Alterazioni della comparsa della pubertà, del comportamento sessuale e dei circuiti a Kisspeptina in un modello murino di esposizione perinatale al Bisphenolo A

Pursuing the most recent studies on some environmental compounds' adverse effects on the neuroendocrine systems, this work investigated the role of different Bisphenol A (BPA) doses in the alterations of puberty onset, reproductive functions and hypothalamic circuits involved in their control by using male and females mice as animal model. Two experiments were done: Exp. 1 analyzed potential organizational effects on the reproductive system of pups that received BPA from mothers during pregnancy and lactation (fetal and critical periods). In Exp. 2, additionally to the Exp. 1 treatment, pups received BPA also in the adult life, thus providing to verify potential BPA activational effects on neuroendocrine systems that control reproductive behavior. Evaluation of the Vaginal Opening (VO) time and a series of tests for the sexual behavior were performed before the sacrifice at the age of 3 months. Immunohistochemical (IHC) analyses were then carried out on mice hypothalamic nuclei involved in the control of puberty onset and sexual behavior, identified as AVPV, PeN and Arc nuclei. The purpose was to analyze the BPA effects on the Kisspeptin (KiSS1) immunoreactivity (ir) of cells and fibers belonging to these nuclei, since KiSS1 is crucial for the control of circuits that regulate the puberty onset and reproductive functions. Confirming previous studies, this work demonstrated that BPA anticipates puberty onset (VO) in all treated females compared to the controls. BPA also affected some aspects of the male sexual behavior in both Experiments, reflecting the prevalence of organizational effects. Other parameters resulted singularly altered in one of the two Experiments each time, reflecting also the presence of activational effects for BPA on the male sexual behavior. In females, BPA failed to induce alterations of the sexual behavior, therefore suggesting the presence of a sex diergism in the BPA sensitivity. Behavioral results partially disagree with IHC analysis of KiSS1-ir in AVPV, PeN and Arc nuclei, that often showed stronger alterations in treated females than in treated males. IHC analysis of OIL/BPA-treated male and female mice globally confirmed the sex dimorphism of KiSS1 distribution within these nuclei. Exp. 1 demonstrated that BPA has profound organizational effects on KiSS1 system. In fact, the number of KiSS1-ir cells significantly increased in both males and females, whereas the total immunoreactivity significantly increased only in females. Results from Exp. 2 suggested the presence of activational effects for BPA that may counteract the Exp. 1 organizational ones in both sexes. In conclusion, BPA effects varied strongly between the different doses, often drifting from a dose-dependent trend, suggesting the presence of several different BPA-sensitive circuits. However, organizational effects were prevailing, suggesting a stronger action for BPA precocious exposure that makes BPA safe-levels different early in the life or in the adulthood. Governments should then consider this findings in order to protect human and animal health from pollutants exposition risks.