Kisspeptin/GPR54 system as potential target for endocrine disruption of reproductive development and function

Kisspeptins, the products of Kiss1 gene acting via G protein-coupled receptor 54 (also termed Kiss1R), have recently emerged as essential gatekeepers of puberty onset and fertility. Compelling evidence has now documented that expression and function of hypothalamic Kiss1 system is sensitive not only to the activational effects but also to the organizing actions of sex steroids during critical stages of development. Thus, studies in rodents have demonstrated that early exposures to androgens and oestrogens are crucial for proper sexual differentiation of the patterns of Kiss1 mRNA expression, whereas the actions of oestrogen along puberty are essential for the rise of hypothalamic kisspeptins during this period. This physiological substrate provides the basis for potential endocrine disruption of reproductive maturation and function by xeno-steroids acting on the kisspeptin system. Indeed, inappropriate exposures to synthetic oestrogenic compounds during early critical periods in rodents persistently decreased hypothalamic Kiss1 mRNA levels and kisspeptin fibre density in discrete hypothalamic nuclei, along with altered gonadotropin secretion and/or gonadotropin-releasing hormone neuronal activation. The functional relevance of this phenomenon is stressed by the fact that exogenous kisspeptin was able to rescue defective gonadotropin secretion in oestrogenized animals. Furthermore, early exposures to the environmentally-relevant oestrogen, bisphenol-A, altered the hypothalamic expression of Kiss1/kisspeptin in rats and mice. Likewise, maternal exposure to a complex cocktail of endocrine disruptors has been recently shown to disturb foetal hypothalamic Kiss1 mRNA expression in sheep. As a whole, these data document the sensitivity of Kiss1 system to changes in sex steroid milieu during critical periods of sexual maturation, and strongly suggest that alterations of endogenous kisspeptin tone induced by inappropriate (early) exposures to environmental compounds with sex steroid activity might be mechanistically relevant for disruption of puberty onset and gonadotropin secretion later in life. The potential interaction of xeno-hormones with other environmental modulators (e.g., nutritional state) of the Kiss1 system warrants further investigation.