Disrupted pro- and antioxidative balance as a mechanism of neurotoxicity induced by perinatal exposure to lead

Abstract

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.