Long-term oral aluminum administration in rabbits. II. Brain and other organs.

Aluminum (Al) was given orally as a citrate salt in either hard or soft water in combination with low or normal dietary calcium intake over the duration of 12 months using 60 healthy, young adult male New Zealand white rabbits, age four to seven months, divided into six groups. Although decreased weight gain was noted, no significant histological changes were found in the central or peripheral nervous system or in multiple other organs except for liver, nor were tissue levels of Al elevated in brain or liver. However, Al in renal tissue was increased after 52 weeks of treatment in Group 1 (which received Al and a low calcium diet), in spleen in Groups 1 and 2 (on Al and a low calcium diet), and in bone in Group 1. Thus, although the mature intestine acts as a relatively impermeable barrier, some Al is, in fact, absorbed and deposited.

Long-term oral or intravenous aluminum administration in rabbits. I. Renal and hepatic changes.

Long-term aluminum (Al) administration was studied in rabbits using intravenous (I.V.) injections of aluminum maltol or oral aluminum citrate in drinking water along with calcium. In the intravenous study, renal and liver tissue Al levels increased and were associated with proximal renal tubular pathology and with hepatic periportal Al-positive multinucleated cells. After oral Al, renal Al levels were increased in the Al-hard water group, while hepatic Al levels were not significantly increased over controls. However, cirrhosis was found in five orally-loaded animals which received Al and/or low dietary calcium or soft water. Collectively, these findings suggest that renal accumulation of Al is causally related to nephrotoxicity; that the lack of renal changes after oral loading is due to low absorption from normal adult gastrointestinal tract and normal functioning of mature kidneys; and that the elevated liver Al levels, achieved after I.V. administration, are related to the presence of hepatic Al-containing giant cells.

Hematological changes after long-term aluminum administration to normal adult rabbits.

The effects of long-term aluminum exposure on erythroid parameters were investigated in a rabbit system. Healthy young adult male rabbits were maintained on drinking water containing five mg per L of aluminum citrate; others were treated with an intravenous solution of aluminum maltol, 0.225 mmol of aluminum per week. In the oral study, decreases in the hematocrit, hemoglobin, and red cell count were observed over a 12-month period in those animals on soft water with a low calcium content and containing aluminum citrate; however, no changes were seen in those on hard water containing aluminum citrate nor in rabbits maintained on a normal diet. Small amounts of aluminum were observed in bone marrow macrophages, usually accompanied by iron, in both the orally- and intravenously-treated animals. There was poor correlation between bone marrow aluminum content and length of exposure.

Aluminium maltol-induced neurocytoskeletal changes in fetal rabbit midbrain in matrix culture.

We have developed a neuronal culture system to evaluate the neurotoxic effects of aluminium maltol on fetal rabbit midbrain sections containing the oculomotor nucleus. Cultures were treated with 5, 7, 9, 11, 13 and 15 mumol/l aluminium maltol or 39 and 45 mumol/l maltol (molal equivalents to 13 and 15 mumol/l aluminium maltol). Control cultures were maintained in nutrient medium alone. Silver-positive neuritic swellings and occasional perikaryal neurofibrillary tangles were observed in cultures treated with 11, 13 and 15 mumol/l aluminium maltol. The number of tangles (involved neurons) produced in aluminium maltol treated cultures were counted and compared to (untreated) controls. We observed a total of 3, 7 and 7% of involved neurons following treatment with 11, 13 and 15 mumol/l aluminium maltol respectively, and none in the control group. By immunohistochemistry, neurofibrillary tangles were immunoreactive with MAbs to phosphorylated (SMI-31), non-phosphorylated, phosphorylation dependent (SMI-32) and phosphorylation independent (SMI-33) epitopes of the high (-H) and middle (-M) molecular weight neurofilament subunits (NF-H/M). By contrast these lesions were nonreactive with MAbs recognizing tau, MAP2 or different beta-tubulin isotypes. The perikaryal tangles consisted of focal accumulations of 10 nm straight filaments by electron microscopy. These findings are in agreement with previous data from rabbit in vivo studies after the administration of aluminium maltol intravenously (Bertholf et al., 1989) or intraventricularly (Katsetos et al., 1990). Using this in vitro system, aluminium-induced neurofibrillary tangles can be consistently produced, and changes in the distribution of neurofilament proteins evaluated. These studies may aid in the assessment of the possible role of aluminium in the aetiology of human neurodegenerative disorders.

Neuronal cytoskeletal lesions induced in the CNS by intraventricular and intravenous aluminium maltol in rabbits.

The antigenicity of neuronal cytoskeletal lesions was studied immunohistochemically in adult New Zealand white rabbits after intraventricular (subacute) and intravenous (chronic) administration of a water-soluble aluminium compound, aluminium (Al) maltol. After short-term intraventricular administration, rabbits developed widespread neurofibrillary degeneration (NFD) involving pyramidal neurons of the isocortex and allocortex, projection neurons of the diencephalon, and nerve cells of the brain stem and spinal cord. There was a predilection for motor neuron involvement and for the infratentorial portions of the neuraxis. Perikarya and proximal neurites were especially affected. Bundles of 10 nm filaments were frequently present. Three of the animals treated intravenously for 12 weeks or longer displayed NFD in the oculomotor complex and in the pyramidal neurons of the occipital isocortex. Following either mode of administration, the affected neurons exhibited immunostaining with a panel of monoclonal antibodies (MAbs) against phosphorylated (SMI-31), non-phosphorylated/phosphatase-sensitive (SMI-32), and dephosphorylation-independent (SMI-33) epitopes of high and middle molecular weight neurofilament (NF) protein subunits. They were non-reactive with MAbs to microtubule-associated protein 2 and the class III neuron-associated beta-tubulin isotype. Our findings indicate that intraventricular Al maltol produces similar, but more widespread degeneration of projection-type neurons than the less water-soluble Al compounds as reported by others. The NFD lesions are compared with those of senile dementia of the Alzheimer type (SDAT) and motor neuron disease.

Critical appraisal of two methods for determining aluminum in blood samples.

We report two methods for determining aluminum concentrations in blood. Method 1, proposed for routine monitoring of patients with chronic renal failure, includes a collection procedure that can be adopted by any renal dialysis unit, with a minimum of sample contamination. Plasma samples are diluted fourfold with HNO3/Triton X-100 matrix modifier. Method 2 is proposed for determining aluminum concentrations in patients with normal renal function, e.g., in drug studies and environmental monitoring. Samples are diluted with an equal volume of Mg(NO3)2 matrix modifier and atomized from a L'vov platform. By either method, analytical recovery of aluminum added to serum ranged between 92% and 105% throughout the linear calibration range. The reference interval (mean +/- SD) for aluminum in 22 healthy subjects by method 2 was 0.044 +/- 0.030 mumol/L.

Aspects of aluminum toxicity.

Aluminum is the most abundant metal in the earth's crust. The widespread occurrence of aluminum, both in the environment and in foodstuffs, makes it virtually impossible for man to avoid exposure to this metal ion. Attention was first drawn to the potential role of aluminum as a toxic metal over 50 years ago, but was dismissed as a toxic agent as recently as 15 years ago. The accumulation of aluminum, in some patients with chronic renal failure, is associated with the development of toxic phenomena; dialysis encephalopathy, osteomalacic dialysis osteodystrophy, and an anemia. Aluminum accumulation also occurs in patients who are not on dialysis, predominantly infants and children with immature or impaired renal function. Aluminum has also been implicated as a toxic agent in the etiology of Alzheimer's disease, Guamiam amyotrophic lateral sclerosis, and parkinsonism-dementia.

Increased concentration of aluminium in the brain of a parenterally fed preterm infant.

Parenteral feeding solutions currently used for preterm infants are contaminated with aluminium. We report the case of an infant who was fed parenterally for 45 days, who died aged 3 months, and who had a considerably increased concentration of aluminium in his brain tissue at necropsy.

Normal biochemical and hematological values in New Zealand white rabbits.

Animal model systems are used extensively for experimental in vivo studies. When biochemical and hematological measurements are made, reference intervals for the animal species must be determined. Here, the subjects for our study were young adult male New Zealand White rabbits. Blood was sampled from 110 normal healthy rabbits. Biochemical and hematological blood variables were measured by methods available in our routine service laboratory, and we report the ranges.