Tena-Sempere M
Department of Cell Biology, Physiology and Immunology, University of Córdoba; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III; and Instituto Maimónides de Investigaciones Biomédicas, Córdoba, Spain.
Int J Androl. 2010 Apr;33(2):360-8. doi: 10.1111/j.1365-2605.2009.01012.x. Epub 2009 Nov 10.
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.
亲吻素是Kiss1基因的产物，通过G蛋白偶联受体54（也称为Kiss1R）发挥作用，最近已成为青春期启动和生育能力的重要守门者。现在有确凿的证据表明，下丘脑Kiss1系统的表达和功能不仅对性类固醇在发育关键阶段的激活作用敏感，而且对其组织作用也敏感。因此，对啮齿动物的研究表明，早期接触雄激素和雌激素对于Kiss1 mRNA表达模式的正常性分化至关重要，而青春期期间雌激素的作用对于这一时期下丘脑亲吻素的升高至关重要。这种生理基础为具有性类固醇活性的异源类固醇作用于亲吻素系统导致生殖成熟和功能的潜在内分泌干扰提供了基础。事实上，在啮齿动物的早期关键时期不恰当地接触合成雌激素化合物会持续降低下丘脑Kiss1 mRNA水平以及离散下丘脑核中的亲吻素纤维密度，同时改变促性腺激素分泌和/或促性腺激素释放激素神经元激活。外源性亲吻素能够挽救雌激素化动物中促性腺激素分泌缺陷这一事实强调了这一现象的功能相关性。此外，早期接触与环境相关的雌激素双酚A会改变大鼠和小鼠下丘脑Kiss1/亲吻素的表达。同样，最近有研究表明，母体接触内分泌干扰物的复杂混合物会干扰绵羊胎儿下丘脑Kiss1 mRNA的表达。总体而言，这些数据证明了Kiss1系统在性成熟关键时期对性类固醇环境变化的敏感性，并强烈表明在生命早期不恰当地（早期）接触具有性类固醇活性的环境化合物所诱导的内源性亲吻素水平改变可能在机制上与青春期启动和促性腺激素分泌的破坏有关。异源激素与Kiss1系统的其他环境调节因子（如营养状态）之间的潜在相互作用值得进一步研究。
