Share This Article:

In-Vitro Determination of Biological and Anabolic Functions of Weak Androgen Dehydroepiandrosterone (DHEA) Using a Variety of Cell Lines

Abstract Full-Text HTML XML Download Download as PDF (Size:2594KB) PP. 105-116
DOI: 10.4236/ojemd.2015.58014    2,577 Downloads   2,953 Views   Citations

ABSTRACT

Dehydroepiandrosterone (DHEA) is a weak androgen and is shown to have anti-cancer, anti-atherogenic, anti-adipogenic and anti-inflammatory effects on mouse, rat and rabbit models. However, human clinical trials data did not support animal findings and were inconclusive. These systemic differences in biological actions between rodents and humans were attributed to the low level of DHEA in rodents. In order to further understand the differences in biological functions between rodents and humans, we resorted to an in-vitroapproach involving mouse, rat and human cell lines to assess DHEA biological and anabolic functions separately and independently without systemic influence. Results indicated that DHEA was effective on mouse and rat cell lines but not on human cell lines, as observed in in-vivo studies. In addition, our in-vitrostudy showed that DHEA was able to induce myogenesis in mouse mesenchymal cells revealing its anabolic function, even though DHEA was considered as a weak androgen. This observation lent credence to the ban on DHEA by IOC medical commission, citing DHEA as an anabolic steroid. These in-vitro experiments suggested that the differences in biological actions of DHEA between rodents and humans existed not only in-vivo at the systemic level, but also in-vitro at the cellular level and thus paving the way to study the mechanism responsible for these differences at the cellular level itself.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Cox, J. , Chang, Y. and Ramaraj, P. (2015) In-Vitro Determination of Biological and Anabolic Functions of Weak Androgen Dehydroepiandrosterone (DHEA) Using a Variety of Cell Lines. Open Journal of Endocrine and Metabolic Diseases, 5, 105-116. doi: 10.4236/ojemd.2015.58014.

References

[1] Symington, T., Duguid, W.P. and Davidson, J.N. (1956) Effect of Exogenous Corticotropin on the Histochemical Pattern of the Human Adrenal Cortex and a Comparison with the Changes during Stress. The Journal of Clinical Endocrinology and Metabolism, 16, 580-598. http://dx.doi.org/10.1210/jcem-16-5-580
[2] Hall, P.F., Sozer, C.C. and Eik-Nes, K.B. (1964) Formation of Dehydroepiandrosterone during in Vivo and in Vitro Biosynthesis of Testosterone by Testicular Tissue. Endocrinology, 74, 35-43.
http://dx.doi.org/10.1210/endo-74-1-35
[3] Aakvaag, A., Hagen, A.A. and Eik-Nes, K.B. (1964) Biosynthesis in Vivo of Testosterone and Androstenedione from Dehydroepiandrosterone-Sodium Sulfate by the Canine Testis and Ovary. Biochimica et Biophysica Acta, 86, 622-627. http://dx.doi.org/10.1016/0304-4165(64)90102-3
[4] Klatz, R. and Kahn, C. (1997) Grow Young with HGH. Harper Collins Publishers Inc., New York, 186-189, 191.
[5] Labrie, F. (1991) Intracrinology. Molecular and Cellular Endocrinology, 78, C113-C118.
http://dx.doi.org/10.1016/0303-7207(91)90116-A
[6] Labrie, F., Belanger, A., Simard, J., Luu-The, V. and Labrie, C. (1995) DHEA and Peripheral Androgen and Estrogen Formation: Intracrinology. Annals of the New York Academy of Sciences, 774, 16-28. http://dx.doi.org/10.1111/j.1749-6632.1995.tb17369.x
[7] Kalimi, M. and Regelson, M. (1990) The Biological Role of Dehydroepiandrosterone (DHEA). Walter de Gruyter, New York.
[8] Webb, S.J., Geoghegan, T.E., Prough, R.A. and Michael Miller, K.K. (2006) The Biological Actions of Dehydroepiandrosterone Involves Multiple Receptors. Drug Metabolism Reviews, 38, 89-116.
http://dx.doi.org/10.1080/03602530600569877
[9] Khorram, O. (1996) DHEA: A Hormone with Multiple Effects. Current Opinion in Obstetrics and Gynecology, 8, 351-354. http://dx.doi.org/10.1097/00001703-199610000-00006
[10] Ravaglia, G., Forti, P., Maioli, F., Boschi, F., Bernardi, M., Pratelli, L., Pizzoferrato, A. and Gasbarrini, G. (1996) The Relationship of Dehydroepiandrosterone Sulfate (DHEAS) to Endocrine-Metabolic Parameters and Functional Status in the Oldest-Old. Results from an Italian Study on Healthy Free-Living Over-Ninety-Year-Olds. The Journal of Clinical Endocrinology and Metabolism, 81, 1173-1178.
[11] Labrie, F., Luu-The, V., Belanger, A., Lin, S.-X., Simard, J., Pelletier, G. and Labrie, C. (2005) Is Dehydroepiandrosterone a Hormone? Journal of Endocrinology, 187, 169-196.
http://dx.doi.org/10.1677/joe.1.06264
[12] http://www.benbest.com/nutrceut/DHEA.html
[13] Williams, J.R. (2000) The Effects of Dehydroepiandrosterone on Carcinogenesis, Obesity, the Immune System and Aging. Lipids, 35, 325-331. http://dx.doi.org/10.1007/s11745-000-0529-7
[14] http://www.invive.com/dhea.html
[15] http://primev.com/DHEA.htm
[16] Gordon, G.B., Shantz, L.M. and Talalay, P. (1987) Modulation of Growth, Differentiation and Carcinogenesis by Dehydroepiandrosterone. Advances in Enzyme Regulation, 26, 355-382.
http://dx.doi.org/10.1016/0065-2571(87)90023-9
[17] Nair, K.S., Rizza, R.A., O’Brien, P., Dhatariya, K., Short, K.R., Nehra, A., Vittone, J.L., Klee, G.G., Basu, A., Basu, R., Cobelli, C., Toffolo, G., Dalla Man, C., Tindall, D.J., Melton III, L.J., Smith, G.E., Khosla, S. and Jensen, M.D. (2006) DHEA in Elderly Women and DHEA or Testosterone in Elderly men. New England Journal of Medicine, 355, 1647-1659. http://dx.doi.org/10.1056/NEJMoa054629
[18] Davis, S.R., Panjari, M. and Stanczyk, F.Z. (2011) DHEA Replacement for Post-Menopausal Women. The Journal of Clinical Endocrinology & Metabolism, 96, 1642-1653. http://dx.doi.org/10.1210/jc.2010-2888
[19] Villareal, D.T. and Holloszy, J.O. (2004) Effect of DHEA on Abdominal Fat and Insulin Action in Elderly Women and Men. Journal of the American Medical Association, 292, 2243-2248.
http://dx.doi.org/10.1001/jama.292.18.2243
[20] Mazat, L., Laofont, S., Berr, C., Debuire, B., Tessier, J.F., Dartigues, J.F. and Baulieu, E.E. (2001) Prospective Measurements of Dehydroepiandrosterone Sulfate in a Cohort of Elderly Subjects: Relationship to Gender, Subjective Health, Smoking Habits, and 10-Year Mortality. Proceedings of the National Academy of Sciences of the United States of America, 98, 8145-8150.
http://dx.doi.org/10.1073/pnas.121177998
[21] Baulieua, E.E., Thomas, G., Legrain, S., Lahlou, N., Roger, M., Debuire, B., Faucounau, V., Girard, L., Hervy, M.P., Latour, F., Leaud, M.C., Mokrane, A., Pitti-Ferrandi, H., Trivalle, C., Lacharrière, O., Nouveau, S., Rakoto-Arison, B., Souberbielle, J.C., Raison, J., Le Bouc, Y., Raynaud, A., Girerd, X. and Forette, F. (2000) Dehydroepiandrosterone (DHEA), DHEA Sulfate, and Aging: Contribution of the DHEAge Study to a Sociobiomedical Issue. Proceedings of the National Academy of Sciences of the United States of America, 97, 4279-4284. http://dx.doi.org/10.1073/pnas.97.8.4279
[22] Labrie, F., Luu-The, V., Martel, C., Chernomoretz, A., Calvo, E., Morissette, J. and Labrie, C. (2006) Dehydroepiandrosterone (DHEA) Is an Anabolic Steroid like Dihydrotestosterone (DHT), the Most Potent Natural Androgen, and Tetrahydrogestrinone (THG). The Journal of Steroid Biochemistry and Molecular Biology, 100, 52-58. http://dx.doi.org/10.1016/j.jsbmb.2006.03.006
[23] Ramaraj, P. and Cox, J.L. (2014) In-Vitro Effect of Sex Steroids on Mouse Melanoma (B16F10) Cell Growth. CellBio, 3, 60-71. http://dx.doi.org/10.4236/cellbio.2014.32007
[24] Ramaraj, P. and Cox, J.L. (2014) In-Vitro Effect of Progesterone on Human Melanoma (BLM) Cell Growth. International Journal of Clinical and Experimental Medicine, 7, 3941-3953.
[25] Mosmann, T. (1983) Rapid Colorimetric Assay for Cellular Growth and Survival: Application to Proliferation and Cytotoxicity Assays. Journal of Immunological Methods, 65, 55-63. http://dx.doi.org/10.1016/0022-1759(83)90303-4
[26] Brown, C., Pan, X. and Hassid, A. (1999) Nitric Oxide and C-Type Atrial Natriuretic Peptide Stimulate Primary Aortic Smooth Muscle Cell Migration via a cGMP-Dependent Mechanism: Relationship to Microfilament Dissociation and Altered Cell Morphology. Circulation Research, 84, 655-667.
http://dx.doi.org/10.1161/01.RES.84.6.655
[27] Ramaraj, P., Artaza, J.N., Sinha-Hikim, I. and Taylor, W.E. (2015) Effect of Androstenedione on Adipogenesis in Murine C3H10T1/2 Mesenchymal Cells. Open Journal of Endocrine and Metabolic Diseases, 5, 9-18. http://dx.doi.org/10.4236/ojemd.2015.52002
[28] Bennet, C.N., Ross, S.E., Longo, K.A., Bajnok, L., Hemati, N., Johnson, K.W., Harrison, S.D. and MacDougald, O.A. (2002) Regulation of Wnt Signaling during Adipogenesis. Journal of Biological Chemistry, 277, 30998-31004. http://dx.doi.org/10.1074/jbc.M204527200
[29] Kawai, S., Yahata, N., Nishida, S., Nagai, K. and Mizushima, Y. (1995) Dehydroepiandrosterone Inhibits B16 Mouse Melanoma Cell Growth by Induction of Differentiation. Anticancer Research, 15, 427-431.
[30] Dowling, S., Cox, J. and Cenedella, R.J. (2009) Inhibition of Fatty Acid Synthase by Orlistat Accelerates Gastric Tumor Cell Apoptosis in Culture and Increases Survival Rates in Gastric Tumor Bearing Mice in Vivo. Lipids, 44, 489-498. http://dx.doi.org/10.1007/s11745-009-3298-2
[31] Williams, M.R., Ling, S., Dawood, T., Hashimura, K., Dai, A., Li, H., Liu, J.P., Funder, J.W., Sudhir, K. and Komesaroff, P.A. (2002) Dehydroepiandrosterone Inhibits Human Vascular Smooth Muscle Cell Proliferation Independent of ARs and ERs. The Journal of Clinical Endocrinology & Metabolism, 87, 176-181. http://dx.doi.org/10.1210/jcem.87.1.8161
[32] Chen, J., Xu, L. and Huang, C. (2014) DHEA Inhibits Vascular Remodeling Following Arterial Injury: A Possible Role in Suppression of Inflammation and Oxidative Stress Derived from Vascular Smooth Muscle Cells. Molecular and Cellular Biochemistry, 388, 75-84. http://dx.doi.org/10.1007/s11010-013-1900-7
[33] McIntosh, M., Hausman, D., Martin, R. and Hausman, G. (1998) Dehydroepiandrosterone Attenuates Preadipocyte Growth in Primary Cultures of Stromal-Vascular Cells. American Journal of Physiology, 275, E285-E293.
[34] Shantz, L.M., Talalay, P. and Gordon, G.B. (1989) Mechanism of Inhibition of Growth of 3T3-L1 Fibroblasts and Their Differentiation to Adipocytes by Dehydroepiandrosterone and Related Steroids: Role of Glucose-6-Phosphate Dehydrogenase. Proceedings of the National Academy of Sciences of the United States of America, 86, 3252-3856. http://dx.doi.org/10.1073/pnas.86.10.3852
[35] Jasuja, R., Ramaraj, P., Mac, R.P., Singh, A.B., Storer, T.W., Artaza, J.N., Miller, A., Singh, R., Taylor, W.E., Lee, M.L., Davidson, T., Sinha-Hikim, I., Gonzalez-Cadavid, N. and Bhasin, S. (2005) Δ-4-Androstene-3,17-Dione Binds Androgen Receptor, Promotes Myogenesis in Vitro, and Increases Serum Testosterone Levels, Fat-Free Mass, and Muscle Strength in Hypogonadal Men. The Journal of Clinical Endocrinology & Metabolism, 90, 855-863. http://dx.doi.org/10.1210/jc.2004-1577
[36] Singh, R., Artaza, J.N., Taylor, W.E., Gonzalez-Cadavid, N.F. and Bhasin, S. (2003) Androgens Stimulate Myogenic Differentiation and Inhibit Adipogenesis in C3H10T1/2 Pluripotent Cells through an Androgen Receptor-Mediated Pathway. Endocrinology, 144, 5081-5088.
[37] Singh, R., Artaza, J.N., Taylor, W.E., Braga, M., Yum, X., Gonzalez-Cadavid, N. and Bhasin, S. (2006) Testosterone Inhibits Adipogenic Differentiation in 3T3-L1 Cells; Nuclear Translocation of Androgen Receptor Complex with Beta-Catenin and T-Cell Factor 4 May Bypass Canonical Wnt Signaling to Down-Regulate Adipogenic Transcription Factors. Endocrinology, 147, 141-154.
http://dx.doi.org/10.1210/en.2004-1649
[38] Bowers, L.D. (1999) Oral DHEA Supplementation Can Increase the Testosterone/Epitestosterone Ratio. Clinical Chemistry, 45, 295-297.
[39] Burke, L.M. (2000) Positive Drug Tests from Supplements. Sportscience, 4.
http://www.sportsci.org/jour/0003/lmb.html
[40] Nybo, K. (2015) A Whole New Ball Game. Biotechniques, 59. http://www.biotechniques.com/news/A-Whole-New-Ball-Game/biotechniques-348117.html?#.VdACTvm6eUl

  
comments powered by Disqus

Copyright © 2019 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.