CONICET | Buscador de Institutos y Recursos Humanos

AXIS OF TRANSGENIC HCGΒ+ MICE OFFSPRING DERIVED FROMCABERGOLINE-TREATED FEMALESS. Rulli1, A. Marcial Lopez1, R. Calandra1, M. Poutanen2, I. Huhtaniemi2, L. Ratner11Instituto de Biología y Medicina Experimental-CONICET Buenos Aires, Argentina, 2Institute ofBiomedicine, University of Turku Turku, FinlandAn increased response of the gonads to luteinizing hormone (LH) or human chorionicgonadotropin (hCG) by binding to the LH/hCG receptor is the pivotal signal that leads to anenhanced steroidogenesis. Altered secretion of LH/hCG has been related to many pathologies ofthe reproductive axis. Transgenic female mice expressing hCGβ under the ubiquitin promoter(hCGβ+) produce elevated levels of hCG, prolactin, progesterone and testosterone, are infertile,obese, and develop pituitary and mammary tumors in old age. We have previously demonstratedthat a short-term treatment of juvenile hCGβ+ females with the dopamine agonist cabergoline isable to normalize the phenotypic changes of hCGβ+ females and to recover fertility in adulthood,even in the presence of high levels of hCG (Endocrinology 153:5980-5992, 2012). The aim ofthis study was to analyze the possible influence of the maternal environment (hCG and/or thecabergoline treatment) on the hypothalamic-pituitary-gonadal axis of both transgenic andnontransgenic offspring. Three-week-old wild-type (WT) or hCGβ+ females were treated withcabergoline (500 μg/dose) every other day for one week. At reproductive age, these femaleswere crossbred with hCGβ+ or WT males, respectively, and the offspring phenotype wasanalyzed at 3 weeks of age and in adulthood. The phenotype of hCGβ+ offspring derived fromcabergoline-treated hCGβ+ females x WT males was normalized, in terms of serum hormoneprofile and ovarian gene expression of Lhcgr, Cyp11a1, Cyp17a1 and Cyp19a1. Furthermore, theestrous cycles were regular and the mice were fully fertile. At six months of age, femalesexhibited normalized pituitary and body weights, without signs of tumor development. Nochanges were found in nontransgenic littermates. In order to define if these findings were due tohCG or to long-lasting effects of cabergoline during gestation, we crossbred cabergoline-treatedWT females x hCGβ+ males. Surprisingly, the phenotype of transgenic hCGβ+ offspring wasnormalized as well. These results showed that a short-term treatment with cabergoline applied tofemales prior to their active reproductive age prevented phenotypic alterations on the offspring.It remains to be investigated if other conditions with altered gonadotropin secretion may also beprevented by a cabergoline treatment to the mother prior to pregnancy, as well as possibleepigenetic mechanisms involved. The fact that a long-lasting specific effect of cabergoline mayimpact on the developing hypothalamic-pituitary-gonadal axis and be manifested later in lifedeserves a more detailed consideration.