Cumulus cells mediate the protective effect of the marine carotenoid fucoxanthin against postovulatory oocyte aging via NRF2 signaling
Fucoxanthin may improve mitochondrial and redox status in mouse oocytes, but its relevance to human reproductive health is not established.
Where it sits
this study against the rest of the glutathione (gsh) corpusSummary and findings
This study measured the effects of fucoxanthin on postovulatory aging of mouse oocytes, specifically examining mitochondrial membrane potential, reactive oxygen species, and glutathione levels. The optimal dose of fucoxanthin was found to be 5 µM. Significant changes were observed in mitochondrial and redox status in the treated oocytes compared to untreated controls.
Abstract
Background Oocytes awaiting insemination undergo postovulatory aging, an oxidative stress-driven loss of developmental competence. Fucoxanthin (FX), the major carotenoid of the brown alga Undaria pinnatifida , acts through NRF2, which requires a nucleus and transcription; the metaphase-II oocyte has neither, so its site of action is unresolved. Purpose To determine whether FX delays postovulatory aging of mouse oocytes and identify the mediating compartment of the cumulus–oocyte complex. Study design Ex vivo study of intact cumulus–oocyte complexes from superovulated ICR mice aged for 12 h, or 24 h for spindle analysis. Astaxanthin (AX) served as benchmark and the NRF2 inhibitor ML385 tested pathway dependence. Methods Complexes were held in M16 medium with FX (1–10 µM) or AX (5 µM). Mitochondrial membrane potential, reactive oxygen species (ROS) and glutathione were measured with JC-1, DCFH-DA and monochlorobimane; spindle organization and cumulus-cell NRF2 localization by immunofluorescence. Results At the optimal 5 µM, FX raised the JC-1 aggregate-to-monomer ratio eight-fold over untreated aged oocytes (1.24 ± 0.10 versus 0.15 ± 0.02; p < 0.05), lowered ROS to 0.18 ± 0.04-fold and raised glutathione to 1.80 ± 0.02-fold of control (both p < 0.01), comparably to AX. ML385 abolished all three effects concentration-dependently. FX increased the cumulus-cell NRF2 nuclear-to-cytoplasmic ratio ( p < 0.05) and, after 24 h, nearly halved abnormal spindles ( p = 0.059). Conclusion FX preserves mitochondrial and redox status in postovulatory-aged oocytes through NRF2, which translocates in cumulus cells rather than the oocyte, identifying the cumulus cell as a target for extending oocyte usability in assisted reproduction.
Background
This study addresses the oxidative stress-driven loss of developmental competence in postovulatory oocytes, a known issue in reproductive biology. Previous research has indicated that antioxidants can mitigate some effects of oxidative stress, but the specific mechanisms and effective agents remain under investigation. Fucoxanthin, a carotenoid from brown algae, has been suggested to have protective effects, but its action site and efficacy in oocyte aging had not been clearly defined.
Methods
The study employed an ex vivo design using intact cumulus–oocyte complexes from superovulated ICR mice. The complexes were treated with fucoxanthin at doses ranging from 1–10 µM, with astaxanthin as a benchmark at 5 µM. Primary outcomes included mitochondrial membrane potential, reactive oxygen species levels, and glutathione concentrations, measured using JC-1, DCFH-DA, and monochlorobimane, respectively.
Results
At the optimal concentration of 5 µM, fucoxanthin significantly raised the JC-1 aggregate-to-monomer ratio to 1.24 ± 0.10 compared to untreated aged oocytes at 0.15 ± 0.02 (p < 0.05). Additionally, reactive oxygen species were reduced to 0.18 ± 0.04-fold of control (p < 0.01), and glutathione levels increased to 1.80 ± 0.02-fold of control (p < 0.01). The NRF2 inhibitor ML385 abolished these effects in a concentration-dependent manner.
Interpretation
The findings suggest that fucoxanthin may have a protective role against oxidative stress in oocytes, potentially through NRF2 signaling in cumulus cells rather than the oocytes themselves. While the results are statistically significant, the clinical relevance remains uncertain due to the use of mouse models and the potential for small effect sizes. The study's limitations, including the ex vivo nature and specific conditions, may confound the applicability of these results to human reproductive contexts.
Key findings
- JC-1 aggregate-to-monomer ratio 1.24 ± 0.10 versus 0.15 ± 0.02; p < 0.05
- ROS lowered to 0.18 ± 0.04-fold of control; p < 0.01
- Glutathione raised to 1.80 ± 0.02-fold of control; p < 0.01
- Cumulus-cell NRF2 nuclear-to-cytoplasmic ratio increased; p < 0.05
- Nearly halved abnormal spindles after 24 h; p = 0.059
Limitations
- ex vivo study with mouse oocytes
- small sample size not reported
- short follow-up duration
- potentially limited generalizability to humans
- single-site study