Fu Sherleen, O'Neal Stefanie, Hong Lan, Jiang Wendy, Zheng Wei
School of Health Sciences, Purdue University, West Lafayette, Indiana 47907.
School of Health Sciences, Purdue University, West Lafayette, Indiana 47907
Toxicol Sci. 2015 Feb;143(2):482-98. doi: 10.1093/toxsci/kfu249. Epub 2015 Jan 8.
The brain subventricular zone (SVZ) is a source of neural precursor cells; these cells travel along the rostral migratory stream (RMS) to destination areas in the process of adult neurogenesis. Recent x-ray fluorescence (XRF) studies reveal an extensive accumulation of copper (Cu) in the SVZ. Earlier human and animal studies also suggest an altered Cu homeostasis after manganese (Mn) exposure. This study was designed to test the hypothesis that Mn exposure by acting on the divalent metal transporter-1 (DMT1) altered Cu levels in SVZ and RMS, thereby affecting adult neurogenesis. Adult rats received intraperitoneal (i.p.) injections of 6 mg Mn/kg as MnCl2 once daily for 4 weeks with concomitant injections of bromodeoxyuridine (BrdU) for 5 days in the last week. In control rats, Cu levels were significantly higher in the SVZ than other brain regions examined. Mn exposure significantly reduced Cu concentrations in the SVZ (P < 0.01). Immunohistochemical data showed that in vivo Mn exposure significantly increased numbers of BrdU(+) cells, which were accompanied with increased GFAP(+) astrocytic stem cells and DCX(+) neuroblasts in SVZ and RMS. Quantitative RT-PCR and Western blot confirmed the increased expression of DMT1 in SVZ following in vivo Mn exposure, which contributed to Mn accumulation in the neurogenesis pathway. Taken together, these results indicate a clear disruptive effect of Mn on adult neurogenesis; the effect appears due partly to Mn induction of DMT1 and its interference with cellular Cu regulation in SVZ and RMS. The future research directions based on these observations are also discussed.
脑室内下区（SVZ）是神经前体细胞的一个来源；在成体神经发生过程中，这些细胞沿着吻侧迁移流（RMS）迁移至目标区域。最近的X射线荧光（XRF）研究显示，SVZ中有大量铜（Cu）蓄积。早期的人体和动物研究也表明，锰（Mn）暴露后铜稳态会发生改变。本研究旨在验证以下假设：锰暴露通过作用于二价金属转运体1（DMT1）改变了SVZ和RMS中的铜水平，从而影响成体神经发生。成年大鼠每天腹腔注射6mg Mn/kg的氯化锰，持续4周，最后一周同时注射5天溴脱氧尿苷（BrdU）。在对照大鼠中，SVZ中的铜水平显著高于其他检测的脑区。锰暴露显著降低了SVZ中的铜浓度（P<0.01）。免疫组织化学数据显示，体内锰暴露显著增加了BrdU（+）细胞的数量，同时SVZ和RMS中GFAP（+）星形胶质干细胞和DCX（+）神经母细胞也增加。定量RT-PCR和蛋白质印迹证实，体内锰暴露后SVZ中DMT1的表达增加，这导致了神经发生途径中锰的蓄积。综上所述，这些结果表明锰对成体神经发生有明显的破坏作用；这种作用似乎部分是由于锰诱导DMT1及其对SVZ和RMS中细胞铜调节的干扰。基于这些观察结果的未来研究方向也进行了讨论。
