Prenatal exposure to testosterone masculinises the female gerbil and promotes the development of lesions in the prostate (Skene’s gland)
Manoel F. Biancardi A , Ana P. S. Perez A , Cássia Regina Suzuki Caires B , Rejane M. Góes B , Patrícia S. L. Vilamaior B , Fernanda C. A. Santos C and Sebastião R. Taboga A B DA Department of Structural and Functional Biology, State University of Campinas, Av. Bertrand Russel s/n, Campinas, São Paulo, 13084864, Brazil.
B Univ. Estadual Paulista – UNESP, Department of Biology, Laboratory of Microscopy and Microanalysis, Rua Cristóvão Colombo, 2265, São José do Rio Preto, São Paulo, 15054000, Brazil.
C Department of Morphology, Federal University of Goiás, Samambaia II, Goiânia, Goiás, 74001970, Brazil.
D Corresponding author. Email: taboga@ibilce.unesp.br
Reproduction, Fertility and Development 27(7) 1000-1011 https://doi.org/10.1071/RD13387
Submitted: 15 November 2013 Accepted: 13 February 2014 Published: 4 April 2014
Abstract
Androgenic imbalance may disrupt prostate development, leading to morphological alterations in adulthood and predisposing this gland to develop diseases during ageing. However, little is known about the endocrine disruption of the prostate that is caused by androgenic compounds, especially in female experimental models. Therefore, this study aimed to evaluate the prostates of aged female gerbils exposed to testosterone at certain periods in intrauterine and postnatal life, to determine whether exposure at a particular age increases susceptibility to prostatic lesions in these animals. To this end, morphological, stereological, immunohistochemical and immunofluorescence analyses were employed. It was found that females exposed to testosterone during intrauterine life were masculinised, showing increased anogenital distance, absence of the vaginal opening and ectopic development of prostatic tissue. Several areas of adenomatous hyperplasia, generally associated with inflammatory foci and mainly located in the ectopic prostatic tissue around the vaginal wall, were also observed. In conclusion, the results showed that abnormal prenatal exposure to testosterone severely affects the reproductive systems of female animals by disrupting normal prostate morphogenesis and increasing susceptibility to the development of prostatic diseases during ageing.
Additional keywords: androgens, endocrine-disrupting chemicals.
References
Alonso-Magdalena, P., Brossner, C., Reiner, A., Cheng, G., Sugiyama, N., Warner, M., and Gustafsson, J. A. (2009). A role for epithelial–mesenchymal transition in the aetiology of benign prostatic hyperplasia. Proc. Natl. Acad. Sci. USA 106, 2859–2863.| A role for epithelial–mesenchymal transition in the aetiology of benign prostatic hyperplasia.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXislSltr4%3D&md5=b29d5de22218e4f58780613cac93cfbcCAS | 19196965PubMed |
Biancardi, M. F., Perez, A. P. S., Góes, R. M., Santos, F. C. A., Vilamaior, P. S. L., and Taboga, S. R. (2012). Prenatal testosterone exposure as a model for the study of endocrine-disrupting chemicals on the gerbil prostate. Exp. Biol. Med. 237, 1298–1309.
| Prenatal testosterone exposure as a model for the study of endocrine-disrupting chemicals on the gerbil prostate.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXhslGiu7o%3D&md5=c058107adf9d2a7583d2b35e99fa24d1CAS |
Black, B. E., and Paschal, B. M. (2004). Intranuclear organisation and function of the androgen receptor. Trends Endocrinol. Metab. 15, 411–417.
| Intranuclear organisation and function of the androgen receptor.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXptFOmur8%3D&md5=9d139698c52ba9900f7d7a19b6708927CAS | 15519887PubMed |
Cordeiro, R. S., Scarano, W. R., Campos, S. G. P., Santos, F. C. A., Vilamaior, P. S. L., Góes, R. M., and Taboga, S. R. (2008). Androgen receptor in the Mongolian gerbil ventral prostate: evaluation during different phases of postnatal development and following androgen blockage. Micron 39, 1312–1324.
| Androgen receptor in the Mongolian gerbil ventral prostate: evaluation during different phases of postnatal development and following androgen blockage.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXhtFCju77I&md5=6bbd6301cf4c9f1dcf264ebe1884562aCAS | 18394909PubMed |
Custódio, A. M. G., Santos, F. C., Campos, S. G., Vilamaior, P. S. L., Oliveira, S. M., Góes, R. M., and Taboga, S. R. (2010). Disorders related with ageing in the gerbil female prostate (Skene’s paraurethral glands). Int. J. Exp. Pathol. 91, 132–143.
| Disorders related with ageing in the gerbil female prostate (Skene’s paraurethral glands).Crossref | GoogleScholarGoogle Scholar |
De Marzo, A. M., Platz, E. A., Sutcliffe, S., Xu, J., Grönberg, H., Drake, C. G., Nakai, Y., Isaacs, W. B., and Nelson, W. G. (2007). Inflammation in prostate carcinogenesis. Nat. Rev. Cancer 7, 256–269.
| 1:CAS:528:DC%2BD2sXjtlyhtLw%3D&md5=e283058c5005bc8f50d78af6fd117bf0CAS | 17384581PubMed |
Grisanzio, C., and Signoretti, S. (2008). p63 in prostate biology and pathology. J. Cell. Biochem. 103, 1354–1368.
| p63 in prostate biology and pathology.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXkslShsrw%3D&md5=01597d4b477e1ff1644d0386c6d08b83CAS | 17879953PubMed |
Hotchkiss, A. K., Furr, J., Makynen, E. A., Ankley, G. T., and Gray, L. E. (2007a). In utero exposure to the environmental androgen trenbolone masculinizes female Sprague–Dawley rats. Toxicol. Lett. 174, 31–41.
| In utero exposure to the environmental androgen trenbolone masculinizes female Sprague–Dawley rats.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXht1anurbP&md5=36201d2757ed06c90ec576b84cd64925CAS | 17931805PubMed |
Hotchkiss, A. K., Lambright, C. S., Ostby, J. S., Parks-Saldutti, L., Vandenberg, J. G., and Gray, L. E. (2007b). Prenatal testosterone exposure permanently masculinises anogenital distance, nipple development and reproductive tract morphology in female Sprague–Dawley rats. Toxicol. Sci. 96, 335–345.
| Prenatal testosterone exposure permanently masculinises anogenital distance, nipple development and reproductive tract morphology in female Sprague–Dawley rats.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXjtlCjt7s%3D&md5=3fd7dad8fb7bc472d21fd67d66a7aab4CAS | 17218470PubMed |
Huttunen, E., Romppanen, T., and Helminen, H. J. (1981). A histoquantitative study on the effects of castration on the rat ventral prostate lobe. J. Anat. 132, 357–370.
| 1:STN:280:DyaL38%2Flt1Ojuw%3D%3D&md5=d178dc2ebc350e9d5d419863be464c0dCAS | 7298488PubMed |
Khan, R. A., Ghani, I., and Wahab, S. (2007). Hydrometrocolpos due to persistent urogenital sinus mimicking neonatal ascites. Iran. J. Pediatr. 18, 67–70.
Meeks, J. J., and Schaeffer, E. M. (2011). Genetic regulation of prostate development. J. Androl. 32, 210–217.
| Genetic regulation of prostate development.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXmtl2itr0%3D&md5=f9eb073cbcd0915c2289c55bb9601fe7CAS | 20930191PubMed |
Nishino, N., and Totsukawa, K. (1996). Study on the oestrous cycle in the Mongolian gerbil (Meriones unguiculatus). Exp. Anim. 45, 283–288.
| Study on the oestrous cycle in the Mongolian gerbil (Meriones unguiculatus).Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK28XlsVarsb8%3D&md5=301a5938cc8d1734e5440138d28fb046CAS | 8840149PubMed |
Perez, A. P. S., Biancardi, M. F., Góes, R. M., Santos, F. C. A., and Taboga, S. R. (2011). Exposure to ethinylestradiol during prenatal development and postnatal supplementation with testosterone causes morphophysiological alterations in the prostate of male and female adult gerbils. Int. J. Exp. Pathol. 92, 121–130.
| Exposure to ethinylestradiol during prenatal development and postnatal supplementation with testosterone causes morphophysiological alterations in the prostate of male and female adult gerbils.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXmtVKjsrk%3D&md5=5384d7a6782a907b48f4fd189453cc63CAS |
Perez, A. P. S., Biancardi, M. F., Vilamaior, P. S. L., Góes, R. M., Santos, F. C. A., and Taboga, S. R. (2012). Microscopic comparative study of the exposure effects of testosterone cypionate and ethinylestradiol during prenatal life on the prostatic tissue of adult gerbils. Microsc. Res. Tech. 75, 1084–1092.
| Microscopic comparative study of the exposure effects of testosterone cypionate and ethinylestradiol during prenatal life on the prostatic tissue of adult gerbils.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XhtVOjsL3O&md5=5d19b43cce6dc87163d3691f4abc98ecCAS |
Prins, G. S., and Putz, O. (2008). Molecular signalling pathways that regulate prostate gland development. Differentiation 76, 641–659.
| Molecular signalling pathways that regulate prostate gland development.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXhtVSrsLfO&md5=6a63d29818d91db8ecb0c86100aa7ce6CAS | 18462433PubMed |
Prins, G. S., Tang, W. L., Belmonte, J., and Ho, S. M. (2008). Perinatal exposure to oestradiol and bisphenol A alters the prostate epigenome and increases susceptibility to carcinogenesis. Basic Clin. Pharmacol. Toxicol. 102, 134–138.
| Perinatal exposure to oestradiol and bisphenol A alters the prostate epigenome and increases susceptibility to carcinogenesis.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXhvF2gs7Y%3D&md5=7b01235f9ea38349a15119373f447f16CAS | 18226066PubMed |
Reis, L. O., Billis, A., Ferreira, F. T., Ikari, L. Y., Stellini, R. F., and Ferreira, U. (2011). Female urethral carcinoma: evidences to origin from Skene’s glands. Urol. Oncol. 29, 218–223.
| Female urethral carcinoma: evidences to origin from Skene’s glands.Crossref | GoogleScholarGoogle Scholar | 19450996PubMed |
Santos, F. C. A., and Taboga, S. R. (2006). Female prostate: a review about the biological repercussions of this gland in humans and rodents. Anim. Reprod. 3, 3–18.
Santos, F. C. A., Leite, R. P., Custódio, A. M. G., Carvalho, K. P., Monteiro-Leal, L. H., Santos, A. B., Góes, R. M., Carvalho, H. F., and Taboga, S. R. (2006). Testosterone stimulates growth and secretory activity of the adult female prostate of the gerbil (Meriones unguiculatus). Biol. Reprod. 75, 370–379.
| Testosterone stimulates growth and secretory activity of the adult female prostate of the gerbil (Meriones unguiculatus).Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XovVWmtbg%3D&md5=53a9ddead5d7ab5042f6e6791d6b8e5cCAS |
Schaeffer, E. M., Marchionni, L., Huang, Z., Simons, B., Blackman, A., Yu, W., Parmigiani, G., and Berman, D. M. (2008). Androgen-induced programs for prostate epithelial growth and invasion arise in embryogenesis and are reactivated in cancer. Oncogene 27, 7180–7191.
| Androgen-induced programs for prostate epithelial growth and invasion arise in embryogenesis and are reactivated in cancer.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXhsVGlu7%2FO&md5=9d20b4ad734442de7fc7bca86e2fc64fCAS | 18794802PubMed |
Söder, O. (2005). Perinatal imprinting by oestrogen and adult prostate disease. Proc. Natl. Acad. Sci. USA 102, 1269–1270.
| Perinatal imprinting by oestrogen and adult prostate disease.Crossref | GoogleScholarGoogle Scholar | 15677320PubMed |
Staack, A., Donjacour, A. A., Brody, J., Cunha, G. R., and Carroll, P. (2003). Mouse urogenital development: a practical approach. Differentiation 71, 402–413.
| Mouse urogenital development: a practical approach.Crossref | GoogleScholarGoogle Scholar | 12969333PubMed |
Takeda, H., Mizuno, T., and Lasnitzki, I. (1985). Autoradiographic studies of androgen-binding sites in the rat urogenital sinus and postnatal prostate. J. Endocrinol. 104, 87–92.
| Autoradiographic studies of androgen-binding sites in the rat urogenital sinus and postnatal prostate.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL2MXktVahuw%3D%3D&md5=33fa80104b7247e47dd016d01f8bdd3eCAS | 3968508PubMed |
Thomson, A. A. (2008). Mesenchymal mechanisms in prostate organogenesis. Differentiation 76, 587–598.
| Mesenchymal mechanisms in prostate organogenesis.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXhtVSrsLbE&md5=8b7d8a844f38bb95057bb132015136fbCAS | 18752494PubMed |
Thomson, A. A., Timms, B. G., Barton, L., Cunha, G. R., and Grace, O. C. (2002). The role of smooth muscle in regulating prostatic induction. Development 129, 1905–1912.
| 1:CAS:528:DC%2BD38XjslSlsrs%3D&md5=969671660e78262323037b21c3ad91d1CAS | 11934856PubMed |
Timms, B. G. (2008). Prostate development: a historical perspective. Differentiation 76, 565–577.
| Prostate development: a historical perspective.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXhtVSrsLbK&md5=2436d6de8f913d6d643a0d20b146723cCAS | 18462432PubMed |
Timms, B. G., and Hofkamp, L. (2011). Prostate development and growth in benign prostatic hyperplasia. Differentiation 82, 173–183.
| Prostate development and growth in benign prostatic hyperplasia.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXht1eitLzI&md5=68b39544cebc0d8894c0a8505f358798CAS | 21939815PubMed |
Timms, B. G., Mohs, T. J., and Didio, L. J. A. (1994). Ductal budding and branching patterns in the developing prostate. J. Urol. 151, 1427–1432.
| 1:STN:280:DyaK2c3htVKltQ%3D%3D&md5=860784e40ee7eacf18f74eeaad0d253bCAS | 8158800PubMed |
Timms, B. G., Lee, C. W., Aumüler, G., and Seits, J. (1995). Instructive induction of prostate growth and differentiation by a defined urogenital sinus mesenchyme. Microsc. Res. Tech. 30, 319–332.
| Instructive induction of prostate growth and differentiation by a defined urogenital sinus mesenchyme.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaK2MzivFOrtg%3D%3D&md5=eaff1f71ec3a65ec5bae8161b18c2ebbCAS | 7606051PubMed |
Timms, B. G., Kembra, L. H., Barton, L., Bradley, S., Richter, C. A., and vom Saal, F. S. (2005). Oestrogenic chemicals in plastic and oral contraceptives disrupt development of the fetal mouse prostate and urethra. Proc. Natl. Acad. Sci. USA 102, 7014–7019.
| 1:CAS:528:DC%2BD2MXksVKns7s%3D&md5=e762dfa186118dbe09544502571cff1bCAS | 15867144PubMed |
Weibel, E. R. (1963). Principles and methods for the morphometric study of the lung and other organs. Lab. Invest. 12, 131–155.
| 1:STN:280:DyaF387ptFequw%3D%3D&md5=129f0c69782eae58b8b49b6ac0e58904CAS | 13999512PubMed |
Welsh, M., Saunders, P. T. K., Fisken, M., Scott, H. M., Hutchison, G. R., Smith, L. B., and Sharpe, R. M. (2008). Identification in rats of a programming window for reproductive tract masculinisation, disruption of which leads to hypospadias and cryptorchidism. J. Clin. Invest. 118, 1479–1490.
| Identification in rats of a programming window for reproductive tract masculinisation, disruption of which leads to hypospadias and cryptorchidism.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXkt1CnurY%3D&md5=f1f731f96e95058336cd7f29fd509e9dCAS | 18340380PubMed |
Wilhelm, D., and Koopman, P. (2006). The makings of maleness towards an integrated view of male sexual development. Nat. Rev. Genet. 7, 620–631.
| The makings of maleness towards an integrated view of male sexual development.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XmvFCmsr4%3D&md5=eafc161e360bd900dafe95cab34ed04dCAS | 16832429PubMed |
Wilson, J. D. (2011). The critical role of androgens in prostate development. Endocrinol. Metab. Clin. North Am. 40, 577–590.
| The critical role of androgens in prostate development.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXhtFeku77I&md5=25b3a59025f12c40095f09873f2ac7f1CAS | 21889722PubMed |
Wolf, C. J., Hotchkiss, A. K., Ostby, J. S., LeBlanc, G. A., and Gray, L. E. (2002). Effects of prenatal testosterone propionate on the sexual development of male and female rats: a dose-response study. Toxicol. Sci. 65, 71–86.
| Effects of prenatal testosterone propionate on the sexual development of male and female rats: a dose-response study.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD38XkvFSitA%3D%3D&md5=c6a21c56500f1058ebbcb83b69f1066fCAS | 11752687PubMed |
Zanatelli, M., Silva, D. A., Shinohara, F. Z., Góes, R. M., Santos, F. C., Vilamaior, P. S., and Taboga, S. R. (2013). Actions of oestradiol and progesterone on the prostate in female gerbils: reversal of the histological effects of castration. Reprod. Fertil. Dev. , .
| Actions of oestradiol and progesterone on the prostate in female gerbils: reversal of the histological effects of castration.Crossref | GoogleScholarGoogle Scholar | 23677028PubMed |
Zaviačič, M. (Ed.) (1999). ‘The Female Prostate: from Vestigial Skene’s Paraurethral Glands and Ducts to Woman’s Functional Prostate.’ (Slovack Academic Press: Bratislava, Slovakia.)