Srivastava Vinod K, Hiney Jill K, Dees William L
Department of Veterinary Integrative Biosciences, College of Veterinary Medicine, Texas A&M University, College Station, Texas 77843-4458.
Endocrinology. 2016 Aug;157(8):3233-41. doi: 10.1210/en.2016-1090. Epub 2016 Jun 16.
Low-dose administration of manganese chloride (MnCl2) causes release of hypothalamic LH-releasing hormone (LHRH) and advances puberty in rat. Recently, this element was shown to up-regulate mammalian target of rapamycin (mTOR), kisspeptin gene (KiSS-1), and LHRH gene expressions in the brain preoptic area (POA)/anteroventral periventricular (AVPV) nucleus. Because these genes are critical for puberty, this study was conducted to identify the upstream mechanism by which Mn activates the mTOR/KiSS-1 pathway. On day 12, immature female rats began receiving a daily supplemental dose of 10 mg/kg of MnCl2 or saline by gavage, and POA/AVPV tissues were collected on day 29 for specific protein assessments. Another experiment assessed in vitro IGF-1 release in response to Mn and assessed signal transduction pathways in the POA/AVPV region after Mn delivery into the third ventricle. Chronic Mn exposure increased (P < .05) basal expressions of mTOR and kisspeptin proteins. Mn increased protein kinase B (Akt) and Ras homolog enriched in brain, both capable of activating mTOR. Central Mn delivery increased expressions of phosphorylated IGF-1 receptor (IGF-1R) (P < .05) and Akt (P < .01) in the POA/AVPV region. The previous central delivery of JB1, an IGF-1R antagonist, blocked Mn-induced expressions of both phosphorylated IGF-1R and Akt. Downstream to Akt, centrally administered Mn increased tuberous sclerosis complex 2 (P < .05), Ras homolog enriched in brain (P < .01), mTOR (P < .05), and kisspeptin (P < .05). Finally, we observed that the early puberty induced by Mn was blocked by the administration of an mTOR inhibitor. These results suggest that Mn acts, at least in part, through the IGF-1/Akt/mTOR pathway to influence prepubertal kisspeptin and LHRH.
低剂量给予氯化锰（MnCl₂）可导致大鼠下丘脑促黄体生成素释放激素（LHRH）释放并使青春期提前。最近，该元素被证明可上调脑视前区（POA）/室周前腹侧核（AVPV）中哺乳动物雷帕霉素靶蛋白（mTOR）、亲吻素基因（KiSS-1）和LHRH基因的表达。由于这些基因对青春期至关重要，因此进行本研究以确定锰激活mTOR/KiSS-1途径的上游机制。在第12天，未成熟雌性大鼠开始通过灌胃每日补充10 mg/kg的MnCl₂或生理盐水，并在第29天收集POA/AVPV组织进行特定蛋白质评估。另一项实验评估了对锰的体外胰岛素样生长因子-1（IGF-1）释放，并在将锰注入第三脑室后评估了POA/AVPV区域的信号转导途径。慢性锰暴露增加了（P < 0.05）mTOR和亲吻素蛋白的基础表达。锰增加了脑内富含的蛋白激酶B（Akt）和Ras同源物，两者均能够激活mTOR。向中枢递送锰增加了POA/AVPV区域中磷酸化IGF-1受体（IGF-1R）（P < 0.05）和Akt（P < 0.01）的表达。先前向中枢递送IGF-1R拮抗剂JB1可阻断锰诱导的磷酸化IGF-1R和Akt的表达。在Akt的下游，向中枢给予锰增加了结节性硬化复合物2（P < 0.05）、脑内富含的Ras同源物（P < 0.01）、mTOR（P < 0.05）和亲吻素（P < 0.05）。最后，我们观察到锰诱导的青春期提前被mTOR抑制剂的给药所阻断。这些结果表明，锰至少部分通过IGF-1/Akt/mTOR途径影响青春期前的亲吻素和LHRH。
