Endocrine Disruption of the Hypothalamic Signaling That Regulates Puberty

描述（由申请人提供）： 流行病学资料表明，性早熟和生育能力受损的发生率正在增加。据推测，暴露于内分泌活性化合物（EAC）可能在这一趋势中发挥作用。在啮齿类动物中，许多EAC都有青春期提前和持续发情的记录，但对EAC产生这些效应的机制知之甚少。这种知识的缺乏使得很难预测潜在的EAC最终如何影响人类健康。在女性中，青春期是下丘脑-垂体-性腺（HPG）轴成熟的结果，并随着刺激排卵的周期性促性腺激素释放激素（GnRH）脉冲的开始而达到高潮。前腹侧室周核（AVPV）是GnRH神经元活动的主要调节器。拟议研究背后的具体假设是，新生儿暴露于EAC双酚A（BPA）和染料木黄酮（GEN）导致青春期中断是由于AVPV的性分化不当，因此雌激素受体（ER）启动的信号转导途径调节GnRH分泌。以下初步数据支持这一假设。首先，这两种化合物都提前了青春期发作。第二，两种化合物 使含有ER？的AVPV神经元表型减雌。第三，GEN扰乱了青春期后的发情周期。 最后，两种化合物都使成人AVPV体积缩小。使用行为，解剖和分子技术，研究人员将比较BPA和GEN与两种雌激素受体（ER？）。表征EAC影响青春期时间和进展的信号转导途径。对于所有研究，给予的EAC剂量将在与人体暴露相关的范围内。 目的1：描述新生儿BPA、GEN、ER的影响？激动剂DPN还是ER激动剂PPT暴露对青春期AVPV中kisspeptin和甘丙肽信号传导的影响。 目的2：定位ER？而ER？在青春期前大鼠AVPV，并确定这种模式是否被BPA，GEN或DPN或PPT破坏。 目的3：研究新生儿暴露于BPA、GEN、DPN或PPT如何影响发情周期和青春期后的性行为。 目标4：表征新生儿BPA、GEN、DPN或PPT对AVPV体积、AVPV ER和kisspeptin含量以及青春期后垂体刺激的GnRH神经元激活的影响。

DESCRIPTION (provided by applicant): Epidemiological data suggest that the incidence of both precocious puberty and impaired fecundity are increasing. It has been hypothesized that exposure to endocrine active compounds (EACs), may play a role in this trend. Advanced puberty and persistent estrus have been documented for many EACs in rodents but very little is known about the mechanisms by which EACs produce these effects. This lack of knowledge makes it difficult to predict how a potential EAC may ultimately affect human health. In females, puberty results from the maturation of the hypothalamic-pituitary-gonadal (HPG) axis and culminates with the onset of cyclic gonadotropin releasing hormone (GnRH) pulses that stimulate ovulation. The anterior ventral periventricular nucleus (AVPV) is the primary regulator of GnRH neuronal activity. The specific hypothesis behind the proposed research is that the disruption of puberty by neonatal exposure to the EACs Bisphenol-A (BPA) and genistein (GEN) results from the improper sexual differentiation of the AVPV and thus the estrogen receptor (ER)-initiated signal transduction pathways that regulate GnRH secretion. This hypothesis is supported by the following preliminary data. First, both compounds advanced pubertal onset. Second, both compounds defeminized an AVPV neuronal phenotype that contains ER?. Third, GEN disrupted the estrus cycle postpuberty. And finally, both compounds defeminized adult AVPV volume. Using behavioral, anatomical and molecular techniques the investigators will compare the effects of BPA and GEN with agonists specific for the two forms of the estrogen receptor (ER? and ER?) to characterize the signal transduction pathways through which EACs affect the timing and progression of puberty. For all studies, the dose of EAC administered will fall within the range relevant to human exposure. AIM 1: Characterize the effect of neonatal BPA, GEN, the ER? agonist DPN or the ER? agonist PPT exposure on kisspeptin and galanin signaling in the AVPV at puberty onset. AIM 2: Map the expression of ER? and ER? in the prepubertal rat AVPV and determine if this pattern is disrupted by BPA, GEN or DPN or PPT. AIM 3: Examine how estrus cyclicity and sexual behavior post-puberty are affected by neonatal exposure to BPA, GEN, DPN or PPT. AIM 4: Characterize the impact of neonatal BPA, GEN, DPN or PPT on AVPV volume, AVPV ER and kisspeptin content, and hormone-stimulated GnRH neuronal activation post-puberty.