The Effects of Exogenous Estrogens on Estrogen Receptors in Male Reproductive Organs
DOI:
https://doi.org/10.18192/riss-ijhs.v1i1.1537Keywords:
Estrogen, Bisphenol A (BPA, 2, 2-bis(4-hydroxyphenyl)), propane, Diethylstilbestrol (DES), endocrine disruption, GPR30Abstract
There is an essential physiological role for estrogen in male reproduction. Conversely, exposure to exogenous sources of estrogen has negative effects on reproductive physiology and fertility in men. Infertility, affecting nearly 15% of couples, is defined as the inability to conceive after one year of unprotected sexual intercourse. In at least 20% of cases, male reproductive pathology is the major cause for a couple’s infertility. Thus, it is essential to investigate potential causes of infertility in adult males. Evidence shows that exposure to certain endocrine disruptors is associated with reduced semen quality and impaired fertility in men. Bisphenol A and Diethylstilbestrol are endocrine disruptors that act as exogenous sources of estrogen and have been associated with male reproductive pathology. This review will examine the role of exogenous estrogens on changes in gene expression of estrogen receptors ERα, ERβ, and GPR30. Previous studies have had conflictive results, suggesting that the effects of exogenous estrogens on male reproduction are multi-faceted. Future studies should focus on determining whether exogenous estrogens have a stimulatory and/or inhibitory effect on gene expression and whether this relationship is dose-dependent or if it follows a more complex dosage pattern.
References
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Eddy, E. M., Washburn, T. F., Bunch, D. O., Goulding, E. H., Gladen, B. C., Lubahn, D. B., & Korach, K. S. (1996). Targeted disruption of the estrogen receptor gene in male mice causes alteration of spermatogenesis and infertility. Endocrinology. 137(11), 4796–4805. Retrieved from http://dx.doi.org/10.1210/ endo.137.11.8895349#sthash.PEufj323.dpuf
Endocrine Disruptors Group. (2009). Bisphenol A References. Columbia, MO: Curators of the University of Missouri. Retrieved from http://endocrinedisruptors.missouri.edu/pdfarticles/ Bisphenol_A_References.doc.
Filardo, E. J., Quinn, J. A., Frackelton, A. R., Jr., & Bland, K. I. (2002). Estrogen action via the G protein-coupled receptor, GPR30: stimulation of adenylyl cyclase and cAMP-mediated attenuation of the epidermal growth factor receptor-to-MAPK signaling axis. Molecular Endocrinology, 16(1), 70–84.
Funakoshi, T., Yanai, A., Shinoda, K., Kawano, M. M., & Mizukami, Y. (2006). G protein-coupled receptor 30 is an estrogen receptor in the plasma membrane. Biochemical and Biophysical Research Communications, 346(3), 904- 910. doi: 10.1016/j.bbrc.2006.05.191
Gilman, A. G. (1987). G Proteins: Transducers of Receptor- Generated Signals. Annual Review of Biochemistry, 56, 615–649. doi: 10.1146/annurev.bi.56.070187.003151
Goyal, H. O., Robateau, A., Braden, T. D., Williams, C. S., Srivastava, K. K., & Ali, K. (2003). Neonatal estrogen exposure of male rats alters reproductive functions at adulthood. Biology of Reproduction, 68(6), 2081-2091. doi: 10.1095/biolreprod.102.010637
Hall, J. M., Course, J. F., & Korach, K. S. (2001). The multifaceted mechanisms of estradiol and estrogen receptor-signalling. Journal of Biological Chemistry, 276, 36869- 36872. doi: 10.1074/jbc.R100029200
Hall J. M., & McDonnell, D. P. (1999). The estrogen receptor β-isoform (ERβ) of the human estrogen receptor modulates ER transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens. Endocrinology, 140(12), 5566–5578. Retrieved from http:// dx.doi.org/10.1210/ endo.140.12.7179#sthash.sNHlA1yv.dpuf
Ho, K. J., & Liao, J. K. (2002). Nonnuclear Actions of Estrogen. Aretriosclerosi, Thrombosis, and Vascular Biology, 22, 1952-1961. doi: 10.1161/01.ATV.0000041200.8594
Kuiper, G. G., Carlsson, B., Grandien, K., Enmark, E., Haggblad, J., Nilsson S., & Gustafsson, J-A. (1997). Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors α and β. Endocrinology, 138(3), 863–870. Retrieved from http:// dx.doi.org/10.1210/endo.138.3.4979#sthash.javzdfDv.dpuf
Malone, K. (1993). Diethylstilbestrol (DES) and breast cancer. Epidemiological Review, 15, 108–109.
Murata, Y., Robertson, K. M., Jones, M. E. E., & Simpson, E. R. (2002). Effect of estrogen deficiency in the male: the ArKO mouse model. Molecular & Cellular Endocrinology, 193(1-2), 7-12. doi: 10.1016/S0303-7207(02)00090-4
O’Donnell, L., Robertson, K. M., Jones, M. E., & Simpson, E. R. (2001). Estrogen and spermatogenesis. Endocrine Reviews, 22(3), 289-318. Retrieved from http://dx.doi.org/10.1210/edrv.22.3.0431#sthash.8rPCkHxy.dpuf
Otto, C., Fuchs, I., Kauselmann, G., Kern, H., Zevnik, B., Andreasen P., ... Fritzemeier, K. H. (2009). GPR30 Does Not Mediate Estrogenic Responses in Reproductive Organs in Mice. Biology of Reproduction, 80(1), 34-41. doi: 10.1095/biolreprod.108.071175
Prossnitz, E. R., Arteburn, J. B., & Sklar, L. A. (2007). GPR30: a G protein-coupled receptor for estrogen. Molecular & Cellular Endocrinology, 265-266, 138-142. doi: 10.1016/j.mce.2006.12.010
Prossnitz, E. R., Oprea, T. I., Sklar, L. A., & Arteburn, J. B. (2008). The ins and outs of GPR30: a transmembrane estrogen receptor. The Journal of Steroid Biochemistry and Molecular Biology, 109 (3-5), 350-353. doi: 10.1016/ j.jsbmb.2008.03.006
Routhledge, E. J., White, R., Parker, M. G., & Sumpter, J. P. (2000). Differential effects of xenoestrogens on coactivator recruitment by estrogen receptor (ER) α and (ER) β. Journal of Biological Chemistry, 275(46), 35986-35993. doi: 10.1074/jbc.M006777200
Roy, D., Palangat, M., Chen, C., Thomas, R. D., Colerangle, J., Atkinson, A., & Yan, Z. (1997). Biochemical and Molecular Changes at the Cellular Level in Response to Exposure to Environmental Estrogen-like Chemicals. Journal of Toxicology and Environmental Health, Part A, 50(1), 10- 30.
Sakaue, M., Ohsako, S., Ishimura, R., Kurosawa, S., Kurohmaru, M., Hayashi, Y.,... Tohyama, C. (2001). Bisphenol A affects spermatogenesis in the adult rat even at a low dose. Journal of Occupational Health, 43(4), 185-190. Retrieved from http://doi.org/10.1539/joh.43.185
Sharpe, R. M., McKinnell, C., Kivlin, C., & Fisher, J. S. (2003). Proliferation and functional maturation of Sertoli cells, and their relevance to disorders of testis function in adulthood. Reproduction, 125(6), 769–784.
Sharpe, R. M., Atanassova, N., McKinnell, C., Parte, P., Turner, K. J., Fisher, J. S.,... Saunders, P. T. (1998). Abnormalities in functional development of the Sertoli cells in rats treated neonatally with diethylstilbestrol: A possible role for estrogens in Sertoli cell development. Biological Reproduction, 59(5), 1084–1094. doi: 10.1095/ biolreprod59.5.1084
Sirianni, R., Chimento, A., Ruggiero, C., De Luca, A., Lap- pano, R., Ando, S.,... Pezzi, V. (2007). The Novel Estrogen Receptor, G Protein-Coupled Receptor 30, Mediates the Proliferative Effects Induced by 17β-Estradiol on Mouse Spermatogonial GC-1 Cell Line. Endocrinology, 149(10), 5043-5051. doi: 10.1210/en.2007-1593
Takao, T., Nanamiya, W., Nazarloo, H. P., Matsumoto, R., Asaba, K., & Hashimoto, K. (2003). Exposure to the environmental estrogen bisphenol A differentially modulated estrogen receptor-alpha and –beta immunoreactivity and mRNA in male mouse testis. Life Sciences, 72(10), 1159- 1169. doi: 10.1016/S0024-3205(02)02364-0
Tena-Sempere, M., Navarro, J., Pinilla, L., Gonzalez L. C., Huhtaniemi, I., & Aguilar, E. (2000). Neonatal exposure to estrogen differentially alters estrogen receptor alpha and beta mRNA expression in rat testis during postnatal development. Journal of Endocrinology, 165(2), 345-357.
Thomas, P., Pang, Y., Filardo, E. J., & Dong, J. (2005). Identity of an Estrogen Membrane Receptor Coupled to a G-protein in Human Breast Cancer Cells. Endocrinology, 146(2), 624-632. Retrieved from http:// dx.doi.org/10.1210/en.2004-1064#sthash.nJq2TT3z.dpuf
vom Saal, F., & Hughes, C. (2005). An Extensive New Literature Concerning Low-Dose Effects of Bisphenol A Shows the Need for a New Risk Assessment. Environmental Health Perspectives, 113(8), 926-933. doi: 10.1289/ ehp.7713
Welshons, W. V., Thayer, K. S., Taylor, J., Judy, B. M., & vom Saal, F. S. (2003). Large effects from small exposures. I. Mechanisms for endocrine-disrupting chemicals with estrogenic activity. Environmental Health Perspectives, 111(8), 994-1006.
Wetherill, Y. B., Akingbemi, B. T., Kanno, J., McLachlan, J. A., Nadal, A.,... Belcher, S. M. (2007). In vitro molecular mechanisms of Bisphenol A action. Reproductive Toxicology, 24(2), 178-198. doi: 10.1016/j.reprotox.2007.05.010
Williams, K., McKinnell, C., Saunders, P. T. K., Walker, M., Fisher, J. S., Turner, K. J.,...Sharpe, R. M. (2001). Neonatal exposure to potent and environmental oestrogens and abnormalities of the male reproductive system in the rat: Evidence for importance of the androgen-oestrogen balance and assessment of the relevance to man. Human Reproduction Update, 7(3), 236–247.
Wozniak, A. L., Bulayeva, N. N., & Watson, C. S. (2005). Xenoestrogens at picomolar to nanomolar concentrations trigger membrane estrogen receptor-alpha-mediated Ca2+ fluxes and protein release in GH3/B6 pituitary tumor cells. Environmental Health Perspectives, 113(4), 431-439. doi: 10.1289/ehp.7505
Akingbemi B.T., Scottas C. M., Koulova A. L., Klinefelter A. M, & Hardy M. P. (2004). Inhibition of testicular steroidogenesis by the xenoestrogen Bisphenol A is associated with reduced pituitary luteinizing hormone secretion and decreased steroidogenic enzyme gene expression in rat Leydig cells. Endocrinology, 145(2), 592-603. Retrieved from http://dx.doi.org/10.1210/en.2003- 1174#sthash.zwTTkxX4.dpuf
Burridge, E. (2003). Bisphenol A: Product profile. European Chemical News, 14-20 April, 17.
Coors, A., Jones, P. D., Giesy, J. P., & Ratte, H. T. (2003). Removal of estrogenic activity from municipal waste landfill leachate assessed with a bioassay based on reporter gene expression. Environmental Science & Technology, 37 (15), 3430-3434.
Eddy, E. M., Washburn, T. F., Bunch, D. O., Goulding, E. H., Gladen, B. C., Lubahn, D. B., & Korach, K. S. (1996). Targeted disruption of the estrogen receptor gene in male mice causes alteration of spermatogenesis and infertility. Endocrinology. 137(11), 4796–4805. Retrieved from http://dx.doi.org/10.1210/ endo.137.11.8895349#sthash.PEufj323.dpuf
Endocrine Disruptors Group. (2009). Bisphenol A References. Columbia, MO: Curators of the University of Missouri. Retrieved from http://endocrinedisruptors.missouri.edu/pdfarticles/ Bisphenol_A_References.doc.
Filardo, E. J., Quinn, J. A., Frackelton, A. R., Jr., & Bland, K. I. (2002). Estrogen action via the G protein-coupled receptor, GPR30: stimulation of adenylyl cyclase and cAMP-mediated attenuation of the epidermal growth factor receptor-to-MAPK signaling axis. Molecular Endocrinology, 16(1), 70–84.
Funakoshi, T., Yanai, A., Shinoda, K., Kawano, M. M., & Mizukami, Y. (2006). G protein-coupled receptor 30 is an estrogen receptor in the plasma membrane. Biochemical and Biophysical Research Communications, 346(3), 904- 910. doi: 10.1016/j.bbrc.2006.05.191
Gilman, A. G. (1987). G Proteins: Transducers of Receptor- Generated Signals. Annual Review of Biochemistry, 56, 615–649. doi: 10.1146/annurev.bi.56.070187.003151
Goyal, H. O., Robateau, A., Braden, T. D., Williams, C. S., Srivastava, K. K., & Ali, K. (2003). Neonatal estrogen exposure of male rats alters reproductive functions at adulthood. Biology of Reproduction, 68(6), 2081-2091. doi: 10.1095/biolreprod.102.010637
Hall, J. M., Course, J. F., & Korach, K. S. (2001). The multifaceted mechanisms of estradiol and estrogen receptor-signalling. Journal of Biological Chemistry, 276, 36869- 36872. doi: 10.1074/jbc.R100029200
Hall J. M., & McDonnell, D. P. (1999). The estrogen receptor β-isoform (ERβ) of the human estrogen receptor modulates ER transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens. Endocrinology, 140(12), 5566–5578. Retrieved from http:// dx.doi.org/10.1210/ endo.140.12.7179#sthash.sNHlA1yv.dpuf
Ho, K. J., & Liao, J. K. (2002). Nonnuclear Actions of Estrogen. Aretriosclerosi, Thrombosis, and Vascular Biology, 22, 1952-1961. doi: 10.1161/01.ATV.0000041200.8594
Kuiper, G. G., Carlsson, B., Grandien, K., Enmark, E., Haggblad, J., Nilsson S., & Gustafsson, J-A. (1997). Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors α and β. Endocrinology, 138(3), 863–870. Retrieved from http:// dx.doi.org/10.1210/endo.138.3.4979#sthash.javzdfDv.dpuf
Malone, K. (1993). Diethylstilbestrol (DES) and breast cancer. Epidemiological Review, 15, 108–109.
Murata, Y., Robertson, K. M., Jones, M. E. E., & Simpson, E. R. (2002). Effect of estrogen deficiency in the male: the ArKO mouse model. Molecular & Cellular Endocrinology, 193(1-2), 7-12. doi: 10.1016/S0303-7207(02)00090-4
O’Donnell, L., Robertson, K. M., Jones, M. E., & Simpson, E. R. (2001). Estrogen and spermatogenesis. Endocrine Reviews, 22(3), 289-318. Retrieved from http://dx.doi.org/10.1210/edrv.22.3.0431#sthash.8rPCkHxy.dpuf
Otto, C., Fuchs, I., Kauselmann, G., Kern, H., Zevnik, B., Andreasen P., ... Fritzemeier, K. H. (2009). GPR30 Does Not Mediate Estrogenic Responses in Reproductive Organs in Mice. Biology of Reproduction, 80(1), 34-41. doi: 10.1095/biolreprod.108.071175
Prossnitz, E. R., Arteburn, J. B., & Sklar, L. A. (2007). GPR30: a G protein-coupled receptor for estrogen. Molecular & Cellular Endocrinology, 265-266, 138-142. doi: 10.1016/j.mce.2006.12.010
Prossnitz, E. R., Oprea, T. I., Sklar, L. A., & Arteburn, J. B. (2008). The ins and outs of GPR30: a transmembrane estrogen receptor. The Journal of Steroid Biochemistry and Molecular Biology, 109 (3-5), 350-353. doi: 10.1016/ j.jsbmb.2008.03.006
Routhledge, E. J., White, R., Parker, M. G., & Sumpter, J. P. (2000). Differential effects of xenoestrogens on coactivator recruitment by estrogen receptor (ER) α and (ER) β. Journal of Biological Chemistry, 275(46), 35986-35993. doi: 10.1074/jbc.M006777200
Roy, D., Palangat, M., Chen, C., Thomas, R. D., Colerangle, J., Atkinson, A., & Yan, Z. (1997). Biochemical and Molecular Changes at the Cellular Level in Response to Exposure to Environmental Estrogen-like Chemicals. Journal of Toxicology and Environmental Health, Part A, 50(1), 10- 30.
Sakaue, M., Ohsako, S., Ishimura, R., Kurosawa, S., Kurohmaru, M., Hayashi, Y.,... Tohyama, C. (2001). Bisphenol A affects spermatogenesis in the adult rat even at a low dose. Journal of Occupational Health, 43(4), 185-190. Retrieved from http://doi.org/10.1539/joh.43.185
Sharpe, R. M., McKinnell, C., Kivlin, C., & Fisher, J. S. (2003). Proliferation and functional maturation of Sertoli cells, and their relevance to disorders of testis function in adulthood. Reproduction, 125(6), 769–784.
Sharpe, R. M., Atanassova, N., McKinnell, C., Parte, P., Turner, K. J., Fisher, J. S.,... Saunders, P. T. (1998). Abnormalities in functional development of the Sertoli cells in rats treated neonatally with diethylstilbestrol: A possible role for estrogens in Sertoli cell development. Biological Reproduction, 59(5), 1084–1094. doi: 10.1095/ biolreprod59.5.1084
Sirianni, R., Chimento, A., Ruggiero, C., De Luca, A., Lap- pano, R., Ando, S.,... Pezzi, V. (2007). The Novel Estrogen Receptor, G Protein-Coupled Receptor 30, Mediates the Proliferative Effects Induced by 17β-Estradiol on Mouse Spermatogonial GC-1 Cell Line. Endocrinology, 149(10), 5043-5051. doi: 10.1210/en.2007-1593
Takao, T., Nanamiya, W., Nazarloo, H. P., Matsumoto, R., Asaba, K., & Hashimoto, K. (2003). Exposure to the environmental estrogen bisphenol A differentially modulated estrogen receptor-alpha and –beta immunoreactivity and mRNA in male mouse testis. Life Sciences, 72(10), 1159- 1169. doi: 10.1016/S0024-3205(02)02364-0
Tena-Sempere, M., Navarro, J., Pinilla, L., Gonzalez L. C., Huhtaniemi, I., & Aguilar, E. (2000). Neonatal exposure to estrogen differentially alters estrogen receptor alpha and beta mRNA expression in rat testis during postnatal development. Journal of Endocrinology, 165(2), 345-357.
Thomas, P., Pang, Y., Filardo, E. J., & Dong, J. (2005). Identity of an Estrogen Membrane Receptor Coupled to a G-protein in Human Breast Cancer Cells. Endocrinology, 146(2), 624-632. Retrieved from http:// dx.doi.org/10.1210/en.2004-1064#sthash.nJq2TT3z.dpuf
vom Saal, F., & Hughes, C. (2005). An Extensive New Literature Concerning Low-Dose Effects of Bisphenol A Shows the Need for a New Risk Assessment. Environmental Health Perspectives, 113(8), 926-933. doi: 10.1289/ ehp.7713
Welshons, W. V., Thayer, K. S., Taylor, J., Judy, B. M., & vom Saal, F. S. (2003). Large effects from small exposures. I. Mechanisms for endocrine-disrupting chemicals with estrogenic activity. Environmental Health Perspectives, 111(8), 994-1006.
Wetherill, Y. B., Akingbemi, B. T., Kanno, J., McLachlan, J. A., Nadal, A.,... Belcher, S. M. (2007). In vitro molecular mechanisms of Bisphenol A action. Reproductive Toxicology, 24(2), 178-198. doi: 10.1016/j.reprotox.2007.05.010
Williams, K., McKinnell, C., Saunders, P. T. K., Walker, M., Fisher, J. S., Turner, K. J.,...Sharpe, R. M. (2001). Neonatal exposure to potent and environmental oestrogens and abnormalities of the male reproductive system in the rat: Evidence for importance of the androgen-oestrogen balance and assessment of the relevance to man. Human Reproduction Update, 7(3), 236–247.
Wozniak, A. L., Bulayeva, N. N., & Watson, C. S. (2005). Xenoestrogens at picomolar to nanomolar concentrations trigger membrane estrogen receptor-alpha-mediated Ca2+ fluxes and protein release in GH3/B6 pituitary tumor cells. Environmental Health Perspectives, 113(4), 431-439. doi: 10.1289/ehp.7505
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