Department of Veterinary Integrative Biosciences, College of Veterinary Medicine, Texas A&M University, College Station, Texas 77843-4458, USA.
Toxicol Sci. 2011 Jun;121(2):389-96. doi: 10.1093/toxsci/kfr057. Epub 2011 Mar 14.
Precocious puberty is a significant child health problem, especially in girls, because 95% of cases are idiopathic. Our earlier studies demonstrated that low-dose levels of manganese (Mn) caused precocious puberty via stimulating the secretion of luteinizing hormone-releasing hormone (LHRH). Because glial-neuronal communications are important for the activation of LHRH secretion at puberty, we investigated the effects of prepubertal Mn exposure on specific glial-derived puberty-related genes known to affect neuronal LHRH release. Animals were supplemented with MnCl(2) (10 mg/kg) or saline by gastric gavage from day 12 until day 22 or day 29, then decapitated, and brains removed. The site of LHRH release is the medial basal hypothalamus (MBH), and tissues from this area were analyzed by real-time PCR for transforming growth factor α (TGFα), insulin-like growth factor-1 (IGF-1), and cyclooxygenase-2 (COX-2) messenger RNA levels. Protein levels for IGF-1 receptor (IGF-1R) were measured by Western blot analysis. LHRH gene expression was measured in the preoptic area/anteroventral periventricular (POA/AVPV) region. In the MBH, at 22 days, IGF-1 gene expression was increased (p < 0.05) with a concomitant increase (p < 0.05) in IGF-1R protein expression. Mn also increased (p < 0.01) COX-2 gene expression. At 29 days, the upregulation of IGF-1 (p < 0.05) and COX-2 (p < 0.05) continued in the MBH. At this time, we observed increased (p < 0.05) LHRH gene expression in the POA/AVPV. Additionally, Mn stimulated prostaglandin E(2) and LHRH release from 29-day-old median eminences incubated in vitro. These results demonstrate that Mn, through the upregulation of IGF-1 and COX-2, may promote maturational events and glial-neuronal communications facilitating the increased neurosecretory activity, including that of LHRH, resulting in precocious pubertal development.
性早熟是一个重要的儿童健康问题，特别是在女孩中，因为 95%的病例是特发性的。我们之前的研究表明，低剂量的锰 (Mn) 通过刺激黄体生成素释放激素 (LHRH) 的分泌导致性早熟。因为神经胶质细胞-神经元的通讯对于青春期 LHRH 分泌的激活很重要，所以我们研究了青春期前 Mn 暴露对特定的神经胶质衍生的与青春期有关的基因的影响，这些基因已知会影响神经元 LHRH 的释放。动物从第 12 天到第 22 天或第 29 天，每天通过胃灌胃补充 MnCl2（10mg/kg）或生理盐水，然后断头，取出大脑。LHRH 释放的部位是内侧基底部下丘脑 (MBH)，并通过实时 PCR 分析来自该区域的组织，以检测转化生长因子 α (TGFα)、胰岛素样生长因子-1 (IGF-1) 和环氧化酶-2 (COX-2) 信使 RNA 水平。通过 Western blot 分析测量 IGF-1 受体 (IGF-1R) 的蛋白水平。通过实时 PCR 测量 LHRH 基因在视前区/腹前内侧室周区 (POA/AVPV) 区域的表达。在 MBH 中，在 22 天时，IGF-1 基因的表达增加（p<0.05），同时 IGF-1R 蛋白的表达也增加（p<0.05）。Mn 还增加了 COX-2 基因的表达（p<0.01）。在 29 天时，MBH 中的 IGF-1（p<0.05）和 COX-2（p<0.05）的上调仍在继续。此时，我们观察到 POA/AVPV 中的 LHRH 基因表达增加（p<0.05）。此外，Mn 刺激了体外培养的 29 日龄正中隆起的前列腺素 E2 和 LHRH 的释放。这些结果表明，Mn 通过上调 IGF-1 和 COX-2，可能促进成熟事件和神经胶质细胞-神经元的通讯，从而促进神经分泌活动的增加，包括 LHRH，导致性早熟的发展。
