Antioxidant strategies to mitigate oxidative stress-induced cryodamage in oocytes

Abstract

Oocyte cryopreservation is an essential procedure in assisted reproductive technologies, aimed at preserving fertility, particularly for women undergoing IVF treatment or at risk of ovarian damage due to radiation, chemotherapy, or surgery. Despite its growing use, the survival and fertilization rates of cryopreserved oocytes remain suboptimal, largely due to cryo-induced oxidative stress. The generation of Reactive Oxygen Species (ROS) during freezing and thawing causes considerable damage to key cellular components, including proteins, lipids, DNA, and mitochondria. This oxidative stress compromises oocyte quality and reduces developmental potential. To address these challenges, the use of additives - especially antioxidants - has shown significant promise in mitigating oxidative damage. Enzymatic antioxidants such as Superoxide Dismutase (SOD) and Catalase (CAT), along with non-enzymatic antioxidants like glutathione, melatonin, and resveratrol, have demonstrated the ability to neutralize ROS and improve oocyte viability and developmental outcomes. Recent studies highlight the potential of Mitoquinone (MitoQ), a mitochondria-targeted antioxidant, to effectively counteract mitochondrial ROS and enhance cellular defense mechanisms during cryopreservation. This review explores the cellular mechanisms of cryodamage, the role of oxidative stress in oocyte cryopreservation, and the potential of various antioxidant strategies to enhance oocyte survival and function. Developing effective antioxidant supplementation approaches may significantly improve the outcomes of cryopreservation in reproductive medicine.

Keywords

antioxidants / oocyte / cryopreservation / oxidative stress

Acknowledgments

Not applicable.

Research ethics

Not applicable.

Informed consent

Not applicable.

Author contributions

Zhao G: Concept and design; Zand E: literature search, drafting of the article.

Use of Large Language Models, AI and Machine Learning Tools

Not applicable.

Conflict of interest

There is no conflict of interest.

Data availability

No datasets were generated for this articlReferences(59)

References

[1] Polge C, Smith A U, Parkes A S. Revival of spermatozoa after vitrification and dehydration at low temperatures. Nature, 1949; 164(4172): 666.

[2] Whittingham D G, Leibo S P, Mazur P. Survival of mouse embryos frozen to -196 and -269 degrees C. Science, 1972; 178(4059): 411-414.

[3] Cao B, Qin J, Pan B, et al. Oxidative stress and oocyte cryopreservation: recent advances in mitigation strategies involving antioxidants. Cells, 2022; 11(22): 3573.

[4] Rall W F, Fahy G M. Ice-free cryopreservation of mouse embryos at -196 degrees C by vitrification. Nature, 1985; 313(6003): 573-575.

[5] Argyle C E, Harper J C, Davies M C. Oocyte cryopreservation: where are we now? Hum Reprod Update, 2016; 22(4): 440-449.

[6] Hou Y P, Dai Y P, Zhu S E, et al. Bovine oocytes vitrified by the open pulled straw method and used for somatic cell cloning supported development to term. Theriogenology, 2005; 64(6): 1381-1391.

[7] Abedpour N, Rajaei F. Vitrification by cryotop and the maturation, fertilization, and developmental rates of mouse oocytes. Iran Red Crescent Med J, 2015; 17(10): e18172.

[8] Ofosu J, Zhang Y, Liu Y, et al. Cryopreservation of mammalian gametes and embryos: implications of oxidative and nitrosative stress and potential role of antioxidants. Front Vet Sci, 2023; 10: 1174756.

[9] Gardner D K, Truong T T. Antioxidants and Antifreeze Proteins in Cryopreservation/Vitrification//Cryopreservation in Assisted Reproduction: A Practitioner's Guide to Methods, Management and Organization. Cham: Springer International Publishing, 2024: 69-74.

[10] Yang J, Pan C, Zhang J, et al. Exploring the potential of biocompatible osmoprotectants as highly efficient cryoprotectants. ACS Appl Mater Interfaces, 2017; 9(49): 42516-42524.

[11] Len J S, Koh W S D, Tan S X. The roles of reactive oxygen species and antioxidants in cryopreservation. Biosci Rep, 2019; 39(8): BSR20191601.

[12] Mazur B. Rational points of abelian varieties with values in towers of number fields. Invent Math, 1972; 18(3): 183-266.

[13] Anisa-Annur S, Wan-Hafizah W J, Nor-Ashikin M N K, et al. Effect of coenzyme Q 10 supplementation on post-vitrification mouse embryo development. Asian Pac J Reprod, 2024; 13(3): 126-132.

[14] Schieber M, Chandel N S. ROS function in redox signaling and oxidative stress. Curr Biol, 2014; 24(10): R453-R462.

[15] Liochev S I. Reactive oxygen species and the free radical theory of aging. Free Radic Biol Med, 2013; 60: 1-4.

[16] Agarwal A, Aponte-Mellado A, Premkumar B J, et al. The effects of oxidative stress on female reproduction: a review. Reprod Biol Endocrinol, 2012; 10: 1-31.

[17] Wang L, Tang J, Wang L, et al. Oxidative stress in oocyte aging and female reproduction. J Cell Physiol, 2021; 236(12): 7966-7983.

[18] Rehman R, Azhar A. Oxidative stress, mechanisms of subfertility, and reproductive disorders in females. Fundamental Principles of Oxidative Stress in Metabolism and Reproduction. London: Academic Press, 2024: 185-200.

[19] Petry A, Görlach A. Regulation of NADPH oxidases by G protein-coupled receptors. Antioxid Redox Signal, 2019; 30(1): 74-94.

[20] Keefe D, Liu L, Marquard K. Telomeres and meiosis in health and disease: telomeres and aging-related meiotic dysfunction in women. Cell Mol Life Sci, 2007; 64(2): 139-143.

[21] Lu W, Zhang Y, Liu D, et al. Telomeres - structure, function, and regulation. Exp Cell Res, 2013; 319(2): 133-141.

[22] Roig I, Liebe B, Egozcue J, et al. Female-specific features of recombinational double-stranded DNA repair in relation to synapsis and telomere dynamics in human oocytes. Chromosoma, 2004; 113(1): 22-33.

[23] Scherthan H. Factors directing telomere dynamics in synaptic meiosis. Biochem Soc Trans, 2006; 34(4): 550-553.

[24] Valdes A M, Andrew T, Gardner J P, et al. Obesity, cigarette smoking, and telomere length in women. Lancet, 2005; 366(9486): 662664.

[25] Zhang J, Rane G, Dai X, et al. Ageing and the telomere connection: an intimate relationship with inflammation. Ageing Res Rev, 2016; 25: 55-69.

[26] Cattan V, Mercier N, Gardner J P, et al. Chronic oxidative stress induces a tissue-specific reduction in telomere length in CAST/Ei mice. Free Radic Biol Med, 2008; 44(8): 1592-1598.

[27] Jurk D, Wilson C, Passos J, et al. Chronic inflammation induces telomere dysfunction and accelerates ageing in mice. Nat Commun, 2014; 2: 4172.

[28] Zijlmans J M J, Martens U M, Poon S S, et al. Telomeres in the mouse have large inter-chromosomal variations in the number of T2AG 3 repeats. Proc Natl Acad Sci, 1997; 94(14): 7423-7428.

[29] Bentov Y, Casper R F. The aging oocyte - can mitochondrial function be improved? Fertil Steril, 2013; 99(1): 18-22.

[30] Zhang Q, Hao J X, Liu B W, et al. Supplementation of mitochondria from endometrial mesenchymal stem cells improves oocyte quality in aged mice. Cell Prolif, 2023; 56(3): e13372.

[31] Goud A P, Goud P T, Diamond M P, et al. Reactive oxygen species and oocyte aging: role of superoxide, hydrogen peroxide, and hypochlorous acid. Free Radic Biol Med, 2008; 44(7): 1295-1304.

[32] Keane J A, Ealy A D. An overview of reactive oxygen species damage occurring during in vitro bovine oocyte and embryo development and the efficacy of antioxidant use to limit these adverse effects. Animals, 2024; 14(2): 330.

[33] Hou X, Zhu S, Zhang H, et al. Mitofusin 1 in oocyte is essential for female fertility. Redox Biol, 2019; 21: 101110.

[34] Shigenaga M K, Hagen T M, Ames B N. Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci, 1994; 91(23): 1077110778.

[35] Matés J M, Pérez-Gómez C, De Castro I N. Antioxidant enzymes and human diseases. Clin Biochem, 1999; 32(8): 595-603.

[36] Alkadi H. A review on free radicals and antioxidants. Infect Disord Drug Targets, 2020; 20(1): 16-26.

[37] Mittag T, Parker R. Multiple modes of protein-protein interactions promote RNP granule assembly. J Mol Biol, 2018; 430(23): 4636-4649.

[38] Putnam A, Thomas L, Seydoux G. RNA granules: functional compartments or incidental condensates? Genes Dev, 2023; 37(9-10): 354-376.

[39] Anderson P, Kedersha N. RNA granules. J Cell Biol, 2006; 172(6): 803-808.

[40] Cadena Sandoval M, Heberle A M, Rehbein U, et al. mTORC 1 crosstalk with stress granules in aging and age-related diseases. Front aging, 2021; 2: 761333.

[41] Standart N, Minshall N. Translational control in early development: CPEB, P-bodies and germinal granules. Biochem Soc Trans, 2008; 36(4): 671-676.

[42] Conti M, Kunitomi C. A genome-wide perspective of the maternal mRNA translation program during oocyte development. Semin Cell Dev Biol, 2024; 154(Pt B): 88-98.

[43] Yang W H, Bloch D B. Probing the mRNA processing body using protein macroarrays and "autoantigenomics". RNA, 2007; 13(5): 704712.

[44] Adjibade P, Mazroui R. Stress granules: stress-induced cytoplasmic mRNPs compartments linked to mRNA translational regulatory pathways. Front RNA Res, 2023; 1: 1226610.

[45] Somfai T, Haraguchi S, Dang-Nguyen T Q, et al. Vitrification of porcine immature oocytes and zygotes results in different levels of DNA damage which reflects developmental competence to the blastocyst stage. Plos One, 2023; 18(3): e0282959.

[46] Yang J, Guo S, Pan B, et al. Melatonin promotes in vitro maturation of vitrified-warmed mouse GV oocytes potentially by modulating MAD2 protein expression of SAC component through MTRs. Cryobiology, 2021; 102: 82-91.

[47] Gutierrez-Castillo E, Diaz F A, Talbot S A, et al. Effect of bovine oocyte vitrification with EGTA and post-warming recovery with resveratrol on meiotic spindle, mitochondrial function, reactive oxygen species, and developmental competence. Theriogenology, 2023; 196: 59-67.

[48] Xu H, Jia C, Cheng W, et al. The effect of L-carnitine additive during in vitro maturation on the vitrification of pig oocytes. Cell Reprogram, 2020; 22(4): 198-207.

[49] Shirzeyli M H, Eini F, Shirzeyli F H, et al. Assessment of mitochondrial function and developmental potential of mouse oocytes after mitoquinone supplementation during vitrification. J Am Assoc Lab Anim Sci, 2021; 60(4): 388-395.

[50] Plotnikov E Y, Zorov D B. Pros and cons of use of mitochondria-targeted antioxidants. Antioxidants (Basel), 2019; 8(8): 316.

[51] Nohalez A, Martinez C, Parrilla I, et al. Exogenous ascorbic acid enhances vitrification survival of porcine in vitro-developed blastocysts but fails to improve the in vitro embryo production outcomes. Theriogenology, 2018; 113: 113-119.

[52] Guerin L R, Moldenhauer L M, Prins J R, et al. Seminal fluid regulates accumulation of FOXP3+ regulatory T cells in the preimplantation mouse uterus through expanding the FOXP3+ cell pool and CCL19-mediated recruitment. Biol Reprod, 2011; 85(2): 397-408.

[53] Tareq K M, Akter Q S, Khandoker M A. Selenium and vitamin E improve the in vitro maturation, fertilization and culture to blastocyst of porcine oocytes. J Reprod Dev, 2012; 58(6): 621-628.

[54] Farzollahi M, Tayefi-Nasrabadi H, Mohammadnejad D, et al. Supplementation of culture media with vitamin E improves mouse antral follicle maturation and embryo development from vitrified ovarian tissue. J Obstet Gynaecol Res, 2016; 42(5): 526-535.

[55] Ito J, Shirasuna K, Kuwayama T, et al. Resveratrol treatment increases mitochondrial biogenesis and improves viability of porcine germinal-vesicle stage vitrified-warmed oocytes. Cryobiology, 2020; 93: 37-43.

[56] Nowak A, Kochan J, Gabryś J, et al. The effect of resveratrol on the developmental competence of feline oocytes vitrified at the metaphase II stage. Theriogenology, 2024; 230: 101-106.

[57] Giaretta E, Spinaci M, Bucci D, et al. Effects of resveratrol on vitrified porcine oocytes. Oxid Med Cell Longev, 2013; 2013(1): 920257.

[58] Pereira B A, Zangeronimo M G, Castillo-Martín M, et al. Supplementing maturation medium with insulin growth factor I and vitrification-warming solutions with reduced glutathione enhances survival rates and development ability of in vitro matured vitrified-warmed pig oocytes. Front Physiol, 2019; 9: 1894.

[59] Somfai T, Ozawa M, Noguchi J, et al. Developmental competence of in vitro-fertilized porcine oocytes after in vitro maturation and solid surface vitrification: effect of cryopreservation on oocyte antioxidative system and cell cycle stage. Cryobiology, 2007; 55(2): 115-126.