The Effects Of Long-term Exposure To Lead On Neurodegenerative Disease In Rats

Background:Several lines of evidence indicated that lead (Pb) exposure was not only with neurodevelopmental toxicity and was an important risk factor for neurodegenerative diseases, however, the relatively little research that lead exposure cause neurodegenerative changes, the mechanism had not been established at all. Therefore, in the current study, we examined the effect and mechanism of long-term exposure to lead on neurodegenerative disease in rats.Methods:Female rats were randomly divided into different exposure groups, and drank distilled water containing either 0 (control),800 (low lead group, LLG) or 1500mg/L lead acetate (high lead group, HLG) for 10 days prior to being bred with male rats. Then the male offspring received either 0 (control),300 (LLG) or 900(HLG) mg/L lead acetate and were followed through old age, with measurements taken at postnatal week 3 (PNW3), postnatal week 41 (PNW41) and postnatal week 70 (PNW70). We examined the effects of Pb exposure on the volume of brain and hippocampus, the neuronal density, neuronal ultra structure changes, and the content of 8-hydroxy 2’deoxyguanosine (8-OHdG) and the expression of amyloid precursor protein (APP), tau, glucose-regulated protein 78 (GRP78) and glucose-regulated protein 94 (GRP94) in the brain of offspring.Results:(1) The lead content of blood and brain were significantly increased with lead exposure dose increased in three aged group, and a dose-response relationship. Also, the lead content of the cortex and hippocampus in PNW41 and PNW70 rats was significantly increased compared to PNW3 in each exposure dose group, but there was no significant difference in blood lead content in different age groups.(2) MRI results showed that the brain volume of lead exposure groups was significantly decreased in PNW70 rats, and the hippocampus volume decline was not obvious. Also, in comparing with the control, the cell density of cortical parietal region and hippocampus CA1 in PNW70 rats was significantly lower in Pb exposure groups, and in DG region showed a downward trend; the cell density of hippocampus CA1 in PNW3 rats was significantly lower in Pb exposure groups. Besides, with the dose of lead exposed increased, cytoplasm, nucleus, endoplasmic reticulum (ER) structure and synaptic structure had suffered vary degrees of damage from ultra structural detection of hippocampus, it could be observed early neuronal apoptosis.(3)Pb exposure significantly increased the expression of APP in PNW3 and PNW70 rats’cortex and hippocampus, and the expression of APP in PNW40 showed an upward trend. Also Pb exposure significantly increased the expression of tau in PNW3 and PNW70 rats’hippocampus, and also significantly increased the expression of tau (Ser396) protein in PNW3 and PNW70 rats’hippocampus, but not in cortex.(4)The content of 8-OHdG was significantly increased with lead exposure dose increased in the brain of PNW3 and PNW70 rats, and a dose-response relationship, but not in PNW40.(5)Pb exposure significantly increased the expression of GRP78 in the old-aged rats’cortex and hippocampus, but not obviously in PNW3 and PNW41 rats. Besides, Pb exposure increased the expression of GRP94 in PNW3 and PNW70 rats’ hippocampus, but not in cortex.Conclusion:(1) All the morphological results and up-regulation the characteristic genes of Alzheimer s Disease prompted that lead exposure rats appeared neurodegenerative change.(2) Lead exposure induced neurodegenerative diseases might be related to the endoplasmic reticulum stress response and the increase of the expression of APP/tau which caused by Pb exposure.(3)Long-term lead exposure induced changes of each index of rats with age stage.