Iron supplementation protects against lead-induced apoptosis through MAPK pathway in weanling rat cortex

Recent studies indicate that iron (Fe) is involved in neurotoxicity caused by inorganic lead (Pb). We studied the role of Fe in the effects Pb-induced cerebral apoptosis during rat development and to explore its possible regulatory mechanism. In the present study, weanling male Sprague–Dawley rats were randomly divided into four groups. Three groups of rats received 400 μg/mL Pb acetate solution in drinking water, among which two of the groups were concurrently given 20 mg/kg and 40 mg/kg FeSO4 solution, respectively, as the low and high Fe group, for 6 weeks. The Fe doses were administered orally by gavage every other day according to animal body weight. For the control group, Na acetate with an acetate concentration equivalent to the high dose of Pb acetate was prepared in the same manner. At the end of the study, exposure to Pb in drinking water significantly promoted internucleosomal DNA fragmentation, enhanced the percentage of TUNEL-positive cells and increased the caspase-3 activities in cortex as compared to the controls. At the same time, it did cause a significant decrease in cortex Fe concentrations. Concomitant supplement with different dose Fe appeared to restore brain Fe level to the normal level. Although the low dose of Fe restored brain Pb level to the normal level and the high dose of Fe did not, both of them reduced the formation of DNA fragments, showed few TUNEL-positive cells with yellow nuclei and inhibited Pb-induced procaspase-3 degradation. Western blot showed that exposure to Pb caused a significant elevation in the phosphorylation of ERK1/2, JNK1/2, and Elk-1. Low Fe supplemental treatment suppressed the phosphorylation of ERK1/2 and JNK1/2 but not Elk-1. Interestingly, high Fe treatment slightly suppressed the phosphorylation of JNK1/2, but significantly elevated the phosphorylation of ERK1/2 and Elk-1. Collectively, the current study suggests that supplementation of Fe during Pb treatment prevents against cytotoxicity and apoptosis induced by Pb insults, in which MAPK pathways play an important role in Pb-induced cerebral apoptosis by activating the MEK-ERK pathway that suppresses JNK signaling.