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Vertebrate reproductive science and technology
RESEARCH ARTICLE

Effects of maternal exposure to an aromatase inhibitor on sexual behaviour and neurochemical and endocrine aspects of adult male rat

Daniela C. C. Gerardin A B , Renata C. Piffer A , Patrícia C. Garcia A , Estefânia G. Moreira B and Oduvaldo C. M. Pereira A C
+ Author Affiliations
- Author Affiliations

A Department of Pharmacology, Institute of Biosciences, Sao Paulo State University—UNESP, 18618-000 Botucatu, Sao Paulo, Brazil.

B Department of Physiological Sciences, Londrina State University—UEL, 86051-990 Londrina, Parana, Brazil.

C Corresponding author. Email: pereira@ibb.unesp.br

Reproduction, Fertility and Development 20(5) 557-562 https://doi.org/10.1071/RD07213
Submitted: 29 November 2007  Accepted: 6 March 2008   Published: 28 April 2008

Abstract

The present study examined the effects of letrozole exposure during brain sexual differentiation on endocrine, behavioural and neurochemical parameters in male rat descendants. Pregnant female rats received 1 mg kg–1 day–1 letrozole or vehicle by oral gavage on gestational Days 21 and 22. Exposure to letrozole reduced anogenital distance in males on postnatal Day (PND) 22. At adulthood (PND 75), plasma testosterone levels and hypothalamic dopaminergic activity were increased, but sexual competence was impaired, because fewer successful sexual behaviours (mount, intromission and principally ejaculation) were observed. The impairment of reproductive function by prenatal exposure to an aromatase inhibitor reinforces the importance of adequate oestrogenic activity during perinatal sexual differentiation for complete masculinisation of the hypothalamus.

Additional keywords: hypothalamus, neurochemistry, sexual differentiation, striatum.


Acknowledgements

The authors are grateful to Eunice Oba for help with the determination of testosterone concentrations. This work constituted part of the doctoral thesis presented to the Universidade de São Paulo—USP by Daniela C. C. Gerardin and was supported by a fellowship from FAPESP (01/03458-0 and 04/08627-3).


References

Abdelnabi, M. A. , and Ottinger, M. A. (2003). Hypothalamic indolamines during embryonic development and effects of steroid exposure. Gen. Comp. Endocrinol. 130, 13–19.
Crossref | GoogleScholarGoogle Scholar | PubMed |

Agmo, A. (1997). Male rat sexual behavior. Brain Res. Brain Res. Protoc. 1, 203–209.
Crossref | GoogleScholarGoogle Scholar | PubMed |

Arteche, E. , Strippoli, G. , Loirand, G. , Pacaud, P. , and Candenas, L. , et al. (1997). An analysis of the mechanisms involved in the okadaic acid induced contraction of the estrogen-primed rat uterus. J. Pharmacol. Exp. Ther. 282, 201–207.
PubMed |

Clark, R. L. , Antonello, J. M. , Grossman, S. J. , Wise, L. D. , Anderson, C. , Bagdon, W. J. , Prahalada, S. , Macdonald, J. S. , and Robertson, R. T. (1990). External genitalia abnormalities in male rats exposed in utero to finasteride, a 5α-reductase inhibitor. Teratology 42, 91–100.
Crossref | GoogleScholarGoogle Scholar | PubMed |

Corbier, P. , Kerdelhue, B. , Picon, R. , and Roffi, J. (1978). Changes in testicular weight and serum gonadotropin and testosterone levels before, during, and after birth in the perinatal rat. Endocrinology 103, 1985–1991.
PubMed |

Csaba, G. , and Karabèlyos, C. (2001). The effect of a single neonatal treatment (hormonal imprinting) with the antihormones, tamoxifen and mifepristone on the sexual behavior of adult rats. Pharmacol. Res. 43, 531–533.
Crossref | GoogleScholarGoogle Scholar | PubMed |

Faber, K. A. , and Hughes, C. L. (1992). Anogenital distance at birth as a predictor of volume of the sexually dimorphic nucleus of the preoptic area of the hypothalamus and pituitary responsiveness in castrated adult rats. Biol. Reprod. 46, 101–104.
Crossref | GoogleScholarGoogle Scholar | PubMed |

Freeman, L. M. , and Rissman, E. F. (1996). Neural aromatization and the control of sexual behavior. Trends Endocrinol. Metab. 7, 334–338.
Crossref | GoogleScholarGoogle Scholar | PubMed |

Gerardin, D. C. C. , and Pereira, O. C. M. (2002). Reproductive changes in male rats treated perinatally with aromatase inhibitor. Pharmacol. Biochem. Behav. 71, 301–305.
Crossref | GoogleScholarGoogle Scholar | PubMed |

Gerardin, D. C. C. , Pereira, O. C. M. , Kempinas, W. G. , Florio, J. C. , Moreira, E. G. , and Bernardi, M. M. (2005). Sexual behavior, neuroendocrine, and neurochemical aspects in male rats exposed prenatally to stress. Physiol. Behav. 84, 97–104.
Crossref | GoogleScholarGoogle Scholar | PubMed |

Gerardin, D. C. C. , Bernardi, M. M. , Moreira, E. G. , and Pereira, O. C. M. (2006). Neuroendocrine and reproductive aspects of adult male rats exposed neonatally to an antiestrogen. Pharmacol. Biochem. Behav. 83, 618–623.
Crossref | GoogleScholarGoogle Scholar | PubMed |

Gréco, B. , Edwards, D. A. , Zumpe, D. , and Clancy, A. N. (1998). Androgen receptor and mating-induced Fos immunoreactivity are co-localized in limbic and midbrain neurons that project to the male rat medial preoptic area. Brain Res. 781, 15–24.
Crossref | GoogleScholarGoogle Scholar | PubMed |

Haynes, B. P. , Dowsett, M. , Dixon, J. M. , and Bhatnagar, A. S. (2003). The pharmacology of letrozole. J. Steroid Biochem. Mol. Biol. 87, 35–45.
Crossref | GoogleScholarGoogle Scholar | PubMed |

Huddleston, G. G. , Michael, R. P. , Zumpe, D. , and Clancy, A. N. (2003). Estradiol in the male rat amygdale facilitates mounting but not ejaculation. Physiol. Behav. 79, 239–246.
Crossref | GoogleScholarGoogle Scholar | PubMed |

Hull, E. M. , Lorrain, D. S. , Du, J. , Matuszewich, L. , Lumley, L. A. , Putnam, S. K. , and Moses, J. (1999). Hormone–neurotransmitter interactions in the control of sexual behavior. Behav. Brain Res. 105, 105–116.
Crossref | GoogleScholarGoogle Scholar | PubMed |

Hull, E. M. , Muschamp, J. W. , and Sato, S. (2004). Dopamine and serotonin: influences on male sexual behavior. Physiol. Behav. 83, 291–307.
PubMed |

Jones, M. E. E. , Boon, W. C. , Proietto, J. , and Simpson, E. R. (2006). Of mice and men: the evolving phenotype of aromatase deficiency. Trends Endocrinol. Metab. 17, 55–64.
Crossref | GoogleScholarGoogle Scholar | PubMed |

Keshet, G. I. , and Weinstock, M. (1995). Maternal naltrexone prevents morphological and behavioral alterations induced in rats by prenatal stress. Pharmacol. Biochem. Behav. 50, 413–419.
Crossref | GoogleScholarGoogle Scholar | PubMed |

Leonard, B. E. (1982). Behavioral teratology: Post-natal consequences of drug exposure in utero. Arch. Toxicol. 5, 48–58.


Lephart, E. D. (1996). A review of brain aromatase cytochrome P450. Brain Res. Brain Res. Rev. 22, 1–26.
Crossref | GoogleScholarGoogle Scholar | PubMed |

Markowski, V. P. , Lumeley, L. A. , Moses, J. , and Hull, E. M. (1994). D1 agonist in the MPOA facilitates copulation in male rats. Pharmacol. Biochem. Behav. 47, 483–486.
Crossref | GoogleScholarGoogle Scholar | PubMed |

Negri-Cesi, P. , Colciago, A. , Motta, M. , Martini, L. , and Celotti, F. (2001). Aromatase expression and activity in male and female cultured rat hypothalamic neurons: effect of androgens. Mol. Cell. Endocrinol. 178, 1–10.
Crossref | GoogleScholarGoogle Scholar | PubMed |

Oliva, S. U. , Messias, A. G. , Silva, D. A. F. , Pereira, O. C. M. , Gerardin, D. C. C. , and Kempinas, W. G. (2006). Impairment of adult male reproductive function in rats exposed to ethanol since puberty. Reprod. Toxicol. 22, 599–605.
Crossref | GoogleScholarGoogle Scholar | PubMed |

Pereira, O. C. M. , Bernardi, M. M. , and Gerardin, D. C. C. (2006). Could neonatal testosterone replacement prevent alterations induced by prenatal stress in male rats? Life Sci. 78, 2767–2771.
Crossref | GoogleScholarGoogle Scholar | PubMed |

Reznikov, A. G. , Nosenko, N. D. , and Tarasenko, L. V. (1999). Prenatal stress and glucocorticoid effects on the developing gender-related brain. J. Steroid Biochem. Mol. Biol. 69, 109–115.
Crossref | GoogleScholarGoogle Scholar | PubMed |

Robbins, A. (1996). Androgens and male sexual behavior, from mice to men. Trends Endocrinol. Metab. 7, 345–350.
Crossref | GoogleScholarGoogle Scholar | PubMed |

Roselli, C. E. , and Klosterman, S. A. (1998). Sexual differentiation of aromatase activity in the rat brain: eggects of perinatal steroid exposure. Endocrinology 139, 3193–3201.
Crossref | GoogleScholarGoogle Scholar | PubMed |

Roselli, C. E. , Cross, E. , Poonyagariyagorn, H. K. , and Stadelman, H. L. (2003). Role of aromatization in anticipatory and consummatory aspects of sexual behavior in male rats. Horm. Behav. 44, 146–151.
Crossref | GoogleScholarGoogle Scholar | PubMed |

Saleh, T. M. , Connell, B. J. , McQuaid, T. , and Cribb, A. E. (2003). Estrogen-induced neurochemical and electrophysiological changes in the parabrachial nucleus of male rat. Brain Res. 990, 58–65.
Crossref | GoogleScholarGoogle Scholar | PubMed |

Teodorov, E. , Salzgeber, S. A. , Felicio, L. F. , Varolli, F. M. F. , and Bernardi, M. M. (2002). Effects of perinatal picrotoxin and sexual experience on heterosexual and homosexual behavior in male rats. Neurotoxicol. Teratol. 24, 235–245.
Crossref | GoogleScholarGoogle Scholar | PubMed |

Tobin, V. A. , and Canny, B. J. (1998). The regulation of gonadotropin-releasing hormone-induced calcium signals in male rat gonadotrophs by testosterone is mediated by dihydrotestosterone. Endocrinology 139, 1038–1045.
Crossref | GoogleScholarGoogle Scholar | PubMed |

Wang, C. T. , Shui, H. A. , Huang, R. L. , Tai, M. Y. , Peng, M. T. , and Tsai, Y. F. (2006). Sexual motivation is desmaculinized, but not feminized, in prenatally stressed male rats. Neuroscience 138, 357–364.
Crossref | GoogleScholarGoogle Scholar | PubMed |

Ward, I. L. , and Weisz, J. (1984). Differential effects of maternal stress on circulating levels of corticosterone, progesterone, and testosterone in male and female rat fetuses and their mothers. Endocrinology 114, 1635–1644.
PubMed |

Weisz, J. , and Ward, I. L. (1980). Plasma testosterone and progesterone titers of pregnant rats, their male and female fetuses, and neonatal offspring. Endocrinology 106, 306–316.
PubMed |