Lead Affects Apoptosis and Related Gene XIAP and Smac Expression in the Hippocampus of Developing Rats

Abstract

Lead (Pb) exposure poses devastating effects on central nervous system development of children. To replicate aspects of this neurotoxicity, we examined the effect of lead on the expression of apoptosis and of apoptosis-related genes, XIAP (X chromosome-linked inhibitor of apoptosis protein) and Smac (second mitochondrial activator of caspase), in the hippocampus of developing rats. A total of 48 rats (30-day old) were randomly divided into four groups for intragastrical perfusion of lead acetate [Pb(Ac)2]: untreated, low (2 mg/kg/d), medium (20 mg/kg/d), and high (200 mg/kg/d) dose groups. Pb content was determined in blood, and the apoptosis indexes and XIAP and Smac gene expression were analyzed in the hippocampus. There was a significant difference in apoptosis indexes (AI) between the exposed and control groups (p < 0.01). AI was highest in the high exposure group. XIAP gene expression was reduced in the exposed groups and the expression was negatively correlated with blood lead levels (BLLs) (p < 0.05). But the four groups did not differ in the expression of Smac (p > 0.05). Our data indicate that exposure to Pb(Ac)2 caused a dose-dependent and significant increase of apoptosis in the hippocampus of developing rats through depressing the expression of the XIAP but not the Smac genes.

Gestational lead exposure induces developmental abnormalities and up-regulates apoptosis of fetal cerebellar cells in rats

“…In vitro lead exposure induces apoptosis in PC12 cells via an increase in Bax and caspase 3 expressions (Xu et al, 2006). In vivo lead exposure resulted in cell death in the hippocampus and other brain regions (Liu et al, 2010).…”

Low-level lead exposure triggers neuronal apoptosis in the developing mouse brain

“…biochemical markers or brain weight) after lead exposure (Bouldin and Krigman, 1975; Guilarte et al, 1995; Press 1977; Winder et al 1983). Although in vivo evidence of apoptosis in rat hippocampal cells has been described, degeneration of specific neurons observed in multiple brain regions, and the manner in which they undergo degeneration, has only recently been identified (Liu et al, 2010). In vitro evidence of an apoptosis in PC 12 cells has been identified by an increase in BAX and activation of caspase-3 (Xu et al, 2006), but the exact mechanism of neurotoxicity remains largely unknown.…”

Adverse Outcome Pathway on chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities

“…In rats (30 PND), it has also been shown that Pb2+ (2, 20 and 200 mg/kg/d) can induce apoptosis (Liu et al, 2010). However, in contrast to the first two in vivo studies, the animals in this experimental approach were old enough to evaluate the most sensitive window of vulnerability of developing neurons to Pb2+ exposure (Liu et al, 2010), confirming that only Pb2+ treatment during synaptogenesis can lead to neuronal cell apoptosis. In vitro evidence of apoptosis induced by Pb2+ also derive from PC12 cells exposed to Pb2+ (0.1, 1, 10 µM) that have shown increased activation of caspase-3 (Xu et al, 2006).…”

“…Two to four weeks old rats treated for 7 days with 15 mg/kg daily dose of lead acetate show increased apoptosis in hippocampus (Sharifi et al, 2002). In rats (30 PND), it has also been shown that Pb2+ (2, 20 and 200 mg/kg/d) can induce apoptosis (Liu et al, 2010). However, in contrast to the first two in vivo studies, the animals in this experimental approach were old enough to evaluate the most sensitive window of vulnerability of developing neurons to Pb2+ exposure (Liu et al, 2010), confirming that only Pb2+ treatment during synaptogenesis can lead to neuronal cell apoptosis.…”