Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.
Department of Pharmaceutical Sciences, MCPHS University, Boston, MA, USA.
Arch Toxicol. 2021 Dec;95(12):3665-3679. doi: 10.1007/s00204-021-03166-1. Epub 2021 Sep 30.
Environmental and occupational exposure to heavy metals remains one of the major concerns in public health. Increased levels of manganese (Mn) pollution are associated with profound neurotoxic effects, including neurobehavioral deficits and disturbances resembling Parkinson's disease. While Mn absorption is in part mediated by iron transporters, recent studies have shown that the levels of iron transporters are modified by alcohol and that chronic alcohol consumption increases body iron stores. However, it is largely unexplored whether alcohol exposure influences the transport and neurotoxicity of Mn. To address this question, we exposed mice to ethanol (10%; v/v) by drinking water for 4 weeks, during which period MnCl (5 mg/kg) or saline solutions were administered daily by intranasal instillation. Ethanol consumption in mice increased brain Mn levels in a dose-dependent manner after Mn instillation, determined by inductively-coupled plasma mass spectrometry, which was accompanied by up-regulation of iron transporters, as assessed by western blotting and qPCR. In addition, alcohol drinking increased hypoxic response and decreased hepcidin expression, providing the molecular mechanism of increased iron transporters and Mn uptake upon alcohol consumption. Moreover, brain dopamine levels, analyzed by HPLC, were decreased after intranasal Mn instillation, which was worsened by alcohol. Likewise, alcohol-Mn co-exposure synergistically altered dopaminergic protein expression. Finally, alcohol binge-drinking, which resembles alcohol drinking manner in humans, increased brain Mn content along with upregulation of iron transporters. Our study suggests that individuals who consume alcohol may have a higher risk of Mn neurotoxicity upon Mn exposure.
环境和职业暴露于重金属仍然是公共卫生的主要关注点之一。锰 (Mn) 污染水平的增加与深刻的神经毒性作用有关，包括神经行为缺陷和类似于帕金森病的紊乱。虽然 Mn 的吸收部分是由铁转运蛋白介导的，但最近的研究表明，铁转运蛋白的水平受酒精的调节，并且慢性酒精摄入会增加体内铁储存。然而，酒精暴露是否会影响 Mn 的运输和神经毒性在很大程度上尚未得到探索。为了解决这个问题，我们通过饮用含 10%（v/v）乙醇的水使小鼠暴露于乙醇 4 周，在此期间每天通过鼻腔内滴注给予 MnCl（5mg/kg）或生理盐水。通过电感耦合等离子体质谱法测定，经 Mn 滴鼻后，小鼠的脑 Mn 水平以剂量依赖性方式增加，这与 Western blot 和 qPCR 评估的铁转运蛋白上调有关。此外，饮酒增加了缺氧反应并降低了铁调素的表达，为酒精摄入增加铁转运蛋白和 Mn 摄取提供了分子机制。此外，通过 HPLC 分析，脑多巴胺水平在鼻腔内 Mn 滴鼻后降低，而酒精使这种情况恶化。同样，酒精-Mn 共同暴露协同改变了多巴胺能蛋白的表达。最后，类似于人类饮酒方式的酒精 binge-drinking 增加了脑 Mn 含量，同时上调了铁转运蛋白。我们的研究表明，摄入酒精的个体在暴露于 Mn 后可能有更高的 Mn 神经毒性风险。
