Metabolomic profiling of serum in aging mice supplemented with tocotrienol-rich fraction for identification of female reproductive aging biomarkers
DOI:
https://doi.org/10.11113/mjfas.v14n4.1132Keywords:
ovarian aging, tocotrienol, metabolomics, embryoAbstract
Ovarian aging has been associated with increased oxidative stress leading to loss of ovarian function and infertility. Tocotrienol, a potent antioxidant, has been proven to exert beneficial effects in the female reproductive system. Serum metabolites were analyzed to examine the biochemical changes and to identify biomarkers related to reproductive aging that could lead to poor embryo quality and development. Female Mus musculus mice were divided into four groups. Six-month-old mice were given tocopherol-stripped corn oil as a vehicle control while other groups were supplemented orally with tocotrienol-rich fraction (TRF) at doses of 90, 120, and 150 mg/kg bodyweight for two months, respectively. After two months, mice from all groups were super ovulated, and euthanized. Embryos were collected at the 2-cell stage and cultured to monitor their development while serum was used for metabolomic analysis. The percentage of normal embryos and development of embryos to blastocyst stage were significantly higher in groups supplemented with TRF. A total of 71 metabolites that are related to reproductive aging were identified in all groups and significant changes were detected in metabolic pathways that include fatty acids, amino acids metabolism and steroid hormone biosynthesis. These changes suggest that aging has a negative impact on cellular energy storage, energy metabolism and oxidative stress that subsequently affect female fertility. Supplementation with TRF prevented the impact of age related metabolic changes on the embryo. Thus, it appears that TRF exerts a protective mechanism towards female reproductive aging.
References
Agarwal, A., Gupta, S., Sharma, R. K. (2005). Role of oxidative stress in female reproduction. Reproductive Biology and Endocrinology: RB&E, 3, 28.
Botros, L., Sakkas, D., & Seli, E. (2008). Metabolomics and its application for non-invasive embryo assessment in IVF. Molecular Human Reproduction, 14(12), 679–690.
Danilovich, N., Ram Sairam, M. (2006). Recent female mouse models displaying advanced reproductive aging. Experimental Gerontology, 41(2), 117–122.
Fong, M., McDunn, J., Kakar, S. S. (2011). Identification of metabolites in the normal ovary and their transformation in primary and metastatic ovarian cancer. PLoS ONE, 6(5), 1-12.
Fujii, J., Iuchi, Y., Okada, F. (2005). Fundamental roles of reactive oxygen species and protective mechanisms in the female reproductive system. Reproductive Biology and Endocrinology, 3(43), 1-10.
Kamsani, Y. S., Rajikin, M. H., Khan, N. A. M. N., Satar, N. A., Chatterjee, A. (2013). Nicotine-induced cessation of embryonic development is reversed by γ-tocotrienol in mice. Medical Science Monitor Basic Research, 19, 87-92.
Ke, C., Hou, Y., Zhang, H., Yang, K., Wang, J., Guo, B., Li, K. (2015). Plasma metabolic profiles in women are menopause dependent. PLoS ONE, 10(11), 1–10.
Khor, S. C., Wan Ngah, W. Z., Mohd Yusof, Y. A., Abdul Karim, N., Makpol, S. (2017). Tocotrienol-rich fraction ameliorates antioxidant defense mechanisms and improves replicative senescence-associated oxidative stress in human myoblasts. Oxidative Medicine and Cellular Longevity, 2017, 1-17.
Lawton, K. A., Berger, A., Mitchell, M., Milgram, K. E., Evans, A. M., Guo, L., Milburn, M. V. (2008). Analysis of the adult human plasma metabolome. Pharmacogenomics, 9(4), 383–397.
Liu, J., Liu, M., Ye, X., Liu, K., Huang, J., Wang, L.,Ji, G., Liu, N., Tang, X., Baltz, J.M., Keefe D.L., Liu, L. (2012). Delay in oocyte aging in mice by the antioxidant N-acetyl-l-cysteine (NAC). Human Reproduction, 27(5), 1411–1420.
Mascarenhas, M. N., Flaxman, S. R., Boerma, T., Vanderpoel, S., Stevens, G. A. (2012). National, regional, and global trends in infertility prevalence since 1990: A systematic analysis of 277 health surveys. PLoS Medicine, 9(12), 1–12.
Mokhtar, N. M., Rajikin, M. H., Zakaria, Z. (2008). Role of tocotrienol-rich palm vitamin E on pregnancy and preimplantation embryos in nicotine-treated rats. Biomedical Research, 19(3), 181–184.
Nagy, A., Gertsenstein, M., Vintersten, K., Behringer, R. (2003). Manipulating the mouse embryo: A laboratory manual (Vol. 3). New York: Cold Spring Harbor Laboratory Press Cold Spring Harbor.
Nasibah, A., Rajikin, M. H., Nor-Ashikin, M. N. K., & Nuraliza, A. S. (2012). Effects of tocotrienol supplementation on pregnancy outcome in mice subjected to maternal corticosterone administration. Journal of Oil Palm Research, 24, 1550–1558.
Norerlyda, H., Fathimah, M., As, N., Mara, U. T. (2015). The Effect of tocotrienol supplementation on plasma estradiol levels and quality of embryos in aging mice. Malaysian Journal of Microscopy, 38(11), 32–38.
Nur Azlina, M. F., Nafeeza, M. I. (2008). Tocotrienol and a-tocopherol reduce corticosterone and noradrenalin levels in rats exposed to restraint stress. Pharmazie, 63(12), 890–892.
Saidatul, A. K., Nasibah, A., Esa, N. Y., Nuraliza, A. (2014). Time-dependant effect of tocotrienol supplementation the quality of aging mouse embryo. Malaysian Journal of Microscopy, 10, 6-12.
Saleh, H. S., Omar, E., and Froemming, G. R. A. (2015). Tocotrienolpreseryes ovarian function in cyclophosphamide therapy. Human and Experimental Toxicology, 34(10), 946-952.
Sanderson, J. T. (2006). The steroid hormone biosynthesis pathway as a target for endocrine-disrupting chemicals. Toxicological Sciences, 94(1), 3–21.
Shahidee, Z. A., Effendi, I., Nasibah, A., Nuraliza, A. S. (2013). A time-dependent study on the effect of corticosterone-induced DNA damage in mouse embryos. Acta Biologica Malaysiana, 2(2), 45-53.
Sukur, Y. E., Balik Kivancli, I., Ozmen, B. (2014). Ovarian aging and premature ovarian failure. Journal of the Turkish German Gynecological Association, 15(3), 190–196.
Xia, L., Zhao, X., Sun, Y., Hong, Y., Gao, Y., Hu, S. (2014). Metabolomic profiling of human follicular fluid from patients with repeated failure of in vitro fertilization using gas chromatography/mass spectrometry. International Journal of Clinical and Experimental Pathology, 7(10), 7220–7229.
