Ludwig Helaina D, Carpenter Jessica M, Filipov Nikolay M
Department of Physiology and Pharmacology, University of Georgia, Athens, Georgia, USA.
Interdisciplinary Toxicology Program, University of Georgia, Athens, Georgia, USA.
J Appl Toxicol. 2025 Apr;45(4):669-684. doi: 10.1002/jat.4739. Epub 2024 Dec 8.
Manganese (Mn) is an essential and important metal; however, overexposures lead to adverse neurological outcomes. Nonoccupational Mn overexposure occurs primarily through consumption of Mn-contaminated drinking water (DW). Sex differences in terms of nervous and immune systems' responsiveness to excessive Mn in the DW are understudied. Thus, this study investigated behavioral and sex differences in response to Mn DW treatment (0.4 g Mn/L for up to 8 weeks) and a lipopolysaccharide (LPS) challenge of adult C57BL/6 mice with GFP-tagged monocytes/microglia. After 6 weeks, in motor function tests, Mn exposure resulted in decreased activity and gait deficits. In two different mood tests (open field test [OFT]/elevated zero maze), Mn-exposed mice exhibited decreased fear/anxiety-like behavior. Two weeks after behavioral assessment, when mice were challenged with LPS, circulating inflammatory cytokines, and acute phase proteins increased in both sexes. After 8 weeks of Mn exposure, liver and brain Mn levels were increased, but Mn alone did not affect circulating cytokines in either sex. Notably, Mn-exposed/LPS-challenged males had potentiated plasma cytokine output, whereas the reverse was seen in females. Males, but not females, continued to exhibit increased fearlessness (i.e., increased OFT center time), even when challenged with LPS. Overall, our results show that Mn DW exposure increases brain Mn levels and it leads to behavioral alterations in both sexes. However, males might be more susceptible to the effect of Mn on mood, and this effect is recalcitrant to an inflammagen challenge. Mn augmented post-LPS cytokine production only in males, further indicating that important Mn effects are sex-biased.
锰（Mn）是一种必需且重要的金属；然而，过度暴露会导致不良的神经学后果。非职业性锰过度暴露主要通过饮用受锰污染的饮用水（DW）发生。关于神经系统和免疫系统对饮用水中过量锰的反应的性别差异研究不足。因此，本研究调查了成年C57BL/6小鼠在接受锰饮用水处理（0.4克锰/升，持续8周）以及脂多糖（LPS）刺激后，带有绿色荧光蛋白标记单核细胞/小胶质细胞的行为和性别差异。6周后，在运动功能测试中，锰暴露导致活动减少和步态缺陷。在两项不同的情绪测试（旷场试验[OFT]/高架零迷宫）中，锰暴露小鼠表现出恐惧/焦虑样行为减少。行为评估两周后，当小鼠受到LPS刺激时，两性循环炎症细胞因子和急性期蛋白均增加。锰暴露8周后，肝脏和大脑中的锰水平升高，但单独的锰对两性的循环细胞因子均无影响。值得注意的是，锰暴露/LPS刺激的雄性小鼠血浆细胞因子输出增强，而雌性小鼠则相反。即使受到LPS刺激，雄性而非雌性小鼠仍持续表现出无畏增加（即旷场试验中心时间增加）。总体而言，我们的结果表明，饮用含锰饮用水会增加大脑锰水平，并导致两性行为改变。然而，雄性可能对锰对情绪的影响更敏感，并且这种影响对炎性原刺激具有抗性。锰仅在雄性小鼠中增强了LPS刺激后的细胞因子产生，进一步表明重要的锰效应存在性别差异。
