Lead stimulates ERK1/2 and p38 MAPK phosphorylation in the hippocampus of immature rats

Abstract

Lead (Pb 2+) is widely recognized as a neurotoxicant whose mechanisms of action are not completely established. We have previously demonstrated that Pb 2+ can activate the p38 MAPK pathway and increase the phosphorylation of Hsp27 in bovine adrenal chromaffin cells and human SH SY5Y cells over a short incubation period (1 h). In the present work we analyzed the effects of Pb 2+ administered in vivo on the level and the phosphorylation state of ERK1/2 and p38 MAPK in the hippocampus of immature rats. Rats were treated with lead acetate (2, 8 or 12 mg/kg, i.p.) or saline (control) over the 8th to 12th postnatal days, and hippocampal slices were prepared on the14th day. The Pb 2+ level in the lead-treated animals increased 2.5–6-fold in the blood (3.0–6.0 μg/dl) and 2.0–3.0-fold in the forebrain (78–103 ng/g wet weight), compared to control (saline). The phosphorylation of both ERK1/2 and p38 MAPK was significantly increased by prior exposure to Pb 2+ in vivo. In in vitro experiments, hippocampal slices from 14-day-old rats were exposed to Pb 2+ (1–10 μM) for 1 and 3 h. There were no changes in the phosphorylation state of ERK and p38 MAPK for 1-h incubation, whereas a significant increase of ERK1/2 and p38 MAPK phosphorylation by Pb 2+ (5 μM) was observed for the 3-h incubation. Cell viability measured using MTT was not modified in any of the conditions tested. These results indicate that the phosphorylation of hippocampal ERK1/2 and p38 MAPK is stimulated by lead in a period of rapid brain development, an effect that may underlie, at least in part, the neurotoxicty elicited by this metal.