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Updated: Jun 25, 2025
Author Spotlight: Investigating the Mechanisms and Inducing Models of Polycystic Ovary Syndrome
Published on: July 5, 2024
Omaveloxolone Prevents Polystyrene Microplastic-Induced Ovarian Granulosa Cell Apoptosis via the Keap1/Nrf2/HO-1
1Department of Gynaecology, Harbin Medical University Cancer Hospital, No.150, Haping Road, Nangang District, Harbin, Heilongjiang, 150081, China. libingjn331@163.com.
Abstract:
Microplastics (MPs) are persistent environmental pollutants that enter the circulatory system and subsequently reduce sperm quantity and quality. However, the influence of polystyrene MPs (PS-MPs) on the ovary and relevant mechanisms remain elusive. Herein, we aimed to examine the impact of PS-MPs on oxidative disorders in ovarian tissues and elucidate the underlying mechanisms. Healthy female rats were treated with different concentrations of 0.5 µm PS-MPs (diluted in deionized H2O) for 90 days. Upon examination of hematoxylin-eosin-stained ovarian tissue sections, the number of growing follicles was reduced in PS-MP-treated rats when compared with that in control rats. Enzyme-linked immunosorbent assays revealed that PS-MP exposure markedly reduced anti-Müllerian hormone (AMH) levels. Treatment with PS-MPs downregulated superoxide dismutase, glutathione, and catalase activities in ovarian tissues while upregulating malondialdehyde levels. Furthermore, exposure to PS-MP blocked the Keap1/Nrf2/HO-1 signal transduction pathway. PS-MPs also triggered apoptosis in the ovarian tissue, as evidenced by increased TUNEL staining and expression levels of cleaved caspase-9, Bax, and Bcl-2. To reactivate the Keap1/Nrf2/HO-1 pathway, rats were co-administered PS-MPs and omaveloxolone (Oma), an Nrf2 activator, for 1 week. We found that Oma could counteract the PS-MP-mediated effects on oxidative disorder, apoptosis, AMH production, and follicle number in rat ovarian tissues. To develop an in vitro model, granulosa cells (GCs) were treated with 10 μM H2O2 for 12 h to induce oxidative stress. H2O2-stimulated GCs exhibited attenuated cell growth and upregulated apoptosis and oxidative stress. Oma administration could ameliorate the H2O2-induced effects in terms of regulating cell viability, apoptosis, and oxidative stress in GCs. In summary, PS-MPs could induce apoptosis and oxidative stress via the Keap1/Nrf2/HO-1 signaling pathway in both rats and GCs.
Insights
Polystyrene microplastics (PS-MPs) harm ovarian function by causing oxidative stress and apoptosis, impacting follicle count and AMH levels. An Nrf2 activator, omaveloxolone, can counteract these detrimental effects.
Area of Science:
- Environmental Toxicology
- Reproductive Biology
- Cellular Mechanisms
Background:
- Microplastics (MPs) are pervasive environmental pollutants with known reproductive toxicity.
- The specific impact of polystyrene microplastics (PS-MPs) on ovarian tissues and the underlying mechanisms are not well understood.
- Investigating PS-MPs' effects on ovarian oxidative stress and apoptosis is crucial for understanding reproductive health risks.
Purpose of the Study:
- To investigate the effects of PS-MPs on oxidative stress and apoptosis in rat ovarian tissues.
- To elucidate the molecular mechanisms, specifically the Keap1/Nrf2/HO-1 signaling pathway, involved in PS-MP-induced ovarian damage.
- To evaluate the therapeutic potential of omaveloxolone (Oma), an Nrf2 activator, in mitigating PS-MP toxicity in ovarian tissues and granulosa cells.
Main Methods:
- Female rats were exposed to varying concentrations of 0.5 µm PS-MPs for 90 days.
- Ovarian tissues were analyzed for follicle count, anti-Müllerian hormone (AMH) levels, oxidative stress markers (superoxide dismutase, glutathione, catalase, malondialdehyde), apoptosis (TUNEL, cleaved caspase-9, Bax, Bcl-2), and the Keap1/Nrf2/HO-1 pathway.
- An in vitro model using granulosa cells (GCs) exposed to hydrogen peroxide (H2O2) was used to mimic oxidative stress, with co-administration of Oma to assess its protective effects.
Main Results:
- PS-MP exposure significantly reduced growing follicle numbers and AMH levels in rats.
- PS-MPs induced oxidative stress by decreasing antioxidant enzyme activities and increasing lipid peroxidation, while also triggering apoptosis in ovarian tissues.
- PS-MPs inhibited the Keap1/Nrf2/HO-1 pathway; omaveloxolone treatment reversed these effects, restoring ovarian function and protecting GCs from H2O2-induced damage.
Conclusions:
- Polystyrene microplastics induce ovarian oxidative stress and apoptosis through the Keap1/Nrf2/HO-1 signaling pathway in female rats.
- PS-MP exposure negatively impacts key reproductive parameters, including follicle development and AMH production.
- Omaveloxolone demonstrates significant potential in ameliorating PS-MP-induced reproductive toxicity by reactivating the Nrf2 pathway.
