Abstract

Subacute exposure to manganese (Mn) produced Parkinson’s disease-like syndrome called Manganism. Chronic onset and progression are characteristics of Manganism, therefore, this study aimed to examine Mn toxicity following chronic exposures. Male Sprague-Dawley rats were injected Mn²⁺ 1 and 5 mg/kg, every 10 days for 150 days (15 injections). Animal body weight and behavioral activities were recorded. At the end of experiments, the brain and liver were collected for morphological and molecular analysis. Chronic Mn exposure did not affect animal body weight gain, but the high dose of Mn treatment caused 20% mortality after 140 days of administration. Motor activity deficits were observed in a dose-dependent manner at 148 days of Mn administration. Immunofluorescence double staining of substantia nigra pars compacta (SNpc) revealed the activation of microglia and loss of dopaminergic neurons. The chronic neuroinflammation mediators TNFα, inflammasome Nlrp3, Fc fragment of IgG receptor IIb, and formyl peptide receptor-1 were increased, implicating chronic Mn-induced neuroinflammation. Chronic Mn exposure also produced liver injury, as evidenced by hepatocyte degeneration with pink, condensed nuclei, indicative of apoptotic lesions. The inflammatory cytokines TNFα, IL-1β, and IL-6 were increased, alone with stress-related genes heme oxygenase-1, NAD(P)H:quinone oxidoreductase-1 and metallothionein. Hepatic transporters, such as multidrug resistant proteins (Abcc1, Abcc2, and Abcc3) and solute carrier family proteins (Slc30a1, Slc39a8 and Slc39a14) were increased in attempt to eliminate Mn from the liver. In summary, chronic Mn exposure produced neuroinflammation and dopaminergic neuron loss in the brain, but also produced inflammation to the liver, with upregulation of hepatic transporters.

Graphic Abstract

中文翻译：

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长期注射锰的间隔时间较长，在大鼠中产生神经毒性和肝毒性。

摘要

亚急性暴露于锰会产生帕金森氏病样综合症，称为锰症。慢性起病和进展是锰症的特征，因此，本研究旨在检查慢性暴露后的锰毒性。雄性Sprague-Dawley大鼠注射Mn ²⁺1和5 mg / kg，每10天一次，持续150天（15次注射）。记录动物体重和行为活动。实验结束时，收集大脑和肝脏进行形态和分子分析。慢性锰暴露并未影响动物体重增加，但高剂量锰治疗在140天给药后导致20％的死亡率。在施用锰的第148天，以剂量依赖性的方式观察到了运动活性不足。黑质致密部（SNpc）的免疫荧光双染色显示小胶质细胞的激活和多巴胺能神经元的丢失。慢性神经炎症介质TNFα，炎性小体Nlrp3，IgG受体IIb的Fc片段和甲酰肽受体-1增加，提示慢性Mn诱导的神经炎症。慢性锰暴露也会产生肝损伤，肝细胞变性并伴有粉红色的，浓缩的核，表明存在凋亡损伤。单独与应激相关的基因血红素加氧酶-1，NAD（P）H：醌氧化还原酶-1和金属硫蛋白增加了炎性细胞因子TNFα，IL-1β和IL-6的水平。尝试增加肝转运蛋白，例如多药耐药蛋白（Abcc1，Abcc2和Abcc3）和溶质载体家族蛋白（Slc30a1，Slc39a8和Slc39a14），以尝试从肝脏中消除Mn。总之，慢性锰暴露会在大脑中产生神经炎症和多巴胺能神经元损失，但也会随着肝脏转运蛋白的上调而对肝脏产生炎症。IL-1β和IL-6升高，与应激相关的基因血红素加氧酶-1，NAD（P）H：醌氧化还原酶-1和金属硫蛋白增加。尝试增加肝转运蛋白，例如多药耐药蛋白（Abcc1，Abcc2和Abcc3）和溶质载体家族蛋白（Slc30a1，Slc39a8和Slc39a14），以尝试从肝脏中消除Mn。总之，慢性锰暴露会在大脑中产生神经炎症和多巴胺能神经元损失，但也会随着肝转运蛋白的上调而对肝脏产生炎症。IL-1β和IL-6升高，与应激相关的基因血红素加氧酶-1，NAD（P）H：醌氧化还原酶-1和金属硫蛋白增加。尝试增加肝转运蛋白，例如多药耐药蛋白（Abcc1，Abcc2和Abcc3）和溶质载体家族蛋白（Slc30a1，Slc39a8和Slc39a14），以尝试从肝脏中消除Mn。总之，慢性锰暴露会在大脑中产生神经炎症和多巴胺能神经元损失，但也会随着肝脏转运蛋白的上调而对肝脏产生炎症。增加Slc39a8和Slc39a14以试图从肝脏中消除Mn。总之，慢性锰暴露会在大脑中产生神经炎症和多巴胺能神经元损失，但也会随着肝脏转运蛋白的上调而对肝脏产生炎症。增加Slc39a8和Slc39a14以试图从肝脏中消除Mn。总之，慢性锰暴露会在大脑中产生神经炎症和多巴胺能神经元损失，但也会随着肝脏转运蛋白的上调而对肝脏产生炎症。

图形摘要