology
- Developmental Biology
- Epigenetics
Background:
- Prenatal hypoxia (PH) is a critical environmental stressor impacting fetal development.
- The effects of PH on ovarian development and function remain incompletely understood.
- Investigating molecular mechanisms is crucial for understanding PH-induced reproductive issues.
Purpose of the Study:
- To investigate the impact of prenatal hypoxia on ovarian function in adult rat offspring.
- To elucidate the underlying molecular and epigenetic mechanisms, focusing on the Nobox gene.
- To assess potential interventions for mitigating hypoxia-induced ovarian dysfunction.
Main Methods:
- Exposure of pregnant Sprague-Dawley rats to hypoxia (10.5% O2) from embryonic day 5 to 21.
- Assessment of ovarian function, estrous cycles, and hormone levels (AMH, FSH) in adult offspring.
- Analysis of Nobox, Gdf9, and Tets gene expression via qPCR and Western blot.
- Evaluation of global DNA hydroxymethylation and specific Nobox gene hydroxymethylation using dot blot and NGS methods.
- In vitro experiments with vitamin C to assess its effect on hydroxymethylation and Nobox expression.
Main Results:
- Prenatal hypoxia offspring exhibited reduced body and ovary weights, abnormal estrous cycles, decreased AMH, elevated FSH, and increased follicular atresia.
- Nobox gene expression was significantly downregulated in PH offspring.
- Reduced hydroxymethylation levels were observed in the Nobox gene promoter region in PH offspring.
- Hypoxia decreased 5-hydroxymethylcytosine (5hmC) and Nobox levels in cultured cells; vitamin C treatment rescued these effects.
Conclusions:
- Prenatal hypoxia induces ovarian dysfunction in rat offspring, characterized by impaired follicular development and hormonal imbalances.
- Epigenetic dysregulation, specifically hypo-hydroxymethylation of the Nobox gene, is a key mechanism linking PH to ovarian dysfunction.
- Vitamin C may offer a protective effect against PH-induced epigenetic changes and subsequent ovarian dysfunction.
Abstract:
Prenatal hypoxia (PH) is a common feature of a suboptimal intrauterine environment affecting the development of fetuses. Whether PH leads to abnormal ovary development is not yet clear. This study investigated ovarian function in offspring exposed to PH and the potential underlying molecular mechanisms. SD female rats (n = 12 per group) at 9 weeks of age were housed in individual cages (21% O2). After the pregnant rats were exposed to hypoxia (10.5% oxygen) from embryonic day (E) 5 to E21, PH offspring were generated. All animals maintained normoxia during lactation. The number of follicles was counted in female offspring at 3 months under an optical microscope. The expression of Nobox, Gdf9, and Tets was detected by quantitative real-time polymerase chain reaction (PCR) and Western blot. Global DNA hydroxymethylation was measured by dot blot. The hydroxymethylation level of the Nobox gene was evaluated with an NGS-based multiple targeted CpG hydroxymethylation analysis method. Body weight and ovary weight were significantly decreased in the PH group compared with the control group. PH offspring have abnormal estrous cycle, decreased serum anti-Mullerian hormone (AMH), and increased serum follicle-stimulating hormone (FSH), and follicular atresia, which are consistent with the clinical manifestations in patients with ovarian dysfunction. In terms of mechanism, the expression of Nobox was significantly decreased in the PH group. Subsequent high-throughput sequencing results showed that the level of hydroxymethylation in the candidate region of the Nobox gene was reduced. Cultured cells treated with hypoxia exhibited lower levels of both 5hmC and Nobox, while vitamin C, a coactivator of Tets, rescued hypo-hydroxymethylation and increased the expression level of Nobox. This study indicated that PH could cause hypo-hydroxymethylation of Nobox through epigenetic regulation and may consequently contribute to ovarian dysfunction in adult rat offspring.
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