基于表观遗传学母源肥胖对卵母细胞质量及胚胎发育的影响
Advances in Research on the Impact of Maternal Obesity on Oocyte Quality and Embryo Development from an Epigenetic Perspective
DOI: 10.12677/acm.2025.152331, PDF,   
作者: 姚 望, 王玉霞*:暨南大学附属第一医院生殖医学科,广东 广州
关键词: 肥胖表观遗传学卵母细胞胚胎Obesity Epigenetic Modification Oocyte Embryo
摘要: 肥胖与众多生殖系统疾病密切相关,如月经不调、生殖细胞质量下降以及流产等。肥胖通过DNA甲基化、组蛋白修饰以及非编码RNA表达等表观遗传学途径广泛影响卵母细胞和胚胎发育成熟的关键过程,这种影响不仅局限于胚胎发育阶段,还可能通过表观遗传修饰的跨代遗传对后代健康带来不良后果。本文对与母源肥胖导致卵母细胞质量下降相关的表观遗传学机制的研究进展进行综述,并联系已报道的相关机制提出干预标靶,以期改善表观遗传修饰对卵母细胞质量的消极影响。
Abstract: Obesity is closely associated with numerous reproductive system disorders, such as irregular menstruation, decreased germ cell quality, and miscarriages. Obesity broadly affects key processes in oocyte and embryo developmental maturation through epigenetic pathways, including DNA methylation, histone modification, and non-coding RNA expression. This impact is not limited to the embryonic development stage but may also lead to adverse outcomes for offspring health through the transgenerational inheritance of epigenetic modifications. This article reviews the research progress on the epigenetic mechanisms related to decreased oocyte quality caused by maternal obesity and proposes intervention targets based on reported related mechanisms, aiming to mitigate the negative effects of epigenetic modifications on oocyte quality.
文章引用:姚望, 王玉霞. 基于表观遗传学母源肥胖对卵母细胞质量及胚胎发育的影响[J]. 临床医学进展, 2025, 15(2): 181-188. https://doi.org/10.12677/acm.2025.152331

参考文献

[1] Reik, W., Dean, W. and Walter, J. (2001) Epigenetic Reprogramming in Mammalian Development. Science, 293, 1089-1093. [Google Scholar] [CrossRef] [PubMed]
[2] Oswald, J., Engemann, S., Lane, N., Mayer, W., Olek, A., Fundele, R., et al. (2000) Active Demethylation of the Paternal Genome in the Mouse Zygote. Current Biology, 10, 475-478. [Google Scholar] [CrossRef] [PubMed]
[3] Gu, T., Guo, F., Yang, H., Wu, H., Xu, G., Liu, W., et al. (2011) The Role of Tet3 DNA Dioxygenase in Epigenetic Reprogramming by Oocytes. Nature, 477, 606-610. [Google Scholar] [CrossRef] [PubMed]
[4] Inoue, A. and Zhang, Y. (2011) Replication-Dependent Loss of 5-Hydroxymethylcytosine in Mouse Preimplantation Embryos. Science, 334, 194-194. [Google Scholar] [CrossRef] [PubMed]
[5] Hou, Y., Zhu, C., Duan, X., Liu, H., Wang, Q. and Sun, S. (2016) Both Diet and Gene Mutation Induced Obesity Affect Oocyte Quality in Mice. Scientific Reports, 6, Article No. 18858. [Google Scholar] [CrossRef] [PubMed]
[6] Han, L., Ren, C., Li, L., Li, X., Ge, J., Wang, H., et al. (2018) Embryonic Defects Induced by Maternal Obesity in Mice Derive from Stella Insufficiency in Oocytes. Nature Genetics, 50, 432-442. [Google Scholar] [CrossRef] [PubMed]
[7] Tang, S., Wu, H., Chen, Q., Tang, T., Li, J., An, H., et al. (2024) Maternal Obesity Induces the Meiotic Defects and Epigenetic Alterations during Fetal Oocyte Development. Advanced Science, 11, e2309184. [Google Scholar] [CrossRef] [PubMed]
[8] Anckaert, E., Romero, S., Adriaenssens, T. and Smitz, J. (2010) Effects of Low Methyl Donor Levels in Culture Medium during Mouse Follicle Culture on Oocyte Imprinting Establishment. Biology of Reproduction, 83, 377-386. [Google Scholar] [CrossRef] [PubMed]
[9] Pang, H., Ling, D., Cheng, Y., Akbar, R., Jin, L., Ren, J., et al. (2021) Gestational High‐Fat Diet Impaired Demethylation of Pparα and Induced Obesity of Offspring. Journal of Cellular and Molecular Medicine, 25, 5404-5416. [Google Scholar] [CrossRef] [PubMed]
[10] Ge, Z., Liang, Q., Hou, Y., Han, Z., Schatten, H., Sun, Q., et al. (2014) Maternal Obesity and Diabetes May Cause DNA Methylation Alteration in the Spermatozoa of Offspring in Mice. Reproductive Biology and Endocrinology, 12, Article No. 29. [Google Scholar] [CrossRef] [PubMed]
[11] Bian, C. and Yu, X. (2013) PGC7 Suppresses TET3 for Protecting DNA Methylation. Nucleic Acids Research, 42, 2893-2905. [Google Scholar] [CrossRef] [PubMed]
[12] Toriyama, K., Au Yeung, W.K., Inoue, A., Kurimoto, K., Yabuta, Y., Saitou, M., et al. (2024) DPPA3 Facilitates Genome-Wide DNA Demethylation in Mouse Primordial Germ Cells. BMC Genomics, 25, Article No. 344. [Google Scholar] [CrossRef] [PubMed]
[13] Nakatani, T., Yamagata, K., Kimura, T., Oda, M., Nakashima, H., Hori, M., et al. (2015) Stella Preserves Maternal Chromosome Integrity by Inhibiting 5hmC‐Induced γH2AX Accumulation. EMBO reports, 16, 582-589. [Google Scholar] [CrossRef] [PubMed]
[14] Uemura, S., Maenohara, S., Inoue, K., Ogonuki, N., Matoba, S., Ogura, A., et al. (2023) UHRF1 Is Essential for Proper Cytoplasmic Architecture and Function of Mouse Oocytes and Derived Embryos. Life Science Alliance, 6, e202301904. [Google Scholar] [CrossRef] [PubMed]
[15] Guo, F., Li, X., Liang, D., Li, T., Zhu, P., Guo, H., et al. (2014) Active and Passive Demethylation of Male and Female Pronuclear DNA in the Mammalian Zygote. Cell Stem Cell, 15, 447-459. [Google Scholar] [CrossRef] [PubMed]
[16] Dawlaty, M.M., Ganz, K., Powell, B.E., Hu, Y., Markoulaki, S., Cheng, A.W., et al. (2011) Tet1 Is Dispensable for Maintaining Pluripotency and Its Loss Is Compatible with Embryonic and Postnatal Development. Cell Stem Cell, 9, 166-175. [Google Scholar] [CrossRef] [PubMed]
[17] Uh, K., Ryu, J., Farrell, K., Wax, N. and Lee, K. (2020) TET Family Regulates the Embryonic Pluripotency of Porcine Preimplantation Embryos by Maintaining the DNA Methylation Level of NANOG. Epigenetics, 15, 1228-1242. [Google Scholar] [CrossRef] [PubMed]
[18] Pan, M., Zhu, C., Ju, J., Xu, Y., Luo, S., Sun, S., et al. (2020) Single‐Cell Transcriptome Analysis Reveals That Maternal Obesity Affects DNA Repair, Histone Methylation, and Autophagy Level in Mouse Embryos. Journal of Cellular Physiology, 236, 4944-4953. [Google Scholar] [CrossRef] [PubMed]
[19] Inagaki, T., Tachibana, M., Magoori, K., Kudo, H., Tanaka, T., Okamura, M., et al. (2009) Obesity and Metabolic Syndrome in Histone Demethylase JHDM2a‐Deficient Mice. Genes to Cells, 14, 991-1001. [Google Scholar] [CrossRef] [PubMed]
[20] Huang, J., Ru, G., Sun, J., Sun, L. and Li, Z. (2022) Elevated RIF1 Participates in the Epigenetic Abnormalities of Zygotes by Regulating Histone Modifications on MuERV-L in Obese Mice. Molecular Medicine, 28, Article No. 17. [Google Scholar] [CrossRef] [PubMed]
[21] Cuyàs, E., Fernández-Arroyo, S., Verdura, S., García, R.Á., Stursa, J., Werner, L., et al. (2017) Metformin Regulates Global DNA Methylation via Mitochondrial One-Carbon Metabolism. Oncogene, 37, 963-970. [Google Scholar] [CrossRef] [PubMed]
[22] Filios, S.R. and Shalev, A. (2015) Β-Cell microRNAs: Small but Powerful. Diabetes, 64, 3631-3644. [Google Scholar] [CrossRef] [PubMed]
[23] Huntzinger, E. and Izaurralde, E. (2011) Gene Silencing by microRNAs: Contributions of Translational Repression and Mrna Decay. Nature Reviews Genetics, 12, 99-110. [Google Scholar] [CrossRef] [PubMed]
[24] Wyse, B.A., Salehi, R., Russell, S.J., Sangaralingam, M., Jahangiri, S., Tsang, B.K., et al. (2023) Obesity and PCOS Radically Alters the snRNA Composition of Follicular Fluid Extracellular Vesicles. Frontiers in Endocrinology, 14, Article 1205385. [Google Scholar] [CrossRef] [PubMed]
[25] Lee, H. (2015) Impact of Maternal Diet on the Epigenome during in Utero Life and the Developmental Programming of Diseases in Childhood and Adulthood. Nutrients, 7, 9492-9507. [Google Scholar] [CrossRef] [PubMed]
[26] Benatti, R.O., Melo, A.M., Borges, F.O., Ignacio-Souza, L.M., Simino, L.A.P., Milanski, M., et al. (2014) Maternal High-Fat Diet Consumption Modulates Hepatic Lipid Metabolism and microRNA-122 (Mir-122) and microRNA-370 (Mir-370) Expression in Offspring. British Journal of Nutrition, 111, 2112-2122. [Google Scholar] [CrossRef] [PubMed]
[27] Enquobahrie, D.A., Wander, P.L., Tadesse, M.G., Qiu, C., Holzman, C. and Williams, M.A. (2017) Maternal Pre-Pregnancy Body Mass Index and Circulating microRNAs in Pregnancy. Obesity Research & Clinical Practice, 11, 464-474. [Google Scholar] [CrossRef] [PubMed]
[28] Soták, M., Clark, M., Suur, B.E. and Börgeson, E. (2024) Inflammation and Resolution in Obesity. Nature Reviews Endocrinology, 21, 45-61. [Google Scholar] [CrossRef] [PubMed]
[29] Park, M.Y., Tu, C., Perie, L., Verma, N., Serdan, T.D.A., Shamsi, F., et al. (2024) Targeted Deletion of Fibroblast Growth Factor 23 Rescues Metabolic Dysregulation of Diet-Induced Obesity in Female Mice. Endocrinology, 165, bqae141. [Google Scholar] [CrossRef] [PubMed]
[30] Bianco, A.C. and McAninch, E.A. (2013) The Role of Thyroid Hormone and Brown Adipose Tissue in Energy Homoeostasis. The Lancet Diabetes & Endocrinology, 1, 250-258. [Google Scholar] [CrossRef] [PubMed]
[31] Wu, Z., Martinez, M.E., St. Germain, D.L. and Hernandez, A. (2016) Type 3 Deiodinase Role on Central Thyroid Hormone Action Affects the Leptin-Melanocortin System and Circadian Activity. Endocrinology, 158, 419-430. [Google Scholar] [CrossRef] [PubMed]
[32] Wulf, A., Harneit, A., Kröger, M., Kebenko, M., Wetzel, M.G. and Weitzel, J.M. (2008) T3-Mediated Expression of PGC-1α via a Far Upstream Located Thyroid Hormone Response Element. Molecular and Cellular Endocrinology, 287, 90-95. [Google Scholar] [CrossRef] [PubMed]
[33] Chen, Y., Yang, Q., Hu, Y., Liu, X., de Avila, J.M., Zhu, M., et al. (2021) Imprinted lncRNA Dio3os Preprograms Intergenerational Brown Fat Development and Obesity Resistance. Nature Communications, 12, Article No. 6845. [Google Scholar] [CrossRef] [PubMed]
[34] Seto, E. and Yoshida, M. (2014) Erasers of Histone Acetylation: The Histone Deacetylase Enzymes. Cold Spring Harbor Perspectives in Biology, 6, a018713. [Google Scholar] [CrossRef] [PubMed]
[35] Sun, L., Marin de Evsikova, C., Bian, K., Achille, A., Telles, E., Pei, H., et al. (2018) Programming and Regulation of Metabolic Homeostasis by HDAC11. EBioMedicine, 33, 157-168. [Google Scholar] [CrossRef] [PubMed]
[36] Khan, S. and Jena, G.B. (2014) Protective Role of Sodium Butyrate, a HDAC Inhibitor on Beta-Cell Proliferation, Function and Glucose Homeostasis through Modulation of P38/ERK MAPK and Apoptotic Pathways: Study in Juvenile Diabetic Rat. Chemico-Biological Interactions, 213, 1-12. [Google Scholar] [CrossRef] [PubMed]
[37] Ye, J. (2013) Improving Insulin Sensitivity with HDAC Inhibitor. Diabetes, 62, 685-687. [Google Scholar] [CrossRef] [PubMed]
[38] Huang, R., Sui, L., Fu, C., Zhai, Y., Dai, X., Zhang, S., et al. (2021) HDAC11 Inhibition Disrupts Porcine Oocyte Meiosis via Regulating α-Tubulin Acetylation and Histone Modifications. Aging, 13, 8849-8864. [Google Scholar] [CrossRef] [PubMed]
[39] Anderson, R.M., Bosch, J.A., Goll, M.G., Hesselson, D., Dong, P.D.S., Shin, D., et al. (2009) Loss of Dnmt1 Catalytic Activity Reveals Multiple Roles for DNA Methylation during Pancreas Development and Regeneration. Developmental Biology, 334, 213-223. [Google Scholar] [CrossRef] [PubMed]
[40] Yang, B.T., Dayeh, T.A., Volkov, P.A., Kirkpatrick, C.L., Malmgren, S., Jing, X., et al. (2012) Increased DNA Methylation and Decreased Expression of PDX-1 in Pancreatic Islets from Patients with Type 2 Diabetes. Molecular Endocrinology, 26, 1203-1212. [Google Scholar] [CrossRef] [PubMed]
[41] Pinney, S.E., Jaeckle Santos, L.J., Han, Y., Stoffers, D.A. and Simmons, R.A. (2011) Exendin-4 Increases Histone Acetylase Activity and Reverses Epigenetic Modifications That Silence Pdx1 in the Intrauterine Growth Retarded Rat. Diabetologia, 54, 2606-2614. [Google Scholar] [CrossRef] [PubMed]
[42] Singh, N., Dueñas‐González, A., Lyko, F. and Medina‐Franco, J.L. (2009) Molecular Modeling and Molecular Dynamics Studies of Hydralazine with Human DNA Methyltransferase. ChemMedChem, 4, 792-799. [Google Scholar] [CrossRef] [PubMed]
[43] Lee, B.H., Yegnasubramanian, S., Lin, X. and Nelson, W.G. (2005) Procainamide Is a Specific Inhibitor of DNA Methyltransferase. Journal of Biological Chemistry, 280, 40749-40756. [Google Scholar] [CrossRef] [PubMed]