Phenotypic characterization of female mice exposed to human chorionic gonadotropin (hCG) in utero.

RATNER LD; DI GIORGIO NP; GONZALEZ-CALVAR SI; POUTANEN M; CALANDRA RS,; HUHTANIEMI IT; RULLI SB

San Francisco

Congreso; Reunión Anual de la Endocrine Society; 2013

The Endocrine Society

It is well known that in utero exposure to hormonal imbalance influences the phenotype of the offspring. We have shown previously that transgenic female mice overexpressing the human chorionic gonadotropin β-subunit (hCGβ+ mice) exhibit constitutively elevated levels of hCG and increased production of testosterone, progesterone and prolactin initiated postnatally. These females are also overweight, infertile and develop pituitary rolactinomas at adult age (1). Recently we identified that hyperprolactinemia is the main cause of infertility in these females. Accordingly, one-week-long treatment with a dopamine agonist (cabergoline) applied to 5-week-old hCGβ+ females reversed the hormone imbalances, prevented the pituitary tumor development and recovered the fertility at adulthooh (2). The aim of this study was to analyze the phenotype and reproductive function of the female offspring derived from the hCGβ+ mothers previously treated with cabergoline during one week at 5 weeks of age. Phenotypic characterization was assessed on 6-month-old wild-type (WTF1) and hCGβ+ female offspring (hCGβ+F1); fertility studies were followed from 3 to 6 months of age. WTF1 females did not show alterations in the body or pituitary weight as compared with the WT females. As expected, all the hCGβ+F1 females had elevated secretion of hCG, while 80% of them exhibited normalized pituitary and body weights (subgroup hCGβ+F1-A). In addition, the hCGβ+F1-A females showed reduced progesterone and prolactin levels as compared with the hCGβ+ females, and presented with normalized estrous cycles and gonadal function. The expression of Drd2, Pit-1 and Prl genes, determined by qRT-PCR in the pituitary glands of hCGβ+F1-A mice, was significantly reduced in comparison to the control hCGβ+ females. Furthermore, hCGβ+F1-A mice were fully fertile, and gave birth several litters during the 3-month-long period analyzed. Since the transgene expression was not compromised in the mothers, the offspring were exposed to elevated levels of hCG during gestation. These results show that the altered hormonal milieu during the fetal life had a significant impact on the offspring?s phenotype, such that 80% of transgenic daughters derived from hCGβ+ mothers exhibited a normal appearance. The presence of hCG during gestation may have a protective effect on the transgenic offspring from the hormonal imbalances and tumor development at adult age.