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Reproductive Biology and Endocrinology
Published in: Reproductive Biology and Endocrinology 1/2019

Open Access 01-12-2019 | Infertility | Research

Activation of Nrf2/Keap1 pathway by oral Dimethylfumarate administration alleviates oxidative stress and age-associated infertility might be delayed in the mouse ovary

Authors: Nana Akino, Osamu Wada-Hiraike, Wataru Isono, Hiromi Terao, Harunori Honjo, Yuichiro Miyamoto, Michihiro Tanikawa, Kenbun Sone, Mana Hirano, Miyuki Harada, Tetsuya Hirata, Yasushi Hirota, Kaori Koga, Katsutoshi Oda, Tomoyuki Fujii, Yutaka Osuga

Published in: Reproductive Biology and Endocrinology | Issue 1/2019

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Abstract

Background

Age-associated infertility is a problem worldwide, and management of oxidative stress is known to be essential. Nuclear factor-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)-antioxidant response element (ARE) signaling pathway works as an essential defense mechanism against oxidative stress, and an oral drug Dimethylfumarate (DMF) is known to activate the pathway.

Methods

We tested the hypothesis that oral DMF could alleviate oxidative stress in the ovary, resulting in salvation of age-associated infertility in a mouse model of reproductive age, and we examined the effects of DMF administration. 20 mg/kg DMF was administrated to female mice from 32 to 48 weeks, and Nrf2 levels, antioxidant levels, ovarian reserve, DNA damage, and oxidative stress were examined.

Results

DMF administration resulted in elevated mRNA and protein levels of Nrf2, antioxidants, and telomere, and serum levels of Nrf2 and anti-mullerian hormone were also elevated. Results of TUNEL assay and Immunohistochemistry of mice ovarian tissues showed that DNA damage and oxidative stress were decreased by DMF administration, and significantly more oocytes were collected along with preservation of 60% more primordial follicles.

Conclusions

Our data suggest that DMF administration activates the Nrf2/Keap1 pathway, elevate levels of antioxidants, and decrease DNA damage and oxidative stress, resulting in improved ovarian reserve in the mouse ovary.
Literature
1.
Ziebe S, Devroey P. Assisted reproductive technologies are an integrated part of national strategies addressing demographic and reproductive challenges. Hum Reprod Update. 2008;14(6):583–92.PubMedCrossRef
2.
Lean SC, Derricott H, Jones RL, Heazell AEP. Advanced maternal age and adverse pregnancy outcomes: a systematic review and meta-analysis. PLoS One. 2017;12(10):e0186287.PubMedPubMedCentralCrossRef
3.
Carolan M, Frankowska D. Advanced maternal age and adverse perinatal outcome: a review of the evidence. Midwifery. 2011;27(6):793–801.PubMedCrossRef
4.
Inhorn MC, Patrizio P. Infertility around the globe: new thinking on gender, reproductive technologies and global movements in the 21st century. Hum Reprod Update. 2015;21(4):411–26.PubMedCrossRef
5.
Baird DT, Collins J, Egozcue J, Evers LH, Gianaroli L, Leridon H, et al. Fertility and ageing. Hum Reprod Update. 2005;11(3):261–76.PubMedCrossRef
6.
te Velde ER, Pearson PL. The variability of female reproductive ageing. Hum Reprod Update. 2002;8(2):141–54.CrossRef
7.
Leridon H. Can assisted reproduction technology compensate for the natural decline in fertility with age? A model assessment. Human reproduction (Oxford, England). 2004;19(7):1548–53.CrossRef
8.
Maheshwari A, Porter M, Shetty A, Bhattacharya S. Women's awareness and perceptions of delay in childbearing. Fertil Steril. 2008;90(4):1036–42.PubMedCrossRef
9.
Mihalas BP, Redgrove KA, McLaughlin EA, Nixon B. Molecular mechanisms responsible for increased vulnerability of the ageing oocyte to oxidative damage. Oxidative Med Cell Longev. 2017;2017:4015874.CrossRef
10.
Al-Gubory KH, Fowler PA, Garrel C. The roles of cellular reactive oxygen species, oxidative stress and antioxidants in pregnancy outcomes. Int J Biochem Cell Biol. 2010;42(10):1634–50.PubMedCrossRef
11.
Devine PJ, Perreault SD, Luderer U. Roles of reactive oxygen species and antioxidants in ovarian toxicity. Biol Reprod. 2012;86(2):27.PubMedCrossRef
12.
Shkolnik K, Tadmor A, Ben-Dor S, Nevo N, Galiani D, Dekel N. Reactive oxygen species are indispensable in ovulation. Proc Natl Acad Sci U S A. 2011;108(4):1462–7.PubMedPubMedCentralCrossRef
13.
Akino N, Wada-Hiraike O, Terao H, Honjoh H, Isono W, Fu H, et al. Activation of Nrf2 might reduce oxidative stress in human granulosa cells. Mol Cell Endocrinol. 2018;470:96–104.PubMedCrossRef
14.
Chen B, Lu Y, Chen Y, Cheng J. The role of Nrf2 in oxidative stress-induced endothelial injuries. J Endocrinol. 2015;225(3):R83–99.PubMedCrossRef
15.
Lu MC, Ji JA, Jiang ZY, You QD. The Keap1-Nrf2-ARE pathway as a potential preventive and therapeutic target: an update. Med Res Rev. 2016;36(5):924–63.PubMedCrossRef
16.
17.
McMahon M, Itoh K, Yamamoto M, Hayes JD. Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression. J Biol Chem. 2003;278(24):21592–600.PubMedCrossRef
18.
Singh B, Chatterjee A, Ronghe AM, Bhat NK, Bhat HK. Antioxidant-mediated up-regulation of OGG1 via NRF2 induction is associated with inhibition of oxidative DNA damage in estrogen-induced breast cancer. BMC Cancer. 2013;13:253.PubMedPubMedCentralCrossRef
19.
Fahey JW, Haristoy X, Dolan PM, Kensler TW, Scholtus I, Stephenson KK, et al. Sulforaphane inhibits extracellular, intracellular, and antibiotic-resistant strains of helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors. Proc Natl Acad Sci U S A. 2002;99(11):7610–5.PubMedPubMedCentralCrossRef
20.
Uruno A, Furusawa Y, Yagishita Y, Fukutomi T, Muramatsu H, Negishi T, et al. The Keap1-Nrf2 system prevents onset of diabetes mellitus. Mol Cell Biol. 2013;33(15):2996–3010.PubMedPubMedCentralCrossRef
21.
Chen PC, Vargas MR, Pani AK, Smeyne RJ, Johnson DA, Kan YW, et al. Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: critical role for the astrocyte. Proc Natl Acad Sci U S A. 2009;106(8):2933–8.PubMedPubMedCentralCrossRef
22.
Akino N, Isono W, Wada-Hiraike O. Predicting suitable timing for artificial reproductive technology treatment in aged infertile women. Reproductive medicine and biology. 2016;15(4):253–9.PubMedPubMedCentralCrossRef
23.
Suneetha A, Raja RK. Role of dimethyl fumarate in oxidative stress of multiple sclerosis: a review. J Chromatogr B Anal Technol Biomed Life Sci. 2016;1019:15–20.CrossRef
24.
Lee DH, Gold R, Linker RA. Mechanisms of oxidative damage in multiple sclerosis and neurodegenerative diseases: therapeutic modulation via fumaric acid esters. Int J Mol Sci. 2012;13(9):11783–803.PubMedPubMedCentralCrossRef
25.
Tanaka M, Shimizu Y. [dimethyl fumarate in multiple sclerosis]. Brain and nerve =. Shinkei kenkyu no shinpo. 2017;69(9):1041–6.PubMed
26.
Wang Q, Chuikov S, Taitano S, Wu Q, Rastogi A, Tuck SJ, et al. Dimethyl fumarate protects neural stem/progenitor cells and neurons from oxidative damage through Nrf2-ERK1/2 MAPK pathway. Int J Mol Sci. 2015;16(6):13885–907.PubMedPubMedCentralCrossRef
27.
Copple IM. The Keap1-Nrf2 cell defense pathway--a promising therapeutic target? Advances in pharmacology (San Diego, Calif). 2012;63:43–79.
28.
Majkutewicz I, Kurowska E, Podlacha M, Myslinska D, Grembecka B, Rucinski J, et al. Age-dependent effects of dimethyl fumarate on cognitive and neuropathological features in the streptozotocin-induced rat model of Alzheimer's disease. Brain Res. 1686;2018:19–33.
29.
Hu X, Rajesh M, Zhang J, Zhou S, Wang S, Sun J, et al. Protection by dimethyl fumarate against diabetic cardiomyopathy in type 1 diabetic mice likely via activation of nuclear factor erythroid-2 related factor 2. Toxicol Lett. 2018;287:131–41.PubMedCrossRef
30.
Casili G, Campolo M, Paterniti I, Lanza M, Filippone A, Cuzzocrea S, et al. Dimethyl fumarate attenuates Neuroinflammation and neurobehavioral deficits induced by experimental traumatic brain injury. J Neurotrauma. 2018;35(13):1437–51.PubMedCrossRef
31.
Giustina AD, Bonfante S, Zarbato GF, Danielski LG, Mathias K, de Oliveira AN Jr, et al. Dimethyl fumarate modulates oxidative stress and inflammation in organs after Sepsis in rats. Inflammation. 2018;41(1):315–27.PubMedCrossRef
32.
Liu Y, Qiu J, Wang Z, You W, Wu L, Ji C, et al. Dimethylfumarate alleviates early brain injury and secondary cognitive deficits after experimental subarachnoid hemorrhage via activation of Keap1-Nrf2-ARE system. J Neurosurg. 2015;123(4):915–23.PubMedCrossRef
33.
Ha CM, Park S, Choi YK, Jeong JY, Oh CJ, Bae KH, et al. Activation of Nrf2 by dimethyl fumarate improves vascular calcification. Vasc Pharmacol. 2014;63(1):29–36.CrossRef
34.
Lastres-Becker I, Garcia-Yague AJ, Scannevin RH, Casarejos MJ, Kugler S, Rabano A, et al. Repurposing the NRF2 activator dimethyl fumarate as therapy against Synucleinopathy in Parkinson's disease. Antioxid Redox Signal. 2016;25(2):61–77.PubMedPubMedCentralCrossRef
35.
Mishra B, Ortiz L, Luderer U. Charged iron particles, components of space radiation, destroy ovarian follicles. Human reproduction (Oxford, England). 2016;31(8):1816–26.CrossRef
36.
Lim J, Lawson GW, Nakamura BN, Ortiz L, Hur JA, Kavanagh TJ, et al. Glutathione-deficient mice have increased sensitivity to transplacental benzo[a]pyrene-induced premature ovarian failure and ovarian tumorigenesis. Cancer Res. 2013;73(2):908–17.PubMedCrossRef
37.
Isono W, Wada-Hiraike O, Kawamura Y, Fujii T, Osuga Y, Kurihara H. Administration of Oral Contraceptives Could Alleviate Age-Related Fertility Decline Possibly by Preventing Ovarian Damage in a Mouse Model. Reproductive sciences (Thousand Oaks, Calif). 2017:1933719117746758.
38.
Shao J, Glorieux C, Liao J, Chen P, Lu W, Liang Z, et al. Impact of Nrf2 on tumor growth and drug sensitivity in oncogenic K-ras-transformed cells in vitro and in vivo. Free Radic Res. 2018:1–11.
39.
Guo H, Adah D, James PB, Liu Q, Li G, Ahmadu P, et al. Xueshuantong injection (lyophilized) attenuates cerebral ischemia/reperfusion injury by the activation of Nrf2-VEGF pathway. Neurochem Res. 2018;43(5):1096–103.PubMedCrossRef
40.
Mutter FE, Park BK, Copple IM. Value of monitoring Nrf2 activity for the detection of chemical and oxidative stress. Biochem Soc Trans. 2015;43(4):657–62.PubMedPubMedCentralCrossRef
41.
Dizdaroglu M, Jaruga P, Birincioglu M, Rodriguez H. Free radical-induced damage to DNA: mechanisms and measurement. Free Radic Biol Med. 2002;32(11):1102–15.PubMedCrossRef
42.
Liu M, Yin Y, Ye X, Zeng M, Zhao Q, Keefe DL, et al. Resveratrol protects against age-associated infertility in mice. Human reproduction (Oxford, England). 2013;28(3):707–17.
43.
Depmann M, Faddy MJ, van der Schouw YT, Peeters PH, Broer SL, Kelsey TW, et al. The relationship between variation in size of the primordial follicle Pool and age at natural menopause. J Clin Endocrinol Metab. 2015;100(6):E845–51.PubMedCrossRef
44.
Findlay JK, Hutt KJ, Hickey M, Anderson RA. How is the number of primordial follicles in the ovarian reserve established? Biol Reprod. 2015;93(5):111.PubMedCrossRef
45.
Kevenaar ME, Meerasahib MF, Kramer P, van de Lang-Born BM, de Jong FH, Groome NP, et al. Serum anti-mullerian hormone levels reflect the size of the primordial follicle pool in mice. Endocrinology. 2006;147(7):3228–34.PubMedCrossRef
46.
47.
48.
Kalmbach KH, Fontes Antunes DM, Dracxler RC, Knier TW, Seth-Smith ML, Wang F, et al. Telomeres and human reproduction. Fertil Steril. 2013;99(1):23–9.PubMedCrossRef
49.
Schaetzlein S, Lucas-Hahn A, Lemme E, Kues WA, Dorsch M, Manns MP, et al. Telomere length is reset during early mammalian embryogenesis. Proc Natl Acad Sci U S A. 2004;101(21):8034–8.PubMedPubMedCentralCrossRef
50.
Liu L, Blasco M, Trimarchi J, Keefe D. An essential role for functional telomeres in mouse germ cells during fertilization and early development. Dev Biol. 2002;249(1):74–84.PubMedCrossRef
51.
Huang J, Okuka M, McLean M, Keefe DL, Liu L. Telomere susceptibility to cigarette smoke-induced oxidative damage and chromosomal instability of mouse embryos in vitro. Free Radic Biol Med. 2010;48(12):1663–76.PubMedCrossRef
52.
53.
Greider CW, Blackburn EH. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell. 1985;43(2 Pt 1):405–13.CrossRef
54.
Ling X, Yang W, Zou P, Zhang G, Wang Z, Zhang X, et al. TERT regulates telomere-related senescence and apoptosis through DNA damage response in male germ cells exposed to BPDE in vitro and to B[a]P in vivo. Environmental pollution (Barking, Essex : 1987). 2018;235:836–49.
55.
Sahin E, Colla S, Liesa M, Moslehi J, Muller FL, Guo M, et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature. 2011;470(7334):359–65.PubMedPubMedCentralCrossRef
Metadata
Title
Activation of Nrf2/Keap1 pathway by oral Dimethylfumarate administration alleviates oxidative stress and age-associated infertility might be delayed in the mouse ovary
Authors
Nana Akino
Osamu Wada-Hiraike
Wataru Isono
Hiromi Terao
Harunori Honjo
Yuichiro Miyamoto
Michihiro Tanikawa
Kenbun Sone
Mana Hirano
Miyuki Harada
Tetsuya Hirata
Yasushi Hirota
Kaori Koga
Katsutoshi Oda
Tomoyuki Fujii
Yutaka Osuga
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Reproductive Biology and Endocrinology / Issue 1/2019
Electronic ISSN: 1477-7827
DOI
https://doi.org/10.1186/s12958-019-0466-y

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