Endocrine Disruption of the Hypothalamic Signaling That Regulates Puberty

描述(由申请人提供)： 流行病学数据表明，性早熟和生育力受损的发生率都在增加。据推测，接触内分泌活性化合物(EAC)可能在这一趋势中发挥作用。许多啮齿类动物的青春期提前和持续发情已被证实，但对EAC产生这些影响的机制知之甚少。这种知识的缺乏使得很难预测潜在的EAC最终可能如何影响人类健康。在女性，青春期是下丘脑-垂体-性腺(HPG)轴成熟的结果，并以刺激排卵的周期促性腺激素释放激素(GnRH)脉冲开始达到顶峰。前腹侧脑室周围核(AVPV)是促性腺激素释放激素(GnRH)神经元活动的主要调节器。这项研究背后的特定假设是，新生儿暴露于EACS、双酚A(BPA)和染料木素(GEN)导致的青春期中断是由于AVPV的性别分化不当，从而导致雌激素受体(ER)启动的调节GnRH分泌的信号转导通路。这一假设得到了以下初步数据的支持。首先，这两种化合物都提前了青春期的开始。第二，这两种化合物 发现了一种含有ER？的AVPV神经元表型。第三，基因打乱了青春期后的发情周期。最后，两种化合物均使成体AVPV体积脱除。使用行为学、解剖学和分子学技术，研究人员将比较双酚A和GEN与两种形式的雌激素受体(ER？ER？)研究EAC影响青春期时间和进程的信号转导途径。对于所有研究，给予EAC的剂量将落在与人类接触相关的范围内。目的1：描述新生儿BPA、GEN、ER？激动剂DPN还是ER？青春期开始时，激动剂PPT对动静脉动静脉曲张中Kispeptin和Galanin信号的影响。目的2：映射ER的表达？急诊室呢？并确定这一模式是否被BPA、GEN、DPN或PPT破坏。目的3：研究新生儿暴露于BPA、GEN、DPN或PPT对发情周期和青春期后性行为的影响。目的：研究新生儿BPA、GEN、DPN或PPT对青春期后AVPV体积、AVPV ER和Kispeptin含量以及激素刺激的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.