The kisspeptin system as putative target for endocrine disruption of puberty and reproductive health

Abstract

The activation of the reproductive axis at puberty and its proper function later on life are founded on a complex series of maturational events that include the sexual differentiation of the brain during early critical periods of development. Brain sex differentiation is driven (mostly) by endogenous sex steroids, which are also important regulators of the neuroendocrine networks governing puberty onset. Accordingly, both phenomena might be sensitive to the disrupting actions of exogenous compounds with sex steroid-like activity that may pose long lasting consequences in terms of reproductive health. Kisspeptins, the products of the Kiss1 gene that act via the receptor, GPR54, are neuropeptides produced at discrete neuronal populations within the hypothalamus with key roles in brain sex differentiation, puberty onset and fertility. A subset of Kiss1 neurons has been recently shown to co-express neurokinin B (NKB), another neuropeptide with important reproductive roles. Compelling evidence has mounted recently that Kiss1 neurons are subjected to sexual dimorphism and physiologically sensitive to the organizing and activational effects of sex steroids, as documented in rodents, sheep and primates (including humans). These features provide the basis for the potential endocrine disruption of reproductive maturation and function by xeno-steroids targeting the Kiss1 system. Indeed, solid, as yet fragmentary, evidence obtained in rodents and sheep suggests that hypothalamic expression of Kiss1 and/or kisspeptin fiber distribution are altered following inappropriate exposures to synthetic estrogenic and/or androgenic compounds during critical periods of development. Of note, administration of androgenic and estrogenic compounds during such critical periods has been shown to alter also the hypothalamic expression of NKB in rodents and sheep. As a whole, the data summarized in this chapter 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 bemechanistically relevant for disruption of puberty onset and gonadotropin secretion later in life. The potential additional interactions of xeno-hormones with related neuropeptide systems (including NKB) and other environmental modulators (such as the nutritional state) of the Kiss1 system merits future investigation. © Springer-Verlag Berlin Heidelberg 2011.