Aluminum in Drinking Water Induces Neuronal Apoptosis Via Endoplasmic Reticulum Stress

EPA Grant Number: R829782
Title: Aluminum in Drinking Water Induces Neuronal Apoptosis Via Endoplasmic Reticulum Stress
Investigators: Savory, John
Current Investigators: Savory, John , Boyd, James C. , Exley, Christopher , Ghribi, Othman , Herman, Mary M.
Institution: University of Virginia
EPA Project Officer: Page, Angela
Project Period: August 1, 2002 through July 31, 2005 (Extended to July 31, 2006)
Project Amount: $821,249
RFA: Health Effects of Chemical Contaminants in Drinking Water (2001) RFA Text |  Recipients Lists
Research Category: Drinking Water , Health Effects , Water

Description:

The main goal of this project is to test the hypothesis that aluminum in drinking water can induce neuronal injury, eventually resulting in the death of some neurons via apoptosis. It is also hypothesized that aging results in increased susceptibility to aluminum in drinking water. It is already established that aluminum ingested orally can gain access to the brain, although the amounts deposited are low in comparison to the relatively large quantities ingested. The hypotheses will be tested in older rabbits subjected to different formulations of drinking water containing low and high concentrations of aluminum. Previous studies of effects of aluminum in drinking water have used relatively insensitive markers of neurotoxic injury. The present proposal will employ markers of such neurotoxic injury which is involved in apoptosis regulation, following aluminum administration to rabbits. Rabbits are particularly well-suited to such studies since they are sensitive to aluminum neurotoxicity and more closely resemble primates than do rodents. Administration of aluminum directly into rabbit brain results in responses of apoptosis regulatory proteins in the endoplasmic reticulum and mitochondria. Studies in the P.I.?s laboratory have focused on crosstalk between these two organelles and have uncovered some important changes, particularly in the endoplasmic reticulum. These changes preceed cytoskeletal alterations and appear to be key regulators of apoptosis. The present objectives are to subject rabbits to drinking water having high and low concentrations of aluminum and to monitor neuronal injury by these novel markers. A further objective is to modify the water with the common additive, fluoride, and with silicic acid to test the hypothesis that these two agents diminish the toxicity of aluminum.

Approach:

New Zealand white rabbits, age 2-3 years, will be exposed to carefully formulated drinking water containing low and high concentrations of aluminum without or with fluoride or silicic acid. Three concentrations of silicic acid and 2 concentrations of fluoride will be included in the studies. After an initial 3-month period on low aluminum water, the exposure will be for an additional 9 months. Periodic sampling of blood, chow and water for aluminum measurements will be carried out. At the termination of the experiment, rabbits will be sacrificed and brain tissue processed for subcellular fractionation and Western blot analysis, and for histologic and immunohistochemical examination.

Expected Results:

High levels of aluminum in drinking water will result in changes in Bcl-2, Bax and caspase-3 in endoplasmic reticulum, caspase-12 activation, TUNEL positivity as well as nuclear translocation of NF-eB and gadd 153. The presence of fluoride or silicic acid in the drinking water will eliminate these effects. These results will indicate that the presence of high concentrations of aluminum in drinking water are indeed a concern to public health.

Supplemental Keywords:

drinking water, risk assessment, exposure, metals, aluminum, fluoride, silicic acid, apoptosis, endoplasmic reticulum, RFA, Health, Scientific Discipline, Waste, Water, Hydrology, Contaminated Sediments, Environmental Chemistry, Risk Assessments, Environmental Microbiology, Drinking Water, ecological risk assessment, monitoring, pathogens, groundwater disinfection, other - exposure, human health effects, water quality parameters, aquifer characteristics, exposure and effects, exposure, contaminated sediment, aluminum, chemical contaminants, neurotoxicity, human exposure, treatment, drinking water distribution system, water quality, apoptosis, drinking water contaminants, water treatment, drinking water treatment, human health risk

Progress and Final Reports:

2002 Progress Report
2003 Progress Report
2004 Progress Report
Final Report