Havarinasab Said, Björn Erik, Nielsen Jesper B, Hultman Per
Molecular and Immunological Pathology (AIR), Department of Molecular and Clinical Medicine, Linköping University, SE-581 85 Linköping, Sweden.
Toxicol Appl Pharmacol. 2007 May 15;221(1):21-8. doi: 10.1016/j.taap.2007.02.009. Epub 2007 Feb 24.
Methylmercury (MeHg) is present in the environment as a result of the global cycling of mercury, although anthropogenic sources may dramatically increase the availability in confined geographical areas. Accumulation of MeHg in the aquatic food chain is the dominating way of exposure in mammals, which accumulate MeHg in all organs, including the brain. Demethylation has been described in the organs, especially in phagocytic cells, but mainly in the flora of the intestinal tract. While most of the inorganic mercury (Hg(2+)) formed in the intestine is excreted, a fraction is reabsorbed which together with the local demethylation increases the organ Hg(2+) concentration. MeHg is a well-known immunosuppressive agent, while Hg(2+) is associated with immunostimulation and autoimmunity especially in genetically susceptible rodents, creating a syndrome, i.e. mercury-induced autoimmunity (HgIA). This study aimed at exploring the effect of MeHg with regard to HgIA, and especially the immunological events after stopping treatment, correlated with the presence of MeHg and Hg(2+) in the organs. Treatment of A.SW mice for 30 days with 4.2 mg MeHg/L drinking water (corresponding to approximately 420 microg Hg/kg body weight/day) caused all the HgIA features observed after primary treatment with inorganic Hg, except systemic immune complex deposits. The total Hg concentration was 5-fold higher in the kidneys as compared with lymph nodes, but the fraction of Hg(2+) was similar (17-20%). After stopping treatment, the renal and lymph node MeHg concentration declined according to first order kinetics during the initial 4-6 weeks, but then slower. A similar decline in the organ Hg(2+) concentration occurred during the initial 2 weeks after stopping treatment but then ceased, causing the Hg(2+) concentration to exceed that of MeHg in the lymph nodes and kidneys after 3 and 8 weeks, respectively. The selective increase in lymph node Hg(2+) fraction is likely to be due to demethylation of MeHg in the macrophage-rich lymphoid tissue. The major autoantibody in HgIA, anti-fibrillarin antibodies, tended to increase during the initial 6 weeks after stopping treatment, while all other HgIA features including antichromatin antibodies declined to control levels after 2-4 weeks. This indicates differences in either dose requirement or induction mechanisms for the different HgIA parameters. The selective accumulation of Hg(2+) in lymph nodes following MeHg treatment should be taken into account when the effect of MeHg on the immune system is evaluated.
甲基汞（MeHg）是汞全球循环的产物，存在于环境中，尽管人为来源可能会显著增加其在特定地理区域的可利用性。水生食物链中甲基汞的积累是哺乳动物接触甲基汞的主要途径，甲基汞会在包括大脑在内的所有器官中蓄积。在器官中，尤其是吞噬细胞中，以及主要在肠道菌群中，已发现有脱甲基作用。虽然肠道中形成的大部分无机汞（Hg(2+)）会被排出，但有一部分会被重新吸收，这与局部脱甲基作用一起增加了器官中Hg(2+)的浓度。甲基汞是一种众所周知的免疫抑制剂，而Hg(2+)与免疫刺激和自身免疫有关，尤其是在具有遗传易感性的啮齿动物中，会引发一种综合征，即汞诱导的自身免疫（HgIA）。本研究旨在探讨甲基汞对HgIA的影响，特别是停止治疗后的免疫事件，并将其与器官中甲基汞和Hg(2+)的存在情况相关联。用4.2毫克/升甲基汞的饮用水（相当于约420微克汞/千克体重/天）对A.SW小鼠进行30天的治疗，除了全身性免疫复合物沉积外，引发了用无机汞初次治疗后观察到的所有HgIA特征。肾脏中的总汞浓度比淋巴结高5倍，但Hg(2+)的比例相似（17 - 20%）。停止治疗后，肾脏和淋巴结中的甲基汞浓度在最初4 - 6周内按照一级动力学下降，但随后下降速度减慢。停止治疗后的最初2周内，器官中Hg(2+)的浓度也出现类似下降，但随后停止下降，导致分别在3周和8周后，淋巴结和肾脏中的Hg(2+)浓度超过甲基汞浓度。淋巴结中Hg(2+)比例的选择性增加可能是由于富含巨噬细胞的淋巴组织中甲基汞的脱甲基作用。HgIA中的主要自身抗体，即抗纤维蛋白原抗体，在停止治疗后的最初6周内有增加的趋势，而所有其他HgIA特征，包括抗染色质抗体，在2 - 4周后下降至对照水平。这表明不同HgIA参数在剂量需求或诱导机制上存在差异。在评估甲基汞对免疫系统的影响时，应考虑甲基汞治疗后Hg(2+)在淋巴结中的选择性蓄积。
