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Dynamics of serum exosome microRNA profile altered by chemically induced estropause and rescued by estrogen therapy in female mice

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Abstract

The decline in the ovarian reserve leads to menopause and reduced serum estrogens. MicroRNAs are small non-coding RNAs, which can regulate gene expression and be secreted by cells and trafficked in serum via exosomes. Serum miRNAs regulate tissue function and disease development. Therefore, the aim of this study was to identify miRNA profiles in serum exosomes of mice induced to estropause and treated with 17β-estradiol (E2). Female mice were divided into three groups including control (CTL), injected with 4-Vinylcyclohexene diepoxide (VCD), and injected with VCD plus E2 (VCD + E2). Estropause was confirmed by acyclicity and a significant reduction in the number of ovarian follicles (p < 0.05). Body mass gain during estropause was higher in VCD and VCD + E2 compared to CTL females (p = 0.02). Sequencing of miRNAs was performed from exosomes extracted from serum, and 402 miRNAs were detected. Eight miRNAs were differentially regulated between CTL and VCD groups, seven miRNAs regulated between CTL and VCD + E2 groups, and ten miRNAs regulated between VCD and VCD + E2 groups. Only miR-200a-3p and miR-200b-3p were up-regulated in both serum exosomes and ovarian tissue in both VCD groups, suggesting that these exosomal miRNAs could be associated with ovarian activity. In the hepatic tissue, only miR-370-3p (p = 0.02) was up-regulated in the VCD + E2 group, as observed in serum. Our results suggest that VCD-induced estropause and E2 replacement have an impact on the profile of serum exosomal miRNAs. The miR-200 family was increased in serum exosomes and ovarian tissue and may be a candidate biomarker of ovarian function.

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The data is available from the corresponding author upon request.

References

  1. Wang X, Wang L, Xiang W. Mechanisms of ovarian aging in women: a review. J Ovarian Res. 2023;16(1):67.

    Article  MathSciNet  PubMed  PubMed Central  Google Scholar 

  2. Finch CE. The menopause and aging, a comparative perspective. J Steroid Biochem Mol Biol. 2014;142:132–41.

    Article  PubMed  CAS  Google Scholar 

  3. Trémollieres FA, Pouilles JM, Ribot CA. Relative influence of age and menopause on total and regional body composition changes in postmenopausal women. Am J Obstet Gynecol. 1996;175(6):1594–600.

    Article  PubMed  Google Scholar 

  4. Ghigliotti G, Barisione C, Garibaldi S, Fabbi P, Brunelli C, Spallarossa P, Altieri P, Rosa G, Spinella G, Palombo D, Arsenescu R, Arsenescu V. Adipose tissue immune response: novel triggers and consequences for chronic inflammatory conditions. Inflammation. 2014;37(4):1337–53.

    Article  PubMed  CAS  Google Scholar 

  5. Mauvais-Jarvis F, Clegg DJ, Hevener AL. The role of estrogens in control of energy balance and glucose homeostasis. Endocr Rev. 2013;34(3):309–38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Pu D, Tan R, Yu Q, Wu J. Metabolic syndrome in menopause and associated factors: a meta-analysis. Climacteric. 2017;20(6):583–91.

    Article  PubMed  CAS  Google Scholar 

  7. Gordon JL, Peltier A, Grummisch JA, Sykes Tottenham L. Estradiol fluctuation, sensitivity to stress, and depressive symptoms in the menopause transition: a pilot study. Front Psychol. 2019;10:1319.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Rozenberg S, Vandromme J, Antoine C. Postmenopausal hormone therapy: risks and benefits. Nat Rev Endocrinol. 2013;9(4):216–27.

    Article  PubMed  CAS  Google Scholar 

  9. Sprague BL, Trentham-Dietz A, Cronin KA. A sustained decline in postmenopausal hormone use: results from the National Health and Nutrition Examination Survey, 1999–2010. Obstet Gynecol. 2012;120(3):595–603.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Koebele SV, Bimonte-Nelson HA. The endocrine-brain-aging triad where many paths meet: female reproductive hormone changes at midlife and their influence on circuits important for learning and memory. Exp Gerontol. 2017;94:14–23.

    Article  PubMed  CAS  Google Scholar 

  11. Zidon TM, Padilla J, Fritsche KL, Welly RJ, McCabe LT, Stricklin OE, Frank A, Park Y, Clegg DJ, Lubahn DB, Kanaley JA, Vieira-Potter VJ. Effects of ERβ and ERα on OVX-induced changes in adiposity and insulin resistance. J Endocrinol. 2020;245(1):165–78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Fuller KNZ, McCoin CS, Von Schulze AT, Houchen CJ, Choi MA, Thyfault JP. Estradiol treatment or modest exercise improves hepatic health and mitochondrial outcomes in female mice following ovariectomy. Am J Physiol Endocrinol Metab. 2021;320(6):E1020-e1031.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Kappeler CJ, Hoyer PB. 4-vinylcyclohexene diepoxide: a model chemical for ovotoxicity. Syst Biol Reprod Med. 2012;58(1):57–62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Li Y, Fang Y, Liu Y, Yang X. MicroRNAs in ovarian function and disorders. J Ovarian Res. 2015;8(1):51.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Pestana-Oliveira N, Kalil B, Leite CM, Carolino ROG, Debarba LK, Elias LLK, Antunes-Rodrigues J, Anselmo-Franci JA. Effects of estrogen therapy on the serotonergic system in an animal model of perimenopause induced by 4-vinylcyclohexen diepoxide (VCD). ENeuro. 2018;5(1):e0247–17.

  16. Reis F, Pestana-Oliveira N, Leite C, Lima F, Brandão ML, Graeff FG, Del-Ben CM, Anselmo-Franci JA. Hormonal changes and increased anxiety-like behavior in a perimenopause-animal model induced by 4-vinylcyclohexene diepoxide (VCD) in female rats. Psychoneuroendocrinology. 2014;49:130–40.

    Article  PubMed  CAS  Google Scholar 

  17. Ávila BM, Zanini BM, Luduvico KP, Hense JD, Garcia DN, Prosczek J, Stefanello FM, Mason JB, Masternak MM, Schneider A. Effect of calorie restriction on redox status during chemically induced estropause in female mice. GeroScience. 2024;46(2):2139–51.

  18. Romero-Aleshire MJ, Diamond-Stanic MK, Hasty AH, Hoyer PB, Brooks HL. Loss of ovarian function in the VCD mouse-model of menopause leads to insulin resistance and a rapid progression into the metabolic syndrome. Am J Physiol Regul Integr Comp Physiol. 2009;297(3):R587–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Keck M, Romero-Aleshire MJ, Cai Q, Hoyer PB, Brooks HL. Hormonal status affects the progression of STZ-induced diabetes and diabetic renal damage in the VCD mouse model of menopause. Am J Physiol Renal Physiol. 2007;293(1):F193–9.

    Article  PubMed  CAS  Google Scholar 

  20. Catalanotto C, Cogoni C, Zardo G. MicroRNA in control of gene expression: an overview of nuclear functions. Int J Mol Sci. 2016;17(10):1712.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Makarova JA, Shkurnikov MU, Wicklein D, Lange T, Samatov TR, Turchinovich AA, Tonevitsky AG. Intracellular and extracellular microRNA: an update on localization and biological role. Prog Histochem Cytochem. 2016;51(3):33–49.

    Article  PubMed  Google Scholar 

  22. Luga V, Zhang L, Viloria-Petit AM, Ogunjimi AA, Inanlou MR, Chiu E, Buchanan M, Hosein AN, Basik M, Wrana JL. Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell. 2012;151(7):1542–56.

    Article  PubMed  CAS  Google Scholar 

  23. Yang C, Robbins PD. The roles of tumor-derived exosomes in cancer pathogenesis. Clin Dev Immunol. 2011;2011:842849.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Clayton A, Turkes A, Dewitt S, Steadman R, Mason MD, Hallett MB. Adhesion and signaling by B cell-derived exosomes: the role of integrins. Faseb j. 2004;18(9):977–9.

    Article  PubMed  CAS  Google Scholar 

  25. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020;367(6478):eaau6977.

  26. D’Anca M, Fenoglio C, Serpente M, Arosio B, Cesari M, Scarpini EA, Galimberti D. Exosome Determinants of Physiological Aging and Age-Related Neurodegenerative Diseases. Front Aging Neurosci. 2019;11:232.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Kangas R, Pöllänen E, Rippo MR, Lanzarini C, Prattichizzo F, Niskala P, Jylhävä J, Sipilä S, Kaprio J, Procopio AD, Capri M, Franceschi C, Olivieri F, Kovanen V. Circulating miR-21, miR-146a and Fas ligand respond to postmenopausal estrogen-based hormone replacement therapy–a study with monozygotic twin pairs. Mech Ageing Dev. 2014;143–144:1–8.

    Article  PubMed  Google Scholar 

  28. Schneider A, Matkovich SJ, Victoria B, Spinel L, Bartke A, Golusinski P, Masternak MM. Changes of ovarian microRNA profile in long-living ames dwarf mice during aging. PLoS ONE. 2017;12(1):e0169213.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Micheli F, Palermo R, Talora C, Ferretti E, Vacca A, Napolitano M. Regulation of proapoptotic proteins Bak1 and p53 by miR-125b in an experimental model of Alzheimer’s disease: protective role of 17β-estradiol. Neurosci Lett. 2016;629:234–40.

    Article  PubMed  CAS  Google Scholar 

  30. Jiang CF, Li DM, Shi ZM, Wang L, Liu MM, Ge X, Liu X, Qian YC, Wen YY, Zhen LL, Lin J, Liu LZ, Jiang BH. Estrogen regulates miRNA expression: implication of estrogen receptor and miR-124/AKT2 in tumor growth and angiogenesis. Oncotarget. 2016;7(24):36940–55.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Gómez-Gómez Y, Organista-Nava J, Ocadiz-Delgado R, García-Villa E, Leyva-Vazquez MA, Illades-Aguiar B, Lambert PF, García-Carrancá A, Gariglio P. The expression of miR-21 and miR-143 is deregulated by the HPV16 E7 oncoprotein and 17β-estradiol. Int J Oncol. 2016;49(2):549–58.

    Article  PubMed  Google Scholar 

  32. Martin M. Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet journal. 2011;17(1):10–2.

    Article  Google Scholar 

  33. Saccon TD, Schneider A, Marinho CG, Nunes AD, Noureddine S, Dhahbi J, Nunez Lopez YO, LeMunyan G, Salvatori R, Oliveira CR. Circulating microRNA profile in humans and mice with congenital GH deficiency. Aging Cell. 2021;20(7):e13420.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Vlachos IS, Zagganas K, Paraskevopoulou MD, Georgakilas G, Karagkouni D, Vergoulis T, Dalamagas T, Hatzigeorgiou AG. DIANA-miRPath v3.0: deciphering microRNA function with experimental support. Nucleic Acids Res. 2015;43(W1):W460-6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Kanehisa M, Goto S. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000;28(1):27–30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Kanehisa M, Sato Y, Kawashima M, Furumichi M, Tanabe M. KEGG as a reference resource for gene and protein annotation. Nucleic Acids Res. 2016;44(D1):D457–62.

    Article  PubMed  CAS  Google Scholar 

  37. Robinson MD, McCarthy DJ, Smyth GK. edgeR: a bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26(1):139–40.

    Article  PubMed  CAS  Google Scholar 

  38. Kosaka N, Iguchi H, Ochiya T. Circulating microRNA in body fluid: a new potential biomarker for cancer diagnosis and prognosis. Cancer Sci. 2010;101(10):2087–92.

    Article  PubMed  CAS  Google Scholar 

  39. Sugatani T, Hruska KA. Down-regulation of miR-21 biogenesis by estrogen action contributes to osteoclastic apoptosis. J Cell Biochem. 2013;114(6):1217–22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Kumar S, Keerthana R, Pazhanimuthu A, Perumal P. Overexpression of circulating miRNA-21 and miRNA-146a in plasma samples of breast cancer patients. 2013;50(3):210–4.

  41. Vinciguerra M, Sgroi A, Veyrat-Durebex C, Rubbia-Brandt L, Buhler LH, Foti M. Unsaturated fatty acids inhibit the expression of tumor suppressor phosphatase and tensin homolog (PTEN) via microRNA-21 up-regulation in hepatocytes#. Hepatology. 2009;49(4):1176–84.

    Article  PubMed  CAS  Google Scholar 

  42. Tchernof A, Desmeules A, Richard C, Laberge P, Daris M, Mailloux J, Rhéaume C, Dupont P. Ovarian hormone status and abdominal visceral adipose tissue metabolism. J Clin Endocrinol Metab. 2004;89(7):3425–30.

    Article  PubMed  CAS  Google Scholar 

  43. Tara M, Souza SC, Aronovitz M, Obin MS, Fried SK, Greenberg AS. Estrogen regulation of adiposity and fuel partitioning: evidence of genomic and non-genomic regulation of lipogenic and oxidative pathways. J Biol Chem. 2005;280(43):35983–91.

    Article  Google Scholar 

  44. Kangas R, Törmäkangas T, Fey V, Pursiheimo J, Miinalainen I, Alen M, Kaprio J, Sipilä S, Säämänen A-M, Kovanen V, Laakkonen EK. Aging and serum exomiR content in women-effects of estrogenic hormone replacement therapy. Sci Rep. 2017;7(1):42702.

    Article  ADS  PubMed  PubMed Central  CAS  Google Scholar 

  45. Yan H, Yang W, Zhou F, Li X, Pan Q, Shen Z, Han G, Newell-Fugate A, Tian Y, Majeti R, Liu W, Xu Y, Wu C, Allred K, Allred C, Sun Y, Guo S. Estrogen improves insulin sensitivity and suppresses gluconeogenesis via the transcription factor foxo1. Diabetes. 2019;68(2):291–304.

    Article  PubMed  CAS  Google Scholar 

  46. Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panourgia MP, Invidia L, Celani L, Scurti M. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev. 2007;128(1):92–105.

    Article  PubMed  CAS  Google Scholar 

  47. Muhammad FS, Goode AK, Kock ND, Arifin EA, Cline JM, Adams MR, Hoyer PB, Christian PJ, Isom S, Kaplan JR, Appt SE. Effects of 4-vinylcyclohexene diepoxide on peripubertal and adult Sprague-Dawley rats: ovarian, clinical, and pathologic outcomes. Comp Med. 2009;59(1):46–59.

    PubMed  PubMed Central  CAS  Google Scholar 

  48. Rogers NH, Perfield JW 2nd, Strissel KJ, Obin MS, Greenberg AS. Reduced energy expenditure and increased inflammation are early events in the development of ovariectomy-induced obesity. Endocrinology. 2009;150(5):2161–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Alvi SM, Zayed Y, Malik R, Peng C. The emerging role of microRNAs in fish ovary: a mini review. Gen Comp Endocrinol. 2021;311:113850.

    Article  PubMed  CAS  Google Scholar 

  50. Kim J, You S. Comprehensive analysis of miRNA-mRNA interactions in ovaries of aged mice. Anim Sci J. 2022;93(1):e13721.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Choi PW, Ng SW. The functions of MicroRNA-200 family in ovarian cancer: beyond epithelial-mesenchymal transition. Int J Mol Sci. 2017;18(6):1207

  52. Rodriguez C, Calle EE, Fakhrabadi-Shokoohi D, Jacobs EJ, Thun MJ. Body mass index, height, and the risk of ovarian cancer mortality in a prospective cohort of postmenopausal women. Cancer Epidemiol Biomark Prev. 2002;11(9):822–8.

    Google Scholar 

  53. Choi P-W, Ng S-W. The functions of microRNA-200 family in ovarian cancer: beyond epithelial-mesenchymal transition. Int J Mol Sci. 2017;18(6):1207.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Hu Z, Mamillapalli R, Taylor HS. Increased circulating miR-370-3p regulates steroidogenic factor 1 in endometriosis. Am J Physiol Endocrinol Metab. 2019;316(3):E373–82.

    Article  PubMed  CAS  Google Scholar 

  55. Attar E, Tokunaga H, Imir G, Yilmaz MB, Redwine D, Putman M, Gurates B, Attar R, Yaegashi N, Hales DB, Bulun SE. Prostaglandin E2 via steroidogenic factor-1 coordinately regulates transcription of steroidogenic genes necessary for estrogen synthesis in endometriosis. J Clin Endocrinol Metab. 2009;94(2):623–31.

    Article  PubMed  CAS  Google Scholar 

  56. Kim DH, Bang E, Ha S, Jung HJ, Choi YJ, Yu BP, Chung HY. Organ-differential roles of Akt/FoxOs axis as a key metabolic modulator during aging. Aging Dis. 2021;12(7):1713.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Wu JJ, Liu J, Chen EB, Wang JJ, Cao L, Narayan N, Fergusson MM, Rovira II, Allen M, Springer DA, Lago CU, Zhang S, DuBois W, Ward T, deCabo R, Gavrilova O, Mock B, Finkel T. Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression. Cell Rep. 2013;4(5):913–20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Schneider A, Zhi X, Moreira F, Lucia T, Mondadori RG, Masternak MM. Primordial follicle activation in the ovary of Ames dwarf mice. J Ovarian Res. 2014;7(1):1–9.

    Article  Google Scholar 

  59. Mylonas KJ, O’Sullivan ED, Humphries D, Baird DP, Docherty M-H, Neely SA, Krimpenfort PJ, Melk A, Schmitt R, Ferreira-Gonzalez S, Forbes SJ, Hughes J, Ferenbach DA. Cellular senescence inhibits renal regeneration after injury in mice, with senolytic treatment promoting repair. Sci Transl Med. 2021;13(594):eabb0203.

    Article  PubMed  CAS  Google Scholar 

  60. Rapisarda V, Borghesan M, Miguela V, Encheva V, Snijders AP, Lujambio A, O’Loghlen A. Integrin beta 3 regulates cellular senescence by activating the TGF-β pathway. Cell Rep. 2017;18(10):2480–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Pruitt SC, Freeland A, Rusiniak ME, Kunnev D, Cady GK. Cdkn1b overexpression in adult mice alters the balance between genome and tissue ageing. Nat Commun. 2013;4(1):2626.

    Article  ADS  PubMed  Google Scholar 

  62. Mayer LP, Pearsall NA, Christian PJ, Devine PJ, Payne CM, McCuskey MK, Marion SL, Sipes IG, Hoyer PB. Long-term effects of ovarian follicular depletion in rats by 4-vinylcyclohexene diepoxide. Reprod Toxicol. 2002;16(6):775–81.

    Article  PubMed  CAS  Google Scholar 

  63. Chen H, Perez JN, Constantopoulos E, McKee L, Regan J, Hoyer PB, Brooks HL, Konhilas J. A method to study the impact of chemically-induced ovarian failure on exercise capacity and cardiac adaptation in mice. JoVE (Journal of Visualized Experiments). 2014;86:e51083.

    Google Scholar 

  64. Lovejoy JC, Champagne C, De Jonge L, Xie H, Smith S. Increased visceral fat and decreased energy expenditure during the menopausal transition. Int J Obes. 2008;32(6):949–58.

    Article  CAS  Google Scholar 

  65. Roesch DM. Effects of selective estrogen receptor agonists on food intake and body weight gain in rats. Physiol Behav. 2006;87(1):39–44.

    Article  PubMed  CAS  Google Scholar 

  66. Qi X, Guo Y, Song Y, Yu C, Zhao L, Fang L, Kong D, Zhao J, Gao L. Follicle-stimulating hormone enhances hepatic gluconeogenesis by GRK2-mediated AMPK hyperphosphorylation at Ser485 in mice. Diabetologia. 2018;61:1180–92.

    Article  PubMed  CAS  Google Scholar 

  67. Depypere H, Dierickx A, Vandevelde F, Stanczyk F, Ottoy L, Delanghe J, Lapauw B. A randomized trial on the effect of oral combined estradiol and drospirenone on glucose and insulin metabolism in healthy menopausal women with a normal oral glucose tolerance test. Maturitas. 2020;138:36–41.

    Article  PubMed  CAS  Google Scholar 

  68. Koebele SV, Nishimura KJ, Bimonte-Nelson HA, Kemmou S, Ortiz JB, Judd JM, Conrad CD. A long-term cyclic plus tonic regimen of 17β-estradiol improves the ability to handle a high spatial working memory load in ovariectomized middle-aged female rats. Horm Behav. 2020;118:104656.

    Article  PubMed  CAS  Google Scholar 

  69. Ji C, Guo X. The clinical potential of circulating microRNAs in obesity. Nat Rev Endocrinol. 2019;15(12):731–43.

    Article  PubMed  CAS  Google Scholar 

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Funding

The authors are thankful for the funding support provided by CAPES, CNPq, and FAPERGS to A.S., the National Institute on Aging of the National Institutes of Health under Award Number R56AG074499 to M.M.M and R56AG069676, R56AG064075, RF1AG071762, R21AG072379, U01AG076928, R21DE032197 to H.Y.; the Department of Defense (W81XWH-18-PRARP AZ180098 to H.Y.); and the Ed and Ethel Moore Alzheimer’s Disease Research Program of the Florida Department of Health (22A17) to H.Y.

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Zanini, B.M., de Avila, B.M., Garcia, D.N. et al. Dynamics of serum exosome microRNA profile altered by chemically induced estropause and rescued by estrogen therapy in female mice. GeroScience (2024). https://doi.org/10.1007/s11357-024-01129-9

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