GPER signaling in spermatogenesis and testicular tumors

Frontiers in Endocrinology

Volumn 5, Issue MAR, 2014, Pages

  Chimento, Adele ^a   Sirianni, Rosa ^a   Casaburi, Ivan ^a   Pezzi, Vincenzo ^a  

^a UNIVERSITY OF CALABRIA   (Italy)

Author keywords

Estrogen receptors; Germ cells; GPER; Spermatogenesis; Testicular tumors

Indexed keywords

CYCLIC GMP DEPENDENT PROTEIN KINASE; CYCLIN D1; EPIDERMAL GROWTH FACTOR RECEPTOR; ESTROGEN RECEPTOR; G PROTEIN COUPLED RECEPTOR; GONADORELIN; MESSENGER RNA; MITOGEN ACTIVATED PROTEIN KINASE; PROTEIN FOS; STRESS ACTIVATED PROTEIN KINASE;

APOPTOSIS; CANCER GROWTH; CELL FUNCTION; CELL PROLIFERATION; CELL SURVIVAL; CELLULAR DISTRIBUTION; ENZYME MECHANISM; GERM CELL TUMOR; HUMAN; HUMAN CELL; IMMUNOHISTOCHEMISTRY; PROTEIN EXPRESSION; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION; SPERMATOGENESIS; TESTIS TUMOR;

EID: 84901002869     PISSN: None     EISSN: 16642392     Source Type: Journal    
DOI: 10.3389/fendo.2014.00030     Document Type: Review

References (139)

1. Boon WC, Chow JD, Simpson ER. The multiple roles of estrogens and the enzyme aromatase. Prog Brain Res (2010) 181:209-32. doi: 10.1016/S0079-6123(08)81012-6.
2. Simpson ER, Clyne C, Rubin G, Boon WC, Robertson K, Britt K, et al. Aromatase-a brief overview. Annu Rev Physiol (2002) 64:93-127. doi:10.1146/annurev.physiol.64.081601.142703.
3. Carpino A, Pezzi V, Rago V, Bilinska B, Ando S. Immunolocalization of cytochrome P450 aromatase in rat testis during postnatal development. Tissue Cell (2001) 33(4):349-53. doi:10.1054/tice.2001.0186.
4. Pezzi V, Sirianni R, Chimento A, Maggiolini M, Bourguiba S, Delalande C, et al. Differential expression of steroidogenic factor-1/adrenal 4 binding protein and liver receptor homolog-1 (LRH-1)/fetoprotein transcription factor in the rat testis: LRH-1 as a potential regulator of testicular aromatase expression. Endocrinology (2004) 145(5):2186-96. doi:10.1210/en.2003-1366.
5. Sierens J, Jakody I, Poobalan Y, Meachem SJ, Knower K, Young MJ, et al. Localization and regulation of aromatase liver receptor homologue-1 in the developing rat testis. Mol Cell Endocrinol (2010) 323(2):307-13. doi:10.1016/j.mce.2010.03.001.
6. Pezzi V, Panno ML, Sirianni R, Forastieri P, Casaburi I, Lanzino M, et al. Effects of tri-iodothyronine on alternative splicing events in the coding region of cytochrome P450 aromatase in immature rat Sertoli cells. J Endocrinol (2001) 170(2):381-93. doi:10.1677/joe.0.1700381.
7. Ando S, Sirianni R, Forastieri P, Casaburi I, Lanzino M, Rago V, et al. Aromatase expression in prepuberal Sertoli cells: effect of thyroid hormone. Mol Cell Endocrinol (2001) 178(1-2):11-21. doi:10.1016/S0303-7207(01)00443-9.
8. Sirianni R, Chimento A, De Luca A, Zolea F, Carpino A, Rago V, et al. Inhibition of cyclooxygenase-2 down-regulates aromatase activity and decreases proliferation of Leydig tumor cells. J Biol Chem (2009) 284(42):28905-16. doi:10.1074/jbc. M109.041020.
9. Sirianni R, Chimento A, Malivindi R, Mazzitelli I, Ando S, Pezzi V. Insulin-like growth factor-I, regulating aromatase expression through steroidogenic factor 1, supports estrogen-dependent tumor Leydig cell proliferation. Cancer Res (2007) 67(17):8368-77. doi:10.1158/0008-5472.CAN-06-4064.
10. Catalano S, Pezzi V, Chimento A, Giordano C, Carpino A, Young M, et al. Triiodothyronine decreases the activity of the proximal promoter (PII) of the aromatase gene in the mouse Sertoli cell line, TM4. Mol Endocrinol (2003) 17(5):923-34. doi:10.1210/me.2002-0102.
11. Akingbemi BT. Estrogen regulation of testicular function. Reprod Biol Endocrinol (2005) 3:51. doi:10.1186/1477-7827-3-51.
12. Prossnitz ER, Maggiolini M. Mechanisms of estrogen signaling and gene expression via GPR30. Mol Cell Endocrinol (2009) 308(1-2):32-8. doi:10.1016/j.mce.2009.03.026.
13. Rochira V, Granata AR, Madeo B, Zirilli L, Rossi G, Carani C. Estrogens in males: what have we learned in the last 10 years? Asian J Androl (2005) 7(1):3-20. doi:10.1111/j.1745-7262.2005.00018.x.
14. Hewitt SC, Harrell JC, Korach KS. Lessons in estrogen biology from knockout and transgenic animals. Annu Rev Physiol (2005) 67:285-308. doi:10.1146/annurev.physiol.67.040403.115914.
15. O'Donnell L, Robertson KM, Jones ME, Simpson ER. Estrogen and spermatogenesis. Endocr Rev (2001) 22(3):289-318. doi:10.1210/er.22.3.289.
16. Lazari MF, Lucas TF, Yasuhara F, Gomes GR, Siu ER, Royer C, et al. Estrogen receptors and function in the male reproductive system. Arq Bras Endocrinol Metabol (2009) 53(8):923-33. doi:10.1590/S0004-27302009000800005.
17. Carreau S, Hess RA. Oestrogens and spermatogenesis. Philos Trans R Soc Lond B Biol Sci (2010) 365(1546):1517-35. doi:10.1098/rstb.2009.0235.
18. Gibson DA, Saunders PT. Estrogen dependent signaling in reproductive tissues-a role for estrogen receptors and estrogen related receptors. Mol Cell Endocrinol (2012) 348(2):361-72. doi:10.1016/j.mce.2011.09.026.
19. Li X, Rahman N. Impact of androgen/estrogen ratio: lessons learned from the aromatase over-expression mice. Gen Comp Endocrinol (2008) 159(1):1-9. doi:10.1016/j.ygcen.2008.07.025.
20. Carreau S, Genissel C, Bilinska B, Levallet J. Sources of oestrogen in the testis and reproductive tract of the male. Int J Androl (1999) 22(4):211-23. doi:10.1046/j.1365-2605.1999.00172.x.
21. Saez JM. Leydig cells: endocrine, paracrine, and autocrine regulation. Endocr Rev (1994) 15(5):574-626. doi:10.1210/edrv-15-5-574.
22. Chimento A, Sirianni R, Casaburi I, Pezzi V. Role of estrogen receptors (ERs) and G protein-coupled estrogen receptor (GPER) in regulation of hypothalamic-pituitary-testis axis and spermatogenesis. Front Endocrinol (Lausanne) (2014) 5:1. doi:10.3389/fendo.2014.00001.
23. Cacciola G, Chioccarelli T, Fasano S, Pierantoni R, Cobellis G. Estrogens and spermiogenesis: new insights from type 1 cannabinoid receptor knockout mice. Int J Endocrinol (2013) 2013:501350. doi:10.1155/2013/501350.
24. Rajpert De-Meyts E, Jorgensen N, Brondum-Nielsen K, Muller J, Skakkebaek NE. Developmental arrest of germ cells in the pathogenesis of germ cell neoplasia. APMIS (1998) 106(1):198-204. doi:10.1111/j.1699-0463.1998.tb01336.x.
25. Sharpe RM, Skakkebaek NE. Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract? Lancet (1993) 341(8857):1392-5. doi:10.1016/0140-6736(93)90953-E.
26. Skakkebaek NE, Berthelsen JG, Giwercman A, Muller J. Carcinoma-in-situ of the testis: possible origin from gonocytes and precursor of all types of germ cell tumours except spermatocytoma. Int J Androl (1987) 10(1):19-28. doi:10.1111/j.1365-2605.1987.tb00161.x.
27. Holl K, Lundin E, Surcel HM, Grankvist K, Koskela P, Dillner J, et al. Endogenous steroid hormone levels in early pregnancy and risk of testicular cancer in the offspring: a nested case-referent study. Int J Cancer (2009) 124(12):2923-8. doi:10.1002/ijc.24312.
28. Rajpert-De Meyts E. Developmental model for the pathogenesis of testicular carcinoma in situ: genetic and environmental aspects. Hum Reprod Update (2006) 12(3):303-23. doi:10.1093/humupd/dmk006.
29. Oosterhuis JW, Looijenga LH. Testicular germ-cell tumours in a broader perspective. Nat Rev Cancer (2005) 5(3):210-22. doi:10.1038/nrc1568.
30. Brokken LJ, Lundberg-Giwercman Y, Rajpert De-Meyts E, Eberhard J, Stahl O, Cohn-Cedermark G, et al. Association of polymorphisms in genes encoding hormone receptors ESR1, ESR2 and LHCGR with the risk and clinical features of testicular germ cell cancer. Mol Cell Endocrinol (2012) 351(2):279-85. doi:10.1016/j.mce.2011.12.018.
31. Chevalier N, Bouskine A, Fenichel P. Role of GPER/GPR30 in tumoral testicular germ cells proliferation. Cancer Biol Ther (2011) 12(1):2-3. doi:10.4161/cbt.12.1.15726.
32. Rago V, Romeo F, Giordano F, Maggiolini M, Carpino A. Identification of the estrogen receptor GPER in neoplastic and non-neoplastic human testes. Reprod Biol Endocrinol (2011) 9:135. doi:10.1186/1477-7827-9-135.
33. Rago V, Romeo F, Giordano F, Ferraro A, Ando S, Carpino A. Identification of ERbeta1 and ERbeta2 in human seminoma, in embryonal carcinoma and in their adjacent intratubular germ cell neoplasia. Reprod Biol Endocrinol (2009) 7:56. doi:10.1186/1477-7827-7-56.
34. Carpino A, Rago V, Pezzi V, Carani C, Ando S. Detection of aromatase and estrogen receptors (ERalpha, ERbeta1, ERbeta2) in human Leydig cell tumor. Eur J Endocrinol (2007) 157(2):239-44. doi:10.1530/EJE-07-0029.
35. Saunders PT, Sharpe RM, Williams K, Macpherson S, Urquart H, Irvine DS, et al. Differential expression of oestrogen receptor alpha and beta proteins in the testes and male reproductive system of human and non-human primates. Mol Hum Reprod (2001) 7(3):227-36. doi:10.1093/molehr/7.3.227.
36. Hess RA, Carnes K. The role of estrogen in testis and the male reproductive tract: a review and species comparison. Anim Reprod Sci (2004) 1:5-30.
37. Carreau S, Silandre D, Bois C, Bouraima H, Galeraud-Denis I, Delalande C. Estrogens: a new player in spermatogenesis. Folia Histochem Cytobiol (2007) 45(Suppl 1):S5-10.
38. Hess RA. The efferent ductules: structure and functions. In: Robaire B, Hinton BT, editors. The Epididymis: From Molecules to Clinical Practice. New York, NY: Kluwer Academic/Plenum Publishers (2002). p. 49-80.
39. Lucas TF, Siu ER, Esteves CA, Monteiro HP, Oliveira CA, Porto CS, et al. 17Beta-estradiol induces the translocation of the estrogen receptors ESR1 and ESR2 to the cell membrane, MAPK3/1 phosphorylation and proliferation of cultured immature rat Sertoli cells. Biol Reprod (2008) 78(1):101-14. doi:10.1095/biolreprod.107.063909.
40. Zhou Q, Nie R, Prins GS, Saunders PT, Katzenellenbogen BS, Hess RA. Localization of androgen and estrogen receptors in adult male mouse reproductive tract. J Androl (2002) 23(6):870-81. doi:10.1002/j.1939-4640.2002.tb02345.x.
41. Kotula-Balak M, Gancarczyk M, Sadowska J, Bilinskai B. The expression of aromatase, estrogen receptor alpha and estrogen receptor beta in mouse Leydig cells in vitro that derived from cryptorchid males. Eur J Histochem (2005) 49(1):59-62. doi:10.4081/928.
42. Fisher JS, Millar MR, Majdic G, Saunders PT, Fraser HM, Sharpe RM. Immunolocalisation of oestrogen receptor-alpha within the testis and excurrent ducts of the rat and marmoset monkey from perinatal life to adulthood. J Endocrinol (1997) 153(3):485-95. doi:10.1677/joe.0.1530485.
43. Pelletier G, El-Alfy M. Immunocytochemical localization of estrogen receptors alpha and beta in the human reproductive organs. J Clin Endocrinol Metab (2000) 85(12):4835-40. doi:10.1210/jcem.85.12.7029.
44. van Pelt AM, de Rooij DG, van der Burg B, van der Saag PT, Gustafsson JA, Kuiper GG. Ontogeny of estrogen receptor-beta expression in rat testis. Endocrinology (1999) 140(1):478-83. doi:10.1210/endo.140.1.6438.
45. Chimento A, Sirianni R, Delalande C, Silandre D, Bois C, Ando S, et al. 17 Beta-estradiol activates rapid signaling pathways involved in rat pachytene spermatocytes apoptosis through GPR30 and ER alpha. Mol Cell Endocrinol (2010) 320(1-2):136-44. doi:10.1016/j.mce.2010.01.035.
46. Yamada-Mouri N, Hirata S, Kato J. Existence and expression of the untranslated first exon of aromatase mRNA in the rat brain. J Steroid Biochem Mol Biol (1996) 58(2):163-6. doi:10.1016/0960-0760(96)00022-2.
47. Chimento A, Sirianni R, Zolea F, Bois C, Delalande C, Ando S, et al. Gper and ESRs are expressed in rat round spermatids and mediate oestrogen-dependent rapid pathways modulating expression of cyclin B1 and Bax. Int J Androl (2011) 34(5 Pt 1):420-9. doi:10.1111/j.1365-2605.2010.01100.x.
48. Lambard S, Galeraud-Denis I, Saunders PT, Carreau S. Human immature germ cells and ejaculated spermatozoa contain aromatase and oestrogen receptors. J Mol Endocrinol (2004) 32(1):279-89. doi:10.1677/jme.0.0320279.
49. Carreau S, Wolczynski S, Galeraud-Denis I. Aromatase, oestrogens and human male reproduction. Philos Trans R Soc Lond B Biol Sci (2010) 365(1546):1571-9. doi:10.1098/rstb.2009.0113.
50. Saunders PT, Millar MR, Macpherson S, Irvine DS, Groome NP, Evans LR, et al. ERbeta1 and the ERbeta2 splice variant (ERbetacx/beta2) are expressed in distinct cell populations in the adult human testis. J Clin Endocrinol Metab (2002) 87(6):2706-15. doi:10.1210/jcem.87.6.8619.
51. Aquila S, Sisci D, Gentile M, Middea E, Siciliano L, Ando S. Human ejaculated spermatozoa contain active P450 aromatase. J Clin Endocrinol Metab (2002) 87(7):3385-90. doi:10.1210/jcem.87.7.8633.
52. Filardo EJ, Quinn JA, Frackelton AR Jr, Bland KI. 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. Mol Endocrinol (2002) 16(1):70-84. doi:10.1210/me.16.1.70.
53. Maggiolini M, Vivacqua A, Fasanella G, Recchia AG, Sisci D, Pezzi V, et al. The G protein-coupled receptor GPR30 mediates c-fos up-regulation by 17Beta-estradiol and phytoestrogens in breast cancer cells. J Biol Chem (2004) 279(26):27008-16. doi:10.1074/jbc. M403588200.
54. Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER. A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science (2005) 307(5715):1625-30. doi:10.1126/science.1106943.
55. Thomas P, Pang Y, Filardo EJ, Dong J. Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells. Endocrinology (2005) 146(2):624-32. doi:10.1210/en.2004-1064.
56. Levin ER. G protein-coupled receptor 30: estrogen receptor or collaborator? Endocrinology (2009) 150(4):1563-5. doi:10.1210/en.2008-1759.
57. Funakoshi T, Yanai A, Shinoda K, Kawano MM, Mizukami Y. G protein-coupled receptor 30 is an estrogen receptor in the plasma membrane. Biochem Biophys Res Commun (2006) 346(3):904-10. doi:10.1016/j.bbrc.2006.05.191.
58. Chakrabarti S, Davidge ST. G-protein coupled receptor 30 (GPR30): a novel regulator of endothelial inflammation. PLoS One (2012) 7(12):e52357. doi:10.1371/journal.pone.0052357.
59. Pupo M, Vivacqua A, Perrotta I, Pisano A, Aquila S, Abonante S, et al. The nuclear localization signal is required for nuclear GPER translocation and function in breast cancer-associated fibroblasts (CAFs). Mol Cell Endocrinol (2013) 376(1-2):23-32. doi:10.1016/j.mce.2013.05.023.
60. Isensee J, Meoli L, Zazzu V, Nabzdyk C, Witt H, Soewarto D, et al. Expression pattern of G protein-coupled receptor 30 in LacZ reporter mice. Endocrinology (2009) 150(4):1722-30. doi:10.1210/en.2008-1488.
61. Sirianni R, Chimento A, Ruggiero C, De Luca A, Lappano R, Ando S, et al. The novel estrogen receptor, G protein-coupled receptor 30, mediates the proliferative effects induced by 17beta-estradiol on mouse spermatogonial GC-1 cell line. Endocrinology (2008) 149(10):5043-51. doi:10.1210/en.2007-1593.
62. Carreau SCA, Bois C, Sirianni R, Delalande C, Pezzi V. Rapid estrogen signaling in spermatogenesis. Immunol Endocr Metab Agents Med Chem (2011) 11:294-305. doi:10.2174/1871522211108040294.
63. Lucas TF, Royer C, Siu ER, Lazari MF, Porto CS. Expression and signaling of G protein-coupled estrogen receptor 1 (GPER) in rat Sertoli cells. Biol Reprod (2010) 83(2):307-17. doi:10.1095/biolreprod.110.084160.
64. Lucas TF, Pimenta MT, Pisolato R, Lazari MF, Porto CS. 17Beta-estradiol signaling and regulation of Sertoli cell function. Spermatogenesis (2011) 1(4):318-24. doi:10.4161/spmg.1.4.18903.
65. Otto C, Fuchs I, Kauselmann G, Kern H, Zevnik B, Andreasen P, et al. GPR30 does not mediate estrogenic responses in reproductive organs in mice. Biol Reprod (2009) 80(1):34-41. doi:10.1095/biolreprod.108.071175.
66. Pedram A, Razandi M, Levin ER. Nature of functional estrogen receptors at the plasma membrane. Mol Endocrinol (2006) 20(9):1996-2009. doi:10.1210/me.2005-0525.
67. Otto C, Rohde-Schulz B, Schwarz G, Fuchs I, Klewer M, Brittain D, et al. G protein-coupled receptor 30 localizes to the endoplasmic reticulum and is not activated by estradiol. Endocrinology (2008) 149(10):4846-56. doi:10.1210/en.2008-0269.
68. Langer G, Bader B, Meoli L, Isensee J, Delbeck M, Noppinger PR, et al. A critical review of fundamental controversies in the field of GPR30 research. Steroids (2010) 75(8-9):603-10. doi:10.1016/j.steroids.2009.12.006.
69. Evans PD, Bayliss A, Reale V. GPCR-mediated rapid, non-genomic actions of steroids: comparisons between DmDopEcR and GPER1 (GPR30). Gen Comp Endocrinol (2014) 195:157-63. doi:10.1016/j.ygcen.2013.10.015.
70. Bjornstrom L, Sjoberg M. Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol Endocrinol (2005) 19(4):833-42. doi:10.1210/me.2004-0486.
71. Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, et al. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science (1995) 270(5241):1491-4. doi:10.1126/science.270.5241.1491.
72. Maggiolini M, Picard D. The unfolding stories of GPR30, a new membrane-bound estrogen receptor. J Endocrinol (2010) 204(2):105-14. doi:10.1677/JOE-09-0242.
73. Carmeci C, Thompson DA, Ring HZ, Francke U, Weigel RJ. Identification of a gene (GPR30) with homology to the G-protein-coupled receptor superfamily associated with estrogen receptor expression in breast cancer. Genomics (1997) 45(3):607-17. doi:10.1006/geno.1997.4972.
74. Feng Y, Gregor P. Cloning of a novel member of the G protein-coupled receptor family related to peptide receptors. Biochem Biophys Res Commun (1997) 231(3):651-4. doi:10.1006/bbrc.1997.6161.
75. Kvingedal AM, Smeland EB. A novel putative G-protein-coupled receptor expressed in lung, heart and lymphoid tissue. FEBS Lett (1997) 407(1):59-62. doi:10.1016/S0014-5793(97)00278-0.
76. Filardo EJ, Quinn JA, Bland KI, Frackelton AR Jr. Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Mol Endocrinol (2000) 14(10):1649-60. doi:10.1210/mend.14.10.0532.
77. Lappano R, De Marco P, De Francesco EM, Chimento A, Pezzi V, Maggiolini M. Cross-talk between GPER and growth factor signaling. J Steroid Biochem Mol Biol (2013) 137:50-6. doi:10.1016/j.jsbmb.2013.03.005.
78. De Marco P, Bartella V, Vivacqua A, Lappano R, Santolla MF, Morcavallo A, et al. Insulin-like growth factor-I regulates GPER expression and function in cancer cells. Oncogene (2013) 32(6):678-88. doi:10.1038/onc.2012.97.
79. Albanito L, Madeo A, Lappano R, Vivacqua A, Rago V, Carpino A, et al. G protein-coupled receptor 30 (GPR30) mediates gene expression changes and growth response to 17beta-estradiol and selective GPR30 ligand G-1 in ovarian cancer cells. Cancer Res (2007) 67(4):1859-66. doi:10.1158/0008-5472.CAN-06-2909.
80. Pandey DP, Lappano R, Albanito L, Madeo A, Maggiolini M, Picard D. Estrogenic GPR30 signalling induces proliferation and migration of breast cancer cells through CTGF. EMBO J (2009) 28(5):523-32. doi:10.1038/emboj.2008.304.
81. Vivacqua A, Romeo E, De Marco P, De Francesco EM, Abonante S, Maggiolini M. GPER mediates the Egr-1 expression induced by 17beta-estradiol and 4-hydroxytamoxifen in breast and endometrial cancer cells. Breast Cancer Res Treat (2012) 133(3):1025-35. doi:10.1007/s10549-011-1901-8.
82. Hess RA, Bunick D, Lee KH, Bahr J, Taylor JA, Korach KS, et al. A role for oestrogens in the male reproductive system. Nature (1997) 390(6659):509-12. doi:10.1038/37352.
83. Antal MC, Krust A, Chambon P, Mark M. Sterility and absence of histopathological defects in nonreproductive organs of a mouse ERbeta-null mutant. Proc Natl Acad Sci U S A (2008) 105(7):2433-8. doi:10.1073/pnas.0712029105.
84. Robertson KM, O'Donnell L, Jones ME, Meachem SJ, Boon WC, Fisher CR, et al. Impairment of spermatogenesis in mice lacking a functional aromatase (cyp 19) gene. Proc Natl Acad Sci U S A (1999) 96(14):7986-91. doi:10.1073/pnas.96.14.7986.
85. Robertson KM, O'Donnell L, Simpson ER, Jones ME. The phenotype of the aromatase knockout mouse reveals dietary phytoestrogens impact significantly on testis function. Endocrinology (2002) 143(8):2913-21. doi:10.1210/en.143.8.2913.
86. Weiss J, Bernhardt ML, Laronda MM, Hurley LA, Glidewell-Kenney C, Pillai S, et al. Estrogen actions in the male reproductive system involve estrogen response element-independent pathways. Endocrinology (2008) 149(12):6198-206. doi:10.1210/en.2008-0122.
87. ChieffiP, Colucci-D'Amato GL, Staibano S, Franco R, Tramontano D. Estradiol-induced mitogen-activated protein kinase (extracellular signal-regulated kinase 1 and 2) activity in the frog (Rana esculenta) testis. J Endocrinol (2000) 167(1):77-84. doi:10.1677/joe.0.1670077.
88. ChieffiP, Colucci-D'Amato L, Guarino F, Salvatore G, Angelini F. 17 Beta-estradiol induces spermatogonial proliferation through mitogen-activated protein kinase (extracellular signal-regulated kinase 1/2) activity in the lizard (Podarcis s. sicula). Mol Reprod Dev (2002) 61(2):218-25. doi:10.1002/mrd.1151.
89. Chimento A, Sirianni R, Casaburi I, Ruggiero C, Maggiolini M, Ando S, et al. 17Beta-estradiol activates GPER-and ESR1-dependent pathways inducing apoptosis in GC-2 cells, a mouse spermatocyte-derived cell line. Mol Cell Endocrinol (2012) 355(1):49-59. doi:10.1016/j.mce.2012.01.017.
90. Royer C, Lucas TF, Lazari MF, Porto CS. 17Beta-estradiol signaling and regulation of proliferation and apoptosis of rat Sertoli cells. Biol Reprod (2012) 86(4):108. doi:10.1095/biolreprod.111.096891.
91. Skakkebaek NE. Possible carcinoma-in-situ of the testis. Lancet (1972) 2(7776):516-7. doi:10.1016/S0140-6736(72)91909-5.
92. Molsberry RL, Carr BR, Mendelson CR, Simpson ER. Human chorionic gonadotropin binding to human fetal testes as a function of gestational age. J Clin Endocrinol Metab (1982) 55(4):791-4. doi:10.1210/jcem-55-4-791.
93. Petersen PM, Giwercman A, Hansen SW, Berthelsen JG, Daugaard G, Rorth M, et al. Impaired testicular function in patients with carcinoma-in-situ of the testis. J Clin Oncol (1999) 17(1):173-9.
94. Saunders PT, Fisher JS, Sharpe RM, Millar MR. Expression of oestrogen receptor beta (ER beta) occurs in multiple cell types, including some germ cells, in the rat testis. J Endocrinol (1998) 156(3):R13-7. doi:10.1677/joe.0.156R013.
95. Yasuda Y, Kihara T, Tanimura T, Nishimura H. Gonadal dysgenesis induced by prenatal exposure to ethinyl estradiol in mice. Teratology (1985) 32(2):219-27. doi:10.1002/tera.1420320210.
96. Cools M, van Aerde K, Kersemaekers AM, Boter M, Drop SL, Wolffenbuttel KP, et al. Morphological and immunohistochemical differences between gonadal maturation delay and early germ cell neoplasia in patients with undervirilization syndromes. J Clin Endocrinol Metab (2005) 90(9):5295-303. doi:10.1210/jc.2005-0139.
97. Hannema SE, Scott IS, Rajpert-De Meyts E, Skakkebaek NE, Coleman N, Hughes IA. Testicular development in the complete androgen insensitivity syndrome. J Pathol (2006) 208(4):518-27. doi:10.1002/path.1890.
98. Rutgers JL, Scully RE. The androgen insensitivity syndrome (testicular feminization): a clinicopathologic study of 43 cases. Int J Gynecol Pathol (1991) 10(2):126-44. doi:10.1097/00004347-199104000-00002.
99. Franco R, Boscia F, Gigantino V, Marra L, Esposito F, Ferrara D, et al. GPR30 is overexpressed in post-puberal testicular germ cell tumors. Cancer Biol Ther (2011) 11(6):609-13. doi:10.4161/cbt.11.6.14672.
100. Mizuno Y, Gotoh A, Kamidono S, Kitazawa S. Establishment and characterization of a new human testicular germ cell tumor cell line (TCam-2). Nihon Hinyokika Gakkai Zasshi (1993) 84(7):1211-8.
101. Kinugawa K, Hyodo F, Matsuki T, Jo Y, Furukawa Y, Ueki A, et al. Establishment and characterization of a new human testicular seminoma cell line, JKT-1. Int J Urol (1998) 5(3):282-7. doi:10.1111/j.1442-2042.1998.tb00604.x.
102. Wallacides A, Chesnel A, Ajj H, Chillet M, Flament S, Dumond H. Estrogens promote proliferation of the seminoma-like TCam-2 cell line through a GPER-dependent ERalpha36 induction. Mol Cell Endocrinol (2012) 350(1):61-71. doi:10.1016/j.mce.2011.11.021.
103. Zhang XT, Kang LG, Ding L, Vranic S, Gatalica Z, Wang ZY. A positive feedback loop of ER-alpha36/EGFR promotes malignant growth of ER-negative breast cancer cells. Oncogene (2011) 30(7):770-80. doi:10.1038/onc.2010.458.
104. Lin SL, Yan LY, Zhang XT, Yuan J, Li M, Qiao J, et al. ER-alpha36, a variant of ER-alpha, promotes tamoxifen agonist action in endometrial cancer cells via the MAPK/ERK and PI3K/Akt pathways. PLoS One (2010) 5(2):e9013. doi:10.1371/journal.pone.0009013.
105. Roger C, Lambard S, Bouskine A, Mograbi B, Chevallier D, Nebout M, et al. Estrogen-induced growth inhibition of human seminoma cells expressing estrogen receptor beta and aromatase. J Mol Endocrinol (2005) 35(1):191-9. doi:10.1677/jme.1.01704.
106. Thomas P, Dong J. Binding and activation of the seven-transmembrane estrogen receptor GPR30 by environmental estrogens: a potential novel mechanism of endocrine disruption. J Steroid Biochem Mol Biol (2006) 102(1-5):175-9. doi:10.1016/j.jsbmb.2006.09.017.
107. Bouskine A, Nebout M, Mograbi B, Brucker-Davis F, Roger C, Fenichel P. Estrogens promote human testicular germ cell cancer through a membrane-mediated activation of extracellular regulated kinase and protein kinase A. Endocrinology (2008) 149(2):565-73. doi:10.1210/en.2007-1318.
108. Chevalier N, Vega A, Bouskine A, Siddeek B, Michiels JF, Chevallier D, et al. GPR30, the non-classical membrane G protein related estrogen receptor, is overexpressed in human seminoma and promotes seminoma cell proliferation. PLoS One (2012) 7(4):e34672. doi:10.1371/journal.pone.0034672.
109. Thomas P, Dressing G, Pang Y, Berg H, Tubbs C, BenninghoffA, et al. Progestin, estrogen and androgen G-protein coupled receptors in fish gonads. Steroids (2006) 71(4):310-6. doi:10.1016/j.steroids.2005.09.015.
110. Kang L, Zhang X, Xie Y, Tu Y, Wang D, Liu Z, et al. Involvement of estrogen receptor variant ER-alpha36, not GPR30, in nongenomic estrogen signaling. Mol Endocrinol (2010) 24(4):709-21. doi:10.1210/me.2009-0317.
111. Dennis MK, Burai R, Ramesh C, Petrie WK, Alcon SN, Nayak TK, et al. In vivo effects of a GPR30 antagonist. Nat Chem Biol (2009) 5(6):421-7. doi:10.1038/nchembio.168.
112. Chevalier N, Bouskine A, Fenichel P. Bisphenol A promotes testicular seminoma cell proliferation through GPER/GPR30. Int J Cancer (2012) 130(1):241-2. doi:10.1002/ijc.25972.
113. Bouskine A, Nebout M, Brucker-Davis F, Benahmed M, Fenichel P. Low doses of bisphenol A promote human seminoma cell proliferation by activating PKA and PKG via a membrane G-protein-coupled estrogen receptor. Environ Health Perspect (2009) 117(7):1053-8. doi:10.1289/ehp.0800367.
114. Eckert D, Nettersheim D, Heukamp LC, Kitazawa S, Biermann K, Schorle H. TCam-2 but not JKT-1 cells resemble seminoma in cell culture. Cell Tissue Res (2008) 331(2):529-38. doi:10.1007/s00441-007-0527-y.
115. de Jong J, Stoop H, Gillis AJ, Hersmus R, van Gurp RJ, van de Geijn GJ, et al. Further characterization of the first seminoma cell line TCam-2. Genes Chromosomes Cancer (2008) 47(3):185-96. doi:10.1002/gcc.20520.
116. Bonefeld-Jorgensen EC, Andersen HR, Rasmussen TH, Vinggaard AM. Effect of highly bioaccumulated polychlorinated biphenyl congeners on estrogen and androgen receptor activity. Toxicology (2001) 158(3):141-53. doi:10.1016/S0300-483X(00)00368-1.
117. Crain DA, Noriega N, Vonier PM, Arnold SF, McLachlan JA, Guillette LJ Jr. Cellular bioavailability of natural hormones and environmental contaminants as a function of serum and cytosolic binding factors. Toxicol Ind Health (1998) 14(1-2):261-73. doi:10.1177/074823379801400116.
118. Massaad C, Barouki R. An assay for the detection of xenoestrogens based on a promoter containing overlapping EREs. Environ Health Perspect (1999) 107(7):563-6. doi:10.1289/ehp.99107563.
119. Calafat AM, Kuklenyik Z, Reidy JA, Caudill SP, Ekong J, Needham LL. Urinary concentrations of bisphenol A and 4-nonylphenol in a human reference population. Environ Health Perspect (2005) 113(4):391-5. doi:10.1289/ehp.7534.
120. Vandenberg LN, Maffini MV, Wadia PR, Sonnenschein C, Rubin BS, Soto AM. Exposure to environmentally relevant doses of the xenoestrogen bisphenol-A alters development of the fetal mouse mammary gland. Endocrinology (2007) 148(1):116-27. doi:10.1210/en.2006-0561.
121. Welshons WV, Nagel SC, vom Saal FS. Large effects from small exposures. III. Endocrine mechanisms mediating effects of bisphenol A at levels of human exposure. Endocrinology (2006) 147(6 Suppl):S56-69. doi:10.1210/en.2005-1159.
122. Alonso-Magdalena P, Laribi O, Ropero AB, Fuentes E, Ripoll C, Soria B, et al. Low doses of bisphenol A and diethylstilbestrol impair Ca2+ signals in pancreatic alpha-cells through a nonclassical membrane estrogen receptor within intact islets of Langerhans. Environ Health Perspect (2005) 113(8):969-77. doi:10.1289/ehp.8002.
123. Bulayeva NN, Watson CS. Xenoestrogen-induced ERK-1 and ERK-2 activation via multiple membrane-initiated signaling pathways. Environ Health Perspect (2004) 112(15):1481-7. doi:10.1289/ehp.7175.
124. Nadal A, Ropero AB, Laribi O, Maillet M, Fuentes E, Soria B. Nongenomic actions of estrogens and xenoestrogens by binding at a plasma membrane receptor unrelated to estrogen receptor alpha and estrogen receptor beta. Proc Natl Acad Sci U S A (2000) 97(21):11603-8. doi:10.1073/pnas.97.21.11603.
125. Noguchi S, Nakatsuka M, Asagiri K, Habara T, Takata M, Konishi H, et al. Bisphenol A stimulates NO synthesis through a non-genomic estrogen receptor-mediated mechanism in mouse endothelial cells. Toxicol Lett (2002) 135(1-2):95-101. doi:10.1016/S0378-4274(02)00252-7.
126. Loomis AK, Thomas P. Effects of estrogens and xenoestrogens on androgen production by Atlantic croaker testes in vitro: evidence for a nongenomic action mediated by an estrogen membrane receptor. Biol Reprod (2000) 62(4):995-1004. doi:10.1095/biolreprod62.4.995.
127. Albanito L, Lappano R, Madeo A, Chimento A, Prossnitz ER, Cappello AR, et al. G-protein-coupled receptor 30 and estrogen receptor-alpha are involved in the proliferative effects induced by atrazine in ovarian cancer cells. Environ Health Perspect (2008) 116(12):1648-55. doi:10.1289/ehp.11297.
128. Li YJ, Song TB, Cai YY, Zhou JS, Song X, Zhao X, et al. Bisphenol A exposure induces apoptosis and upregulation of Fas/FasL and caspase-3 expression in the testes of mice. Toxicol Sci (2009) 108(2):427-36. doi:10.1093/toxsci/kfp024.
129. Drevelengas A, Kalaitzoglou I, Destouni E, Skordalaki A, Dimitriadis A. Bilateral Sertoli cell tumor of the testis: MRI and sonographic appearance. Eur Radiol (1999) 9(9):1934. doi:10.1007/s003300050954.
130. Chumsri S, Howes T, Bao T, Sabnis G, Brodie A. Aromatase, aromatase inhibitors, and breast cancer. J Steroid Biochem Mol Biol (2011) 125(1-2):13-22. doi:10.1016/j.jsbmb.2011.02.001.
131. Chimento A, Casaburi I, Bartucci M, Patrizii M, Dattilo R, Avena P, et al. Selective GPER activation decreases proliferation and activates apoptosis in tumor Leydig cells. Cell Death Dis (2013) 4:e747. doi:10.1038/cddis.2013.275.
132. Adachi T, Kar S, Wang M, Carr BI. Transient and sustained ERK phosphorylation and nuclear translocation in growth control. J Cell Physiol (2002) 192(2):151-9. doi:10.1002/jcp.10124.
133. Chen J-R, Plotkin LI, Aguirre JI, Han L, Jilka RL, Kousteni S, et al. Transient versus sustained phosphorylation and nuclear accumulation of ERKs underlie anti-versus pro-apoptotic effects of estrogens. J Biol Chem (2005) 280(6):4632-8. doi:10.1074/jbc. M411530200.
134. Chimento A, Casaburi I, Rosano C, Avena P, De Luca A, Campana C, et al. Oleuropein and hydroxytyrosol activate GPER/GPR30-dependent pathways leading to apoptosis of ER-negative SKBR3 breast cancer cells. Mol Nutr Food Res (2013). doi:10.1002/mnfr.201300323.
135. Casaburi I, Puoci F, Chimento A, Sirianni R, Ruggiero C, Avena P, et al. Potential of olive oil phenols as chemopreventive and therapeutic agents against cancer: a review of in vitro studies. Mol Nutr Food Res (2013) 57(1):71-83. doi:10.1002/mnfr.201200503.
136. Appenroth D, Winnefeld K, Braunlich H. Nephrotoxicity and pharmacokinetics of cisplatinum in young and adult rats. Biomed Biochim Acta (1988) 47(8):791-7.
137. Thompson SW, Davis LE, Kornfeld M, Hilgers RD, Standefer JC. Cisplatin neuropathy. Clinical, electrophysiologic, morphologic, and toxicologic studies. Cancer (1984) 54(7):1269-75. doi:10.1002/1097-0142(19841001)54:7<1269::AID-CNCR2820540707>3.0.CO;2-9.
138. Drasga RE, Einhorn LH, Williams SD, Patel DN, Stevens EE. Fertility after chemotherapy for testicular cancer. J Clin Oncol (1983) 1(3):179-83.
139. Meistrich ML, Finch M, da Cunha MF, Hacker U, Au WW. Damaging effects of fourteen chemotherapeutic drugs on mouse testis cells. Cancer Res (1982) 42(1):122-31.