Hostname: page-component-76d6cb85b7-rxvq6 Total loading time: 0 Render date: 2026-07-13T11:50:20.495Z Has data issue: false hasContentIssue false
  • English
  • Français

Structural and metabolic cumulus cell alteration affects oocyte quality in underweight women

Published online by Cambridge University Press:  22 December 2023

Hong Ji ,
Qing Zhang ,
Lu Ding ,
Rongjuan Chen ,
Fu Liu  and
Ping Li Open the ORCID record for Ping Li [Opens in a new window]
Hong Ji
Affiliation:
Department of Reproductive Medicine, Women and Children’s Hospital, School of Medicine, Xiamen University, Zhenhai Road 10, 361003 Xiamen, Fujian Province, People’s Republic of China Xiamen Key Laboratory of Reproduction and Genetics, Zhenhai Road 10, 361003, Xiamen, Fujian Province, People’s Republic of China
Qing Zhang
Affiliation:
Department of Reproductive Medicine, Women and Children’s Hospital, School of Medicine, Xiamen University, Zhenhai Road 10, 361003 Xiamen, Fujian Province, People’s Republic of China Xiamen Key Laboratory of Reproduction and Genetics, Zhenhai Road 10, 361003, Xiamen, Fujian Province, People’s Republic of China
Lu Ding
Affiliation:
Department of Reproductive Medicine, Women and Children’s Hospital, School of Medicine, Xiamen University, Zhenhai Road 10, 361003 Xiamen, Fujian Province, People’s Republic of China Xiamen Key Laboratory of Reproduction and Genetics, Zhenhai Road 10, 361003, Xiamen, Fujian Province, People’s Republic of China
Rongjuan Chen
Affiliation:
Department of Reproductive Medicine, Women and Children’s Hospital, School of Medicine, Xiamen University, Zhenhai Road 10, 361003 Xiamen, Fujian Province, People’s Republic of China Xiamen Key Laboratory of Reproduction and Genetics, Zhenhai Road 10, 361003, Xiamen, Fujian Province, People’s Republic of China
Fu Liu*
Affiliation:
Department of Human Anatomy and Histoembryology, Xiamen Medical College, Guankou Middle Road 1999, 361023, Xiamen, Fujian Province, People’s Republic of China
Ping Li*
Affiliation:
Department of Reproductive Medicine, Women and Children’s Hospital, School of Medicine, Xiamen University, Zhenhai Road 10, 361003 Xiamen, Fujian Province, People’s Republic of China Xiamen Key Laboratory of Reproduction and Genetics, Zhenhai Road 10, 361003, Xiamen, Fujian Province, People’s Republic of China
*
Corresponding author: Ping Li; Email: saarc2001@sina.com and Fu Liu; Email: jpliufu@163.com
Corresponding author: Ping Li; Email: saarc2001@sina.com and Fu Liu; Email: jpliufu@163.com
Get access Rights & Permissions [Opens in a new window]

Summary

This study aimed to investigate the structural and metabolic changes in cumulus cells of underweight women and their effects on oocyte maturation and fertilization. The cytoplasmic ultrastructure was analyzed by electron microscopy, mitochondrial membrane potential by immunofluorescence, and mitochondrial DNA copy number by relative quantitative polymerase chain reaction. The expression of various proteins including the oxidative stress-derived product 4-hydroxynonenal (4-HNE) and autophagy and apoptosis markers such as Vps34, Atg-5, Beclin 1, Lc3-I, II, Bax, and Bcl-2 was assessed and compared between groups. Oocyte maturation and fertilization rates were lower in underweight women (P < 0.05), who presented with cumulus cells showing abnormal mitochondrial morphology and increased cell autophagy. Compared with the mitochondrial DNA copies of the control group, those of the underweight group increased but not significantly. The mitochondrial membrane potential was similar between the groups (P = 0.8). Vps34, Atg-5, Lc3-II, Bax, and Bcl-2 expression and 4-HNE levels were higher in the underweight group compared with the control group (P < 0.01); however, the Bax/Bcl-2 ratio was lower in the underweight group compared with the control group (P = 0.031). Additionally, Beclin 1 protein levels were higher in the underweight group compared with the control group but without statistical significance. In conclusion, malnutrition and other conditions in underweight women may adversely affect ovulation, and the development, and fertilization of oocytes resulting from changes to the intracellular structure of cumulus cells and metabolic processes. These changes may lead to reduced fertility or unsatisfactory reproduction outcomes in women.

Keywords

Autophagy proteinCumulus cellsMitochondriaMitochondrial DNAUnderweight

Information

Type
Research Article
Information
Zygote , Volume 32 , Issue 1 , February 2024 , pp. 77 - 86
Check for updates
Copyright
© The Author(s), 2023. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

Footnotes

*

These authors contributed equally to this work.

References

Aardema, H., van Tol, H. T. A. and Vos, P. L. A. M. (2019). An overview on how cumulus cells interact with the oocyte in a condition with elevated NEFA levels in dairy cows. Animal Reproduction Science, 207, 131–137. doi: 10.1016/j.anireprosci.2019.06.003 CrossRefGoogle Scholar
Alpha Scientists in Reproductive Medicine and ESHRE Special Interest Group of Embryology (2011). The Istanbul consensus workshop on embryo assessment: Proceedings of an expert meeting. Human Reproduction, 26(6), 1270–1283. doi: 10.1093/humrep/der037 Google Scholar
Annesley, S. J. and Fisher, P. R. (2019). Mitochondria in health and disease. Cells, 8(7), 680. doi: 10.3390/cells8070680 CrossRefGoogle ScholarPubMed
Attali, E. and Yogev, Y. (2021). The impact of advanced maternal age on pregnancy outcome. Best Practice and Research. Clinical Obstetrics and Gynaecology, 70, 2–9. doi: 10.1016/j.bpobgyn.2020.06.006 CrossRefGoogle ScholarPubMed
Azizollahi, S., Bagheri, M., Haghollahi, F., Mohammadi, S. M. and Hossein Rashidi, B. H. (2021). Clinical and molecular effects of GnRH agonist and antagonist on the cumulus cells in the in vitro fertilization cycle. International Journal of Fertility and Sterility, 15(3), 202–209. doi: 10.22074/IJFS.2020.136161.1012 Google ScholarPubMed
Barth, S., Glick, D. and Macleod, K. F. (2010). Autophagy: Assays and artifacts. Journal of Pathology, 221(2), 117–124. doi: 10.1002/path.2694 CrossRefGoogle ScholarPubMed
Biase, F. H. and Kimble, K. M. (2018). Functional signaling and gene regulatory networks between the oocyte and the surrounding cumulus cells. BMC Genomics, 19(1), 351. doi: 10.1186/s12864-018-4738-2 CrossRefGoogle ScholarPubMed
Boldura, O. M., Marc, S., Otava, G., Hutu, I., Balta, C., Tulcan, C. and Mircu, C. (2021) Utilization of rosmarinic and ascorbic acids for maturation culture media in order to increase sow oocyte quality prior to IVF. Molecules, 26(23), 7215. doi: 10.3390/molecules26237215 Google ScholarPubMed
Boutari, C., Pappas, P. D., Mintziori, G., Nigdelis, M. P., Athanasiadis, L., Goulis, D. G. and Mantzoros, C. S. (2020). The effect of underweight on female and male reproduction. Metabolism: Clinical and Experimental, 107, 154229. doi: 10.1016/j.metabol.2020.154229 CrossRefGoogle ScholarPubMed
Chen, T. Y., Stott, P., Athorn, R. Z., Bouwman, E. G. and Langendijk, P. (2012). Undernutrition during early follicle development has irreversible effects on ovulation rate and embryos. Reproduction, Fertility, and Development, 24(6), 886–892. doi: 10.1071/RD11292 CrossRefGoogle ScholarPubMed
Corsetti, G., Pasini, E., Romano, C., Chen-Scarabelli, C., Scarabelli, T. M., Flati, V., Saravolatz, L. and Dioguardi, F. S. (2021). How can malnutrition affect autophagy in chronic heart failure? Focus and perspectives. International Journal of Molecular Sciences, 22(7), 3332. doi: 10.3390/ijms22073332 CrossRefGoogle Scholar
Cuervo, A. M. and Macian, F. (2012). Autophagy, nutrition and immunology. Molecular Aspects of Medicine, 33(1), 2–13. doi: 10.1016/j.mam.2011.09.001 Google ScholarPubMed
D’Arcy, M. S. (2019). Cell death: A review of the major forms of apoptosis, necrosis and autophagy. Cell Biology International, 43(6), 582–592. doi: 10.1002/cbin.11137 CrossRefGoogle ScholarPubMed
Da Broi, M. G., Jordão, A. A. Jr, Ferriani, R. A. and Navarro, P. A. (2018). Oocyte oxidative DNA damage may be involved in minimal/mild endometriosis-related infertility. Molecular Reproduction and Development, 85(2), 128–136. doi: 10.1002/mrd.22943 CrossRefGoogle ScholarPubMed
Desquiret-Dumas, V., Clément, A., Seegers, V., Boucret, L., Ferré-L’Hotellier, V., Bouet, P. E., Descamps, P., Procaccio, V., Reynier, P. and May-Panloup, P. (2017). The mitochondrial DNA content of cumulus granulosa cells is linked to embryo quality. Human Reproduction, 32(3), 607–614. doi: 10.1093/humrep/dew341 Google ScholarPubMed
Dong, C. X. and Yin, S. A. (2018). The ten-year retrospect of nutrition and health status of pregnant women in China. Zhonghua Yu Fang Yi Xue Za Zhi [Chinese Journal of Preventive Medicine], 52(1), 94–100. doi: 10.3760/cma.j.issn.0253-9624.2018.01.019 Google ScholarPubMed
Dumesic, D. A., Meldrum, D. R., Katz-Jaffe, M. G., Krisher, R. L. and Schoolcraft, W. B. (2015). Oocyte environment: Follicular fluid and cumulus cells are critical for oocyte health. Fertility and Sterility, 103(2), 303–316. doi: 10.1016/j.fertnstert.2014.11.015 CrossRefGoogle ScholarPubMed
Ferreira, D. J. S., da Silva Pedroza, A. A., Braz, G. R. F., da Silva-Filho, R. C., Lima, T. A., Fernandes, M. P., Doi, S. Q. and Lagranha, C. J. (2016). Mitochondrial bioenergetics and oxidative status disruption in brainstem of weaned rats: Immediate response to maternal protein restriction. Brain Research, 1642, 553–561. doi: 10.1016/j.brainres.2016.04.049 CrossRefGoogle ScholarPubMed
Gardner, D. K. and Schoolcraft, W. B. (1999). In vitro culture of human blastocysts. In R. Jansen & D. Mortimer (Eds.), Toward reproductive certainty: Fertility and genetics beyond 1999 (pp. 378–388). Parthenon Publishing Group.Google Scholar
Hennet, M. L. and Combelles, C. M. H. (2012). The antral follicle: A microenvironment for oocyte differentiation. International Journal of Developmental Biology, 56(10–12), 819–831. doi: 10.1387/ijdb.120133cc CrossRefGoogle ScholarPubMed
Hirao, Y. (2012). Oocyte growth in vitro: Potential model for studies of oocyte-granulosa cell interactions. Reproductive Medicine and Biology, 11(1), 1–9. doi: 10.1007/s12522-011-0096-3 CrossRefGoogle ScholarPubMed
Hollenstein, D. M. and Kraft, C. (2020). Autophagosomes are formed at a distinct cellular structure. Current Opinion in Cell Biology, 65, 50–57. doi: 10.1016/j.ceb.2020.02.012 CrossRefGoogle Scholar
Høst, E., Mikkelsen, A. L., Lindenberg, S. and Smidt-Jensen, S. (2000). Apoptosis in human cumulus cells in relation to maturation stage and cleavage of the corresponding oocyte. Acta Obstetricia et Gynecologica Scandinavica, 79(11), 936–940. doi: 10.3109/00016340009169238 CrossRefGoogle Scholar
Hunter, E., Avenell, A., Maheshwari, A., Stadler, G. and Best, D. (2021). The effectiveness of weight-loss lifestyle interventions for improving fertility in women and men with overweight or obesity and infertility: A systematic review update of evidence from randomized controlled trials. Obesity Reviews, 22(12), e13325. doi: 10.1111/obr.13325 CrossRefGoogle ScholarPubMed
Kansaku, K., Munakata, Y., Itami, N., Shirasuna, K., Kuwayama, T. and Iwata, H. (2018). Mitochondrial dysfunction in cumulus–oocyte complexes increases cell-free mitochondrial DNA. Journal of Reproduction and Development, 64(3), 261–266. doi: 10.1262/jrd.2018-012 CrossRefGoogle ScholarPubMed
Lahmann, N. A., Tannen, A. and Suhr, R. (2016). Underweight and malnutrition in home care: A multicenter study. Clinical Nutrition, 35(5), 1140–1146. doi: 10.1016/j.clnu.2015.09.008 CrossRefGoogle ScholarPubMed
Li, Y., Zhao, T., Li, J., Xia, M., Li, Y., Wang, X., Liu, C., Zheng, T., Chen, R., Kan, D., Xie, Y., Song, J., Feng, Y., Yu, T. and Sun, P. (2022). Oxidative stress and 4-hydroxy-2-nonenal (4-HNE): implications in the pathogenesis and treatment of aging-related diseases. Journal of Immunology Research, 2022, 2233906. doi: 10.1155/2022/2233906 Google ScholarPubMed
Liu, S., Jiang, L., Zhong, T., Kong, S., Zheng, R., Kong, F., Zhang, C., Zhang, L. and An, L. (2015). Effect of acrylamide on oocyte nuclear maturation and cumulus cells apoptosis in mouse in vitro . PLOS ONE, 10(8), e0135818. doi: 10.1371/journal.pone.0135818 CrossRefGoogle ScholarPubMed
Liu, Q., Zhang, J., Wen, H., Feng, Y., Zhang, X., Xiang, H., Cao, Y., Tong, X., Ji, Y. and Xue, Z. (2018). Analyzing the transcriptome profile of human cumulus cells related to embryo quality via RNA sequencing. BioMed Research International, 2018, 9846274. doi: 10.1155/2018/9846274 CrossRefGoogle ScholarPubMed
Liu, L. Y., Zafman, K. B. and Fox, N. S. (2020). Weight gain and pregnancy outcomes in underweight women with twin gestations. Journal of Maternal-Fetal and Neonatal Medicine, 33(17), 2877–2881. doi: 10.1080/14767058.2018.1562544 CrossRefGoogle ScholarPubMed
Maiuri, M. C., Zalckvar, E., Kimchi, A. and Kroemer, G. (2007). Self-eating and self-killing: Crosstalk between autophagy and apoptosis. Nature Reviews. Molecular Cell Biology, 8(9), 741–752. doi: 10.1038/nrm2239 CrossRefGoogle ScholarPubMed
Medeiros, T. C. and Graef, M. (2019). Autophagy determines mtDNA copy number dynamics during starvation. Autophagy, 15(1), 178–179. doi: 10.1080/15548627.2018.1532263 Google ScholarPubMed
Medeiros, T. C., Thomas, R. L., Ghillebert, R. and Graef, M. (2018). Autophagy balances mtDNA synthesis and degradation by DNA polymerase POLG during starvation. Journal of Cell Biology, 217(5), 1601–1611. doi: 10.1083/jcb.201801168 CrossRefGoogle ScholarPubMed
Mintziori, G., Nigdelis, M. P., Mathew, H., Mousiolis, A., Goulis, D. G. and Mantzoros, C. S. (2020). The effect of excess body fat on female and male reproduction. Metabolism: Clinical and Experimental, 107, 154193. doi: 10.1016/j.metabol.2020.154193 CrossRefGoogle ScholarPubMed
Mizushima, N. and Komatsu, M. (2011). Autophagy: renovation of cells and tissues. Cell, 147(4), 728–741. doi: 10.1016/j.cell.2011.10.026 CrossRefGoogle ScholarPubMed
Papa, S., Martino, P. L., Capitanio, G., Gaballo, A., De Rasmo, D., Signorile, A. and Petruzzella, V. (2012). The oxidative phosphorylation system in mammalian mitochondria. Advances in Experimental Medicine and Biology, 942, 3–37. doi: 10.1007/978-94-007-2869-1_1 CrossRefGoogle ScholarPubMed
Perelman, A., Wachtel, C., Cohen, M., Haupt, S., Shapiro, H. and Tzur, A. (2012). JC-1: Alternative excitation wavelengths facilitate mitochondrial membrane potential cytometry. Cell Death and Disease, 3(11), e430. doi: 10.1038/cddis.2012.171 CrossRefGoogle ScholarPubMed
Perry, S. W., Norman, J. P., Barbieri, J., Brown, E. B. and Gelbard, H. A. (2011). Mitochondrial membrane potential probes and the proton gradient: A practical usage guide. BioTechniques, 50(2), 98–115. doi: 10.2144/000113610 CrossRefGoogle ScholarPubMed
Pyo, J. O., Yoo, S. M., Ahn, H. H., Nah, J., Hong, S. H., Kam, T. I., Jung, S. and Jung, Y. K. (2013). Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nature Communications, 4, 2300. doi: 10.1038/ncomms3300 Google ScholarPubMed
Rich-Edwards, J. W., Spiegelman, D., Garland, M., Hertzmark, E., Hunter, D. J., Colditz, G. A., Willett, W. C., Wand, H. and Manson, J. E. (2002). Physical activity, body mass index, and ovulatory disorder infertility. Epidemiology, 13(2), 184–190. doi: 10.1097/00001648-200203000-00013 Google ScholarPubMed
Richani, D., Dunning, K. R., Thompson, J. G. and Gilchrist, R. B. (2021). Metabolic co-dependence of the oocyte and cumulus cells: Essential role in determining oocyte developmental competence. Human Reproduction Update, 27(1), 27–47. doi: 10.1093/humupd/dmaa043 CrossRefGoogle ScholarPubMed
Sharma, S., Sharma, P., Bailey, T., Bhattarai, S., Subedi, U., Miller, C., Ara, H., Kidambi, S., Sun, H., Panchatcharam, M. and Miriyala, S. (2022). Electrophilic aldehyde 4-hydroxy-2-nonenal mediated signaling and mitochondrial dysfunction. Biomolecules, 12(11), 1555. doi: 10.3390/biom12111555 CrossRefGoogle ScholarPubMed
Silva, S. C. A., Braz, G. R. F., do Nascimento, L. C. P., Santana, D. F., da Siva Pedroza, A. A., Silva, T. L. A., Fernandes, M. P., Sellitti, D. F. and Lagranha, C. J. (2019). Influence of maternal protein malnutrition on oxidative stress and regulators of mitochondrial biogenesis in female rat hearts over succeeding generations. Life Sciences, 232, 116579. doi: 10.1016/j.lfs.2019.116579 CrossRefGoogle ScholarPubMed
Skuratovskaia, D. A., Sofronova, J. K., Zatolokin, P. A., Popadin, K. Y., Vasilenko, M. A., Litvinova, L. S. and Mazunin, I. O. (2018). Additional evidence of the link between mtDNA copy number and the body mass index. Mitochondrial DNA. Part A, DNA Mapping, Sequencing, and Analysis, 29(8), 1240–1244. doi: 10.1080/24701394.2018.1436170 CrossRefGoogle ScholarPubMed
Song, J., Zhang, J., Fawzi, W. and Huang, Y. (2020). Double burden of malnutrition among Chinese women of reproductive age and their social determinants. Nutrients, 12(10), 3102. doi: 10.3390/nu12103102 CrossRefGoogle ScholarPubMed
Sutton-McDowall, M. L., Gilchrist, R. B. and Thompson, J. G. (2010). The pivotal role of glucose metabolism in determining oocyte developmental competence. Reproduction, 139(4), 685–695. doi: 10.1530/REP-09-0345 CrossRefGoogle ScholarPubMed
Turathum, B., Gao, E. M. and Chian, R. C. (2021). The function of cumulus cells in oocyte growth and maturation and in subsequent ovulation and fertilization. Cells, 10(9), 2292. doi: 10.3390/cells10092292 Google ScholarPubMed
Uyar, A., Torrealday, S. and Seli, E. (2013). Cumulus and granulosa cell markers of oocyte and embryo quality. Fertility and Sterility, 99(4), 979–997. doi: 10.1016/j.fertnstert.2013.01.129 CrossRefGoogle ScholarPubMed
WHO Expert Consultation (2004). Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet (London, England), 363(9403), 157–163. doi: 10.1016/S0140-6736(03)15268-3 CrossRefGoogle Scholar
World Health Organization. (2010). WHO Laboratory Manual for the Examination and processing of Human Semen (5th edn). World Health Organization Press. Available online: https://www.who.int/publications/i/item/9789240030787.Google Scholar
Zhang, Q., Ji, H., Shi, J., Wang, L., Ding, L., Jiang, Y., Huang, X., Qiu, P. and Li, P. (2021). Digital PCR detection of mtDNA/gDNA ratio in embryo culture medium for prediction of embryo development potential. Pharmacogenomics and Personalized Medicine, 14, 521–531. doi: 10.2147/PGPM.S304747 CrossRefGoogle ScholarPubMed
Zhu, M., Shen, Q., Li, X. and Kang, J. (2020). Removal of peri-ovarian adipose tissue affects follicular development and lipid metabolism. Biology of Reproduction, 103(6), 1199–1208. doi: 10.1093/biolre/ioaa144 CrossRefGoogle ScholarPubMed