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Chronic exposure to low levels of aluminum alters cerebral cell signaling in response to acute MPTP administration

Department of Community and Environmental Medicine, Center for Occupational and Environmental Health, University of California, Irvine, California, USA

A Campbell

Pharmaceutical Sciences, Western University of Health Sciences, Pomona, California, USA

SF Ali

Neurochemistry Laboratory, Division of Neurotoxicology, National Center for Toxicological Research Food and Drug Administration, Jefferson, Arkansas, USA

P Cong

Department of Community and Environmental Medicine, Center for Occupational and Environmental Health, University of California, Irvine, California, USA

SC Bondy

Department of Community and Environmental Medicine, Center for Occupational and Environmental Health, University of California, Irvine, California, USA

Two-month-old male B/6C3F1 mice were treated for 10 weeks with 100 µM aluminum lactate (Al) in drinking water. This dose of Al did not alter body weight, and there was no evidence of systemic toxicity. The degree of phosphorylation of several kinases which lead to transcription factor activation (reflecting the extent of their activation) was studied. The proportion of extracellular signal-regulated kinase (ERK) that was activated was depressed in cortex but not in the hippocampus following treatment but c-Jun N-terminal kinase (JNK), p38, IB phosphorylation was unaltered in either tissue. Treatment of mice with 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) alone produced no significant changes in the degree of activation of any transcription factor studied. When MPTP dosing had been preceded by extended exposure to low levels of Al in drinking water, ERK activation was profoundly depressed in cortex and hippocampus, whereas JNK in hippocampus and IB in cortex were greatly elevated. These changes consequent to exposure to both Al and MPTP were accompanied by an increase in NF-B in both regions, whereas AP-1 was elevated in the hippocampus alone. Neither agent alone modulated AP-1 or NF-B. Thus a synergistic interaction occurred between the toxicants. This interaction tended to promote the functioning of a kinase largely associated with inflammation and to depress that of ERK, which is associated with maintenance of cell survival. It is concluded that exposure to levels of Al with no evident toxicity can worsen the response to an acute challenge with MPTP. Al treatment alone was able to increase striatal 3,4-dihydroxyphenylacetic acid levels, suggesting an elevation of the rate of dopamine turnover in the striatum. However, no interaction in alteration of monoamine levels was found between Al and MPTP.

Key Words: aluminum • cell signaling • inflammation • MPTP

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