Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Powstańców Wlkp. 72 str., 70-111 Szczecin, Poland.
Brain Res. 2012 Jan 30;1435:56-71. doi: 10.1016/j.brainres.2011.11.062. Epub 2011 Dec 9.
The aim of this paper was to examine if pre- and neonatal exposure that results in lead (Pb) concentration below 'safe level' (10 μg/dL) in offspring blood may cause disruption of the pro/antioxidant balance in the developing rat brain. We studied oxidative stress intensity (malondialdehyde (MDA) concentration) as well as mRNA, protein expression and the activity of copper/zinc superoxide dismutase (SOD1), manganese superoxide dismutase (SOD2), glutathione peroxidase (GPx), phospholipid hydroperoxide glutathione peroxidase (GPx4), catalase (CAT), glutathione reductase (GSR). We also measured glutathione (GSH) concentrations in selected structures of the rat brain (forebrain cortex, FC, cerebellum, C, and hippocampus, H) and showed cellular localization of GPx4, SOD1 and SOD2 expressions in the hippocampus by immunohistochemical examinations. Despite low Pb level in blood we observed decrease of the activity of some antioxidant enzymes as well as mRNA and protein expression downregulation associated with an increase of MDA level and CAT expression upregulation, especially in the hippocampus region. At the subcellular level, downregulation of SOD2 expression and decreased enzyme activity as well as mitochondrial pool of GSH suggest also that mitochondrial mechanisms might account for Pb neurotoxicity mechanism. For some enzymes, we found differences in the effects of Pb on the level of expression and activity. The activity of CAT decreased despite an increase in mRNA and protein expression; and likewise the activities SOD1, GPx1 GPx4 decreased, despite substantially unchanged level of expression. These effects may be the result of impairment of catalytic function of the enzyme protein caused by Pb interaction or of reduction in the availability of cofactors. We conclude that antioxidant system of the hippocampus of immature rat brain is highly vulnerable to perinatal Pb exposure. Therefore, oxidative stress may be one of the possible mechanisms disturbing cellular metabolism in this structure. Disruption of pro- and antioxidant balance should be considered as a potential mechanism of the observed Pb adverse effects, leading to the impaired learning ability caused by Pb exposure in children.
本文旨在探讨新生儿期和围生期血铅浓度低于“安全水平”（10μg/dL）是否会导致发育中大鼠大脑的促/抗氧化平衡紊乱。我们研究了氧化应激强度（丙二醛（MDA）浓度）以及铜/锌超氧化物歧化酶（SOD1）、锰超氧化物歧化酶（SOD2）、谷胱甘肽过氧化物酶（GPx）、磷脂氢过氧化物谷胱甘肽过氧化物酶（GPx4）、过氧化氢酶（CAT）、谷胱甘肽还原酶（GSR）的 mRNA、蛋白表达和活性。我们还测量了大鼠脑（大脑皮质、FC、小脑、C 和海马、H）选定结构中的谷胱甘肽（GSH）浓度，并通过免疫组织化学检查显示了 GPx4、SOD1 和 SOD2 在海马中的细胞定位。尽管血液中的 Pb 水平较低，但我们观察到一些抗氧化酶的活性以及与 MDA 水平升高和 CAT 表达上调相关的 mRNA 和蛋白表达下调，尤其是在海马区。在亚细胞水平上，SOD2 表达下调和酶活性降低以及线粒体池 GSH 减少也表明线粒体机制可能是 Pb 神经毒性机制的原因。对于一些酶，我们发现 Pb 对表达和活性的影响存在差异。尽管 mRNA 和蛋白表达增加，但 CAT 活性下降；同样，SOD1、GPx1、GPx4 的活性下降，尽管表达水平基本不变。这些影响可能是由于 Pb 相互作用导致酶蛋白的催化功能受损，或者是由于辅助因子的可用性降低所致。我们得出结论，未成熟大鼠海马的抗氧化系统对围生期 Pb 暴露高度敏感。因此，氧化应激可能是干扰该结构细胞代谢的可能机制之一。促/抗氧化平衡的破坏应被视为观察到的 Pb 不良影响的潜在机制之一，导致儿童 Pb 暴露导致学习能力受损。
