Arezoo Campbell

Aluminum as a toxicant

Although aluminum is the most abundant metal in nature, it has no known biological function. However, it is known that there is a causal role for aluminum in dialysis encephalopathy, microcytic anemia, and osteomalacia. Aluminum has also been proposed to play a role in the pathogenesis of Alzheimer’s disease (AD) even though this issue is controversial. The exact mechanism of aluminum toxicity is not known but accumulating evidence suggests that the metal can potentiate oxidative and inflammatory events, eventually leading to tissue damage. This review encompasses the general toxicology of aluminum with emphasis on the potential mechanisms by which it may accelerate the progression of chronic age-related neurodegenerative disorders.

The significance of environmental factors in the etiology of Alzheimer's disease

The proposition that environmental agents, such as diet, aluminum, and viruses, are as important as genetic factors in the etiology of Alzheimers disease (AD) was advanced by the authors at the Challenging Views of Alzheimers Disease meeting held in Cincinnati on July 28 and 29, 2001. Diet, dietary fat, and to a lesser extent, total energy (caloric intake), were found to be significant risk factors for the development of AD in a dozen countries, while fish consumption was found to be a significant risk reduction factor. An acid-forming diet, such as one high in dietary fat or total energy, can lead to increased serum and brain concentrations of aluminum and transition metal ions, which are implicated in oxidative stress potentially leading to the neurological damage characteristic of AD. Many of the risk factors for AD, such as cholesterol and fat, and risk reduction factors, such as whole grain cereals and vegetables, are shared with ischemic heart disease. Aluminum may cause neurological damage and a number of studies have linked aluminum to an increased risk for developing AD. The evidence for viral agents playing a role in AD is the strong association between the presence of HSV1 in brain and carriage of an apoE-epsilon4 allele in the case of AD patients but not of controls; statistical analysis shows the association is causal. Diet, aluminum, and viral infections may increase the prevalence of AD by eliciting inflammation, which may cause the neurological damage that results in AD.

Chronic exposure to aluminum in drinking water increases inflammatory parameters selectively in the brain.

A link between aluminum (Al) exposure and age‐related neurological disorders has long been proposed. Although the exact mechanism by which the metal may influence disease processes is unknown, there is evidence that exposure to Al causes an increase in both oxidative stress and inflammatory events. These processes have also been suggested to play a role in Alzheimers disease (AD), and exposure to the metal may contribute to the disorder by potentiating these events. Al lactate (0.01, 0.1, and 1 mM) in drinking water for 10 weeks increased inflammatory processes in the brains of mice. The lowest of these levels is in the range found to increase the prevalence of AD in regions where the concentrations of the metal are elevated in residential drinking water (Flaten [2001] Brain Res. Bull. 55:187–196). Nuclear factor‐κB as well as tumor necrosis factor‐α (TNF‐α) and interleukin 1α (IL‐1α) levels were increased in the brains of treated animals. The mRNA for TNF‐α was also up‐regulated following treatment. Enhancement of glial fibrillary acidic protein levels and reactive microglia was seen in the striatum of Al‐treated animals. The level of amyloid beta (Aβ40) was not significantly altered in the brains of exposed animals. Insofar as no parallel changes were observed in the serum or liver of treated animals, the proinflammatory effects of the metal may be selective to the brain. Al exposure may not be sufficient to cause abnormal production of the principal component of senile plaques directly but does exacerbate underlying events associated with brain aging and thus could contribute to progression of neurodegeneration.

Inhaled ultrafine particulate matter affects CNS inflammatory processes and may act via MAP kinase signaling pathways

In addition to evidence that inhalation of ambient particulate matter (PM) can increase cardiopulmonary morbidity and mortality, the brain may also constitute a site adversely effected by the environmental presence of airborne particulate matter. We have examined the association between exposure to PM and adverse CNS effects in apolipoprotein E knockout (ApoE-/-) mice exposed to two levels of concentrated ultrafine particulate matter in central Los Angeles. Mice were euthanized 24h after the last exposure and brain, liver, heart, lung and spleen tissues were collected and frozen for subsequent bioassays. There was clear evidence of aberrant immune activation in the brains of exposed animals as judged by a dose-related increase in nuclear translocation of two key transcription factors, NF-kappaB and AP-1. These factors are involved in the promotion of inflammation. Increased levels of glial fibrillary acidic protein (GFAP) were also found consequent to particulate inhalation suggesting that glial activation was taking place. In order to determine the mechanism by which these events occurred, levels of several MAP kinases involved in activation of these transcription factors were assayed by Western blotting. There were no significant changes in the proportion of active (phosphorylated) forms of ERK-1, IkB and p38. However, the fraction of JNK in the active form was significantly increased in animals receiving the lower concentration of concentrated ambient particles (CAPs). This suggests that the signaling pathway by which these transcription factors are activated involves the activation of JNK.

Inflammation, Neurodegenerative Diseases, and Environmental Exposures

Abstract: The etiology of neurodegenerative disorders is multifactorial and consists of an interaction between aging, environmental factors, and genetic predisposition. Neuronal cell loss in specific regions of the central nervous system and the resulting clinical symptoms are used to characterize different neurological syndromes. While the selectivity of neuronal cell death is not clearly understood, it is in part attributed to the physiological role and microenvironment of the impacted cells. In this review, innate immune responses in the central nervous system are described. Chronic upregulation of this pathway, orchestrated mainly by microglial cells, may jeopardize neuronal integrity through the prolonged production of toxic inflammatory mediators. Environmental exposures that further enhance the innate immune response may accelerate microglia‐driven neurodegeneration. Environmental factors that can trigger inflammatory events in the central nervous system are lipopolysaccharide, aluminum, and particulate matter present in air pollution. These factors may enhance existing age‐related inflammation in the central nervous system and thus accelerate neuronal toxicity.

Effect of prolonged exposure to diesel engine exhaust on proinflammatory markers in different regions of the rat brain.

BackgroundThe etiology and progression of neurodegenerative disorders depends on the interactions between a variety of factors including: aging, environmental exposures, and genetic susceptibility factors. Enhancement of proinflammatory events appears to be a common link in different neurological impairments, including Alzheimers disease, Parkinsons disease, amyotrophic lateral sclerosis, and multiple sclerosis. Studies have shown a link between exposure to particulate matter (PM), present in air pollution, and enhancement of central nervous system proinflammatory markers. In the present study, the association between exposure to air pollution (AP), derived from a specific source (diesel engine), and neuroinflammation was investigated. To elucidate whether specific regions of the brain are more susceptible to exposure to diesel-derived AP, various loci of the brain were separately analyzed. Rats were exposed for 6 hrs a day, 5 days a week, for 4 weeks to diesel engine exhaust (DEE) using a nose-only exposure chamber. The day after the final exposure, the brain was dissected into the following regions: cerebellum, frontal cortex, hippocampus, olfactory bulb and tubercles, and the striatum.ResultsBaseline levels of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-1 alpha (IL-1α) were dependent on the region analyzed and increased in the striatum after exposure to DEE. In addition, baseline level of activation of the transcription factors (NF-κB) and (AP-1) was also region dependent but the levels were not significantly altered after exposure to DEE. A similar, though not significant, trend was seen with the mRNA expression levels of TNF-α and TNF Receptor-subtype I (TNF-RI).ConclusionsOur results indicate that different brain regions may be uniquely responsive to changes induced by exposure to DEE. This study once more underscores the role of neuroinflammation in response to ambient air pollution, however, it is valuable to assess if and to what extent the observed changes may impact the normal function and cellular integrity of unique brain regions.

Mechanisms by which metals promote events connected to neurodegenerative diseases

Although the exact causative phenomenon responsible for the onset and progression of neurodegenerative disorders is at present unresolved, there are some clues as to the mechanisms underlying these chronic diseases. This review addresses mechanisms by which endogenous or environmental factors, through interaction with redox active metals, may initiate a common cascade of events terminating in neurodegeneration.

Particulate matter, oxidative stress and neurotoxicity.

Particulate matter (PM), a component of air pollution has been epidemiologically associated with sudden deaths, cardiovascular and respiratory illnesses. The effects are more pronounced in patients with pre-existing conditions such as asthma, diabetes or obstructive pulmonary disorders. Clinical and experimental studies have historically focused on the cardiopulmonary effects of PM. However, since PM particles carry numerous biocontaminants that are capable of triggering free radical production and cytokine release, the possibility that PM may affect organs systems sensitive to oxidative stress must be considered. Four independent studies that summarize the neurochemical and neuropathological changes found in the brains of PM exposed animals are described here. These were recently presented at two 2007 symposia sponsored by the Society of Toxicology (Charlotte, NC) and the International Neurotoxicology Association (Monterey, CA).

Aluminum and copper in drinking water enhance inflammatory or oxidative events specifically in the brain

Inflammatory and oxidative events are up-regulated in the brain of AD patients. It has been reported that in animal models of AD, exposure to aluminum (Al) or copper (Cu) enhanced oxidative events and accumulation of amyloid beta (Abeta) peptides. The present study was designed to evaluate the effect of a 3-month exposure of mice to copper sulfate (8 microM), aluminum lactate (10 or 100 microM), or a combination of the salts. Results suggest that although Al or Cu may independently initiate inflammatory or oxidative events, they may function cooperatively to increase APP levels.

ALUMINUM-INDUCED OXIDATIVE EVENTS IN CELL LINES: GLIOMA ARE MORE RESPONSIVE THAN NEUROBLASTOMA

Aluminum, a trivalent cation unable to undergo redox reactions, has been linked to many diseases such as dialysis dementia and microcytic anemia without iron deficiency. It has also been implicated in Alzheimers disease although this is controversial. Because cell death due to oxidative injury is suspected to be a contributory factor in many neurological diseases and aluminum neurotoxicity, glioma (C-6) and neuroblastoma (NBP2) cells were utilized to assess early changes in oxidative parameters consequent to a 48-h exposure to aluminum sulfate. A 500-microM concentration of this salt produced a significant increase in reactive oxygen species (ROS) production and a significant decrease in glutathione (GSH) content in glioma cells. However, the same concentration of the aluminum salt did not lead to any significant changes in the neuroblastoma cells. Mitochondrial respiratory activity in glioma cells was also found to be significantly higher in the aluminum treated cells. As judged by morin-metal complex formation, aluminum can enter glioma cells much more readily than neuroblastoma cells. Thus, it is possible that the cerebral target following an acute exposure to aluminum may be glial rather than neuronal.