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Swiss Webster mice received diets containing 7 (control), 100, 500, or 1000 microg aluminum (Al)/g throughout development (conception to 35 days of age) and were tested behaviorally as adults (>90 days of age). The basal diet contained the same percent of recommended dietary amounts of phosphate, calcium, iron, magnesium, and zinc as young women usually consume. These "realistic" dietary conditions led to 12--15% growth retardation in the Al1000 group at the time of testing. Females were evaluated in a cognitive task (Morris water maze) at 3 months of age and males were evaluated in a motor test battery at 5 months of age. Al1000 females (n=16) were slower than controls in learning the Morris maze, as suggested by fewer mice with low latencies during the first three sessions of the four-session learning series. Influences of Al on cue utilization were also found in probe sessions eliminating salient or nonsalient cues. With motor testing, the Al1000 males (n=20) had significantly lower hindlimb grip strength than controls, an effect that was eliminated by covariance analysis with body weight. Subtle influences of Al on rotarod and wire suspension tests were also noted. The data suggest that developmental Al exposure under normal, but less than optimal, dietary conditions can lead to subtle but long-term effects on growth and brain function in adulthood.

In three experiments, high aluminum diets (1000 microg Al/g diet) were fed to mice throughout their life span to determine whether neurodegenerative changes were seen with aging. Brain Al concentrations were slightly lower in Al-treated mice than controls. Generally, no increased mortality or gross evidence of neurodegeneration was seen in Al-treated mice. Eighteen and 24 month old Swiss Webster mice fed the high aluminum diet differed from controls on some neurobehavioral tests, but differences were no greater than previously seen with shorter term exposure in younger mice. Both brain Al concentration and susceptibility to oxidative damage, as measured with TBARS, were lower in the Al-treated aged mice than in controls. In addition, Al-treated aged Swiss Webster and C57BL/6J mice showed somewhat enhanced performance in the Morris water maze. Finally, Al treatment did not exacerbate the effect of MPTP treatment on a grip strength measure in either 66 or 235 day old male mice. Swiss Webster and C57BL/6J mice do not appear to provide useful models for studying Al-induced neurodegenerative changes in aging.

Swiss-Webster mice were exposed to diets containing 7 or 1000 microg aluminum (Al)/g as Al lactate from conception through maturity (45 days of age). This exposure has previously been shown to cause changes in CNS myelin composition and peroxidizability; in this study myelin sheath widths were measured. Initially, samples of epon embedded, toluidine blue stained cervical spinal cord sectioned at 0.5 mm were examined light microscopically. Qualitatively, Al-treated mice appeared to have a diffuse paleness in nerve tracts. No indication of myelin structural damage (splitting, degeneration) was noted. Quantitative microscopy was performed using images captured with Scion Image Dage 1.59 at 1000x with oil. Axon perimeters and sheaths were measured with NIH image using a standardized sampling pattern in the right medial dorsal and ventral regions of the cervical spinal cord in 6 mice (3 male, 3 female) per group. Mean myelin sheath widths were 16% smaller in the Al-treated group compared to controls (p=.03). There was no effect of sex or region (dorsal/ventral). Axon perimeters were also smaller on the average in the Al treated group but this difference was not significant (p=.16). The relationship between sheath width and axon diameter was similar in the two groups. The density of myelinated axons was greater in some areas for the Al-treated group. The data indicate that dietary aluminum exposure can interfere with myelination in the spinal cord.

Transferrin (Tf) is known primarily for its role in the transport and cellular uptake of iron (Fe). Tf is also the major serum binding protein for Al. In this study, primary rat oligodendrocyte, neuron and astrocyte cultures were found to differ in Tf mediated Fe and Al uptake and in the effect of Al-Tf on Fe-Tf uptake during 4 h incubation periods. When incubated with Al-Tf (1.25 microM), oligodendrocytes displayed a 3- to 4-fold increase (p=.0002) in Al, neurons demonstrated a much smaller (p=.06) increase, and no increase was seen for astrocytes. When incubated with equimolar Al citrate or Al chloride, no increase in cellular Al was seen in any of the three cell types. Oligodendrocytes, astrocytes and neurons all demonstrated greater 59Fe uptake from Fe-Tf than Fe chloride. This uptake could be inhibited by excess Fe-Tf in oligodendrocytes and neurons, but not astrocytes. A small but significant inhibition of 59Fe uptake from Fe-Tf was seen after addition of Al-Tf to the incubation medium of oligodendrocytes, but not neurons or astrocytes. Oligodendrocytes may be particularly vulnerable to the accumulation of excess intracellular Al, and to interference of Al with Fe uptake. Such effects could contribute to Al-induced neurotoxicity if they result in altered myelin formation or maintenance.

Puberty is a period of rapid growth and nervous system maturation, but it is little studied as a sensitive period for neurotoxicant effects. In this experiment, diets containing 7 (control), 100, 500, 750, or 1000-microg aluminum (Al.)/g diet as Al lactate and 3.2% citrate (to promote Al absorption) were fed to male mice beginning at puberty (45 days of age) for either 4 or 8 weeks. ANOVAs were conducted to identify group differences from control, and regression analysis with Al intake was used to evaluate dose-response trends. Dose-responsive effects of dietary Al on brain weight, Al, and Mn concentration, and on grip strength were seen at the end of the 4-week exposure. Although brain Al concentration was also elevated at the end of the 8-week exposure, no dose-responsive effects on other variables were noted. Neither exposure influenced auditory startle amplitude. The period after puberty was sensitive to dietary Al exposure, but affected variables apparently recovered when exposure continued into young adulthood.

In the first part of the present study we investigated the effects of pre-natal and early postnatal exposure of mice to high levels of dietary Al3+ on myelin lipid composition and lipid oxidation. We found: (1) a significantly higher (104%; P<0.01) content of brain myelin galactolipids in the high-Al3+ group than in controls, and, (2) a significant correlation (r2=0.70; P<0.01) between the concentration of myelin galactolipids and TBARS (2-thiobarbituric acid-reactive substances) content, a parameter of lipid oxidation. Based on these results, we evaluated in an in vitro model (liposomes) whether galactolipids could affect the capacity of Al3+ to stimulate Fe2+-initiated lipid oxidation, and whether this effect could be due to the promotion of changes in membrane physical properties (membrane phase separation and rigidification). The presence of galactolipids (10-40 mol%) in the liposomes caused a concentration-dependent increase in the stimulatory effect of Al3+ on Fe2+-induced TBARS production, and on the ability of Al3+ to induce phase separation and membrane rigidification. The capacity of Al3+ (10-100 microM) to induce lateral phase separation in liposomes composed of phosphatidylcholine/phosphatidylserine/galactolipid (36:24:40, molar ratio) was correlated significantly (r2=0.99; P<0. 001) with the stimulatory action of Al3+ on Fe2+-induced TBARS production. We propose that the high content of galactolipids found in myelin from Al3+-intoxicated mice could favour Al3+-induced changes in membrane physical properties, with the subsequent acceleration of lipid oxidation rates.

Previous studies demonstrated better performance of operant tasks in mice fed excess aluminum (Al) in the diet. The current study examined whether (a) Al leads to impairment of spatial alternation after extended practice, (b) Al enhances performance of an operant task that emphasizes motor learning and ability (differential reinforcement of high rates, DRH), and (c) Al enhances food motivation as reflected in progressive ratio (PR) performance. Male Swiss Webster mice were fed purified diets containing 7 (control), 500, or 1000 microg Al/g diet. Subgroups were fed excess Al diets during development (conception to 35 days postnatal) or as adults (35 days postnatal through the end of testing). Operant training and testing were conducted at 50 days postnatal. Data indicated that extended training of developmentally exposed mice did not lead to performance deficits, that DRH performance of both developmentally and adult-exposed mice was enhanced, and that food motivation (PR task) was significantly greater in the adult-exposed group with a similar trend in the developmentally exposed group. Aluminum may bias performance of food-motivated tasks by influencing food motivation.

The capacity of Al3+ to promote oxidative damage to brain membranes was investigated both in vitro and in vivo. In vitro, Al3+ and related metals (Sc3+, Ga3+, In3+, Be2+, Y3+, and La3+) stimulated Fe2+-initiated lipid and protein oxidation in brain myelin and synaptic membranes. Al3+, Sc3+, Y3+, and La3+ significantly promoted protein-associated carbonyl production in myelin, while in synaptic membranes, the stimulatory effect was observed in the presence of Ga3+, In3+, Y3+, Sc3+, and La3+. In myelin the magnitude of the stimulation of lipid oxidation followed the order Sc3+, Y3+, La3+ > Al3+, Ga3+, In3+ > Be2+. When compared to mitochondria and microsomal and synaptic membranes, myelin showed a marked susceptibility to Al3+-mediated lipid peroxidation. The differential susceptibility of myelin compared to synaptic membranes could not be explained by differences in membrane composition, since the relative content of negatively charged phospholipids (binding sites) was similar for both membranes, and myelin had a lower content of poly-unsaturated fatty acids (substrates of lipid oxidation) and a higher concentration of alpha-tocopherol compared to synaptic membranes. In a model of Al3+ intoxication imposed to mice during pregnancy and early development, a 72% higher content of lipid peroxidation products was found in brain myelin. The fluidity of myelin evaluated by the polarization fluorescence of 1,3-diphenylhexatriene was significantly higher in the Al3+-intoxicated mice than in controls. Since myelin has a high relative content of lipid:protein compared to other membranes, these results support our hypothesis that ions without redox capacity can stimulate in vitro and in vivo lipid oxidation by promoting phase separation and membrane rigidification, thus accelerating lipid oxidation.

Al is found in the developing conceptus, but little information is available concerning its tissue distribution and its changes in concentration with age. Because Al has affinity for many of the same biological ligands as the essential mineral cations Ca, Mg, Zn, Fe, and Mn, we hypothesized that Al might show a pattern of developmental concentrations that was similar to one or more of these elements in the brain, a major target of Al toxicity. Concentrations of Al, Ca, Mg, Zn, Fe, and Mn were measured in spinal cord, brainstem, cerebellum, and forebrain of guinea pig fetuses on gestation day (GD) 30 and 45, at birth, and on postnatal day (PND) 3, 6, and 12. Dams were fed commercial guinea pig chow, which contained 47 micrograms Al/g. Tissue Al and Mn were measured with electrothermal atomic absorption spectrophotometry (ETAAS), and the other elements with inductively coupled axial plasma spectroscopy (ICAP-AES). Al concentrations in the brain regions were highest in spinal cord, brainstem, and cerebellum, and decreased during late gestation and lactation. Al did not show marked increases in regional brain concentrations during the final third of gestation as did Fe, Mg, and Zn. In contrast to Fe and Ca, Al did not accumulate in placenta. Al was the only element to show higher concentrations in spinal cord than in any other tissue at birth. In summary, the tissue distribution of Al did not follow that of essential cations as examined in this study.

Information concerning developmental aluminum (Al) toxicity is available from clinical studies and from animal testing. An Al toxicity syndrome including encephalopathy, osteomalacia, and anemia has been reported in uremic children receiving dialysis. In addition, some components of the syndrome, particularly osteomalacia, have been reported in non-dialyzed uremic children receiving Al-based phosphate binders, nonuremic infants receiving parenteral nutrition with Al-containing fluids, and nonuremic infants given high doses of Al antacids. The number of children in clinical populations that are at risk of Al toxicity is not known and needs to be determined. Work in animal models (rats, mice, and rabbits) demonstrates that Al is distributed transplacentally and is present in milk. Oral Al administration during pregnancy produces a syndrome including growth retardation, delayed ossification, and malformations at doses that also lead to reduced maternal weight gain. The severity of the effects is highly dependent on the form of Al administered. In the postnatal period, reduced pup weight gain and effects on neuromotor development have been described as a result of developmental exposures. The significance of these findings for human health requires better understanding of the amount and bioavailability of Al in food, drinking water, and medications and from sources unique to infants and children such as breast milk, soil ingestion, and medications used specifically by pregnant women and children. We also need a better understanding of the unique biological actions of Al that may occur during developmental periods, and unique aspects of the developing organism that make it more or less susceptible to Al toxicity.

High dietary A1 can result in lowered tissue Mn and Fe concentrations in weanling mice. Possible mechanisms underlying this effect of A1 (altered milk Fe and Mn content, altered absorption or retention of Fe and Mn) were investigated in this experiment. To determine if milk composition was changed, milk was analyzed for Fe and Mn at 0, 3, 7, and 12 days postnatal. To determine if A1 influenced absorption and/or retention of Fe and Mn, a single milk meal containing 54Mn and 59Fe was administered by gavage to 12 day old pups and tissues were obtained 6 and 24 h later. Pup body and tissue weights were not affected by the high A1 diet. Milk from dams fed high A1 diets (1000 micrograms A1/g, n = 11, A11000) had similar Fe and Mn concentrations as milk from dams fed a control diet (7 micrograms A1/g, n = 11), although A1 concentrations were higher. Absorption and tissue distribution of 54Mn and 59Fe, as determined at the 6 h timepoint, were unaffected by maternal diet group (control n = 16, AL1000 n = 10). However, total retention of both 54Mn and 59Fe was 8-10% lower in the AL1000 pups 24 h after gavage (P = 0.030 for Mn and 0.017 for Fe). These data suggest that high dietary A1 during development alters the ability of nursing mouse pups to retain absorbed Fe and Mn.

Transferrin (Tf) is a major transport protein for both iron (Fe) and aluminum (Al), as well as manganese (Mn) and it can mediate cellular uptake of these elements via cell surface Tf receptors. To study the effect of Al-Tf on Tf receptor regulation, primary oligodendrocyte cultures were prepared from cortices of newborn rats. The effects of Al-Tf on 54Mn and 59Fe uptake were compared to those of apo-, Fe-, or Mn-Tf (1.25 microM). To examine changes in cell surface Tf binding capacity, preincubation (4 h, 37 degrees C) was performed with apo-, Al- or Fe-Tf and homologous receptor binding studies were subsequently conducted with 125I-Fe-Tf at 4 degrees C. Incubation with Al-Tf, but not with equimolar amounts of Al chloride or Al citrate, led to dose-related increases in cellular Al. Incubation with either Al- or Fe-Tf decreased 59Fe uptake, while incubation with either Al- or Mn-Tf decreased 54Mn uptake. Surface Tf receptor sites/cell were 1.05, 0.60 and 0.46 x 10(5) after incubations with equivalent amounts of apo-, Fe-, and Al-Tf respectively. The data suggest that Al-Tf down-regulates surface Tf receptors on oligodendrocytes and can limit Fe and Mn uptake through this mechanism.

Swiss Webster mice were exposed to excess dietary aluminum (500 or 1000 micrograms Al/g as Al lactate) from conception until weaning or from conception through adulthood (pre- and postweaning). Controls were fed a 7 micrograms Al/g diet. Excess Al diets did not influence pregnancy outcome, pup mortality, and body or organ weights. Al diets of 1000 micrograms/g led to enhanced cagemate aggression in offspring as adults. At 50 days of age, mice were trained for operant tasks and subsequently 35 sessions of delayed spatial alternation or discrimination reversal testing were conducted. Both the 500 and the 1000 micrograms Al/g diets led to faster attainment of criterion during the training phase of the operant studies, but did not influence performance of the two tasks. At the conclusion of the study (150-170 days of age), neurobehavioral measures and tissue trace metals (Al, Fe, Mn) were determined. Both the 500 and the 1000 micrograms Al/g diets led to reduced grip strength and the 1000 micrograms Al/g diet was associated with lower Fe concentrations in brain and spinal cord. Brain, spinal cord, and liver Al concentrations were elevated only in adults with continued exposure after weaning. Throughout the experiment, mice exposed before and after weaning were apparently no more affected on behavioral measures than those exposed only until weaning. It is concluded that developmental exposure to 500 and the 1000 micrograms Al/g diets had distinctive long-term effects on behavioral measures that were not dose dependent and were not further intensified by continuing exposure as adults.

Using an automated method, reduced auditory startle responsiveness was detected in Swiss Webster mice fed excess aluminum in diet (1000 micrograms Al/g) as compared to controls (7 micrograms Al/g). Excess aluminum diets were fed either from conception to weaning (developmental group) or from conception and continuing to 52 days of age (continuous group). At 22 days of age, lower response amplitudes were seen in the aluminum exposed groups than in controls. At 52 days of age, more rapid reduction in response amplitude across initial trial blocks was noted. Effects were more prominent in the continuously exposed than the developmentally exposed group at 52 days of age. Reduced auditory startle responsiveness is interpreted as part of a pattern of subtle motor impairment and marginally reduced activity and responsiveness in mice fed excess aluminum in diet.

Swiss Webster mice were exposed to excess dietary aluminum (Al) (1000 micrograms Al/g diet, Al as Al lactate) from conception to 6 months of age. Splenic lymphocytes (10(6) per culture) were incubated for 24 hrs with concanavalin A (5 micrograms/ml). Concentrations of interleukin-2, interferon-gamma and tumor necrosis factor-alpha, as measured in supernatants via ELISA with monoclonal antibodies, were depressed in spleen cells from aluminum treated mice relative to controls. Experiments using the fluorescence activated cell sorter demonstrated a shift in T-cell populations from treated mice with a deficiency of CD4+ cells. These findings suggest a deficit in immune effector cell function after long term in vivo aluminum exposure.

The present study was performed to determine aluminum uptake, retention, and neurotoxic effects in the presence of dietary citrate. Six-week-old female Swiss-Webster mice were fed semipurified diets containing 3.5% sodium citrate and either 3 micrograms Al/g diet (3 Al) or 1,000 micrograms Al/g diet (1,000 Al) as AlCl3. After 5 to 7 weeks of feeding these diets, changes in behavior were assessed using the National Institute of Environmental Health Sciences Neurobehavioral Test Battery. Liver and bone Al concentrations in the 1,000 Al group were higher than in the 3 Al group at both the 5- and 7-week time points. Spinal cord Al concentrations in the 1,000 Al group were 200% higher at 5 weeks (P < .01) than in controls, and brain nuclear fraction Al concentrations in the 1,000 Al group were 150% higher at 5 and 7 weeks (P < .01) than in the 3 Al group. The Neurobehavioral Test Battery showed lower grip strength and greater startle responsiveness in the 1,000 Al group compared with the 3 Al group at both the 5- and 7-week time points. Based on reports that Al can act as a pro-oxidant, we examined Al-induced brain lipid and protein oxidative damage; neither was evident in the Al-intoxicated mice. In summary, feeding of Al and citrate to mice resulted in Al accumulation in the central nervous system, and this accumulation was associated with overt signs of neurotoxicity. Brain protein and lipid oxidative damage was not associated with early manifestation of Al toxicity.

Previous studies have shown that excess dietary Al during development can affect neurobehavioral measures and decrease tissue Mn of 21-day-old weanling mice without a corresponding increase in tissue Al concentrations. Al and Mn have similar tissue concentrations and similar affinities for transferrin, which is the major plasma transport protein for Al and Mn as well as Fe. In the present study, brain Al, Mn and Fe were studied at 6, 12, 18 and 24 days of age in offspring of Swiss Webster mice fed a semipurified diet containing excess Al (Al[+], 1000 micrograms Al/g diet, Al as Al lactate), marginal Mn (Mn[-], 3 micrograms Mn/g diet) or both excess Al and marginal Mn (Al[+]Mn[-]) from conception to day 24 postnatal (weaning on day 18). Brain Al concentrations were higher at 6 days of age than at later ages and were significantly elevated by the excess Al diet (P = 0.017) but returned to control levels by weaning. Brain Mn concentrations increased from day 6 to day 24 and were lower in the Mn deficient groups (P < 0.001) and also in the excess Al group (P = 0.024) than in controls. Brain Fe concentrations were not influenced by diet. Similar patterns were seen in liver as in brain. The marginal Mn diet led to postnatal growth retardation which was more severe in litters of dams fed Al[+]Mn[-] diets than in litters fed Mn[-] diet. These data suggest that excess Al in diet can interact specifically with Mn metabolism during development.

In order to determine sensitive periods for induction of neurodevelopmental effects of aluminum (Al), mice were fed either 25 (control) or 1000 (high Al) micrograms Al/g diet (as Al lactate) from conception through lactation and litters were fostered either within or between groups at birth. Birth parameters were not influenced by Al intake. Food intake and body weight were 10%-12% lower during lactation in dams fed the high Al diets. Both gestation and lactation high Al exposure led to growth retardation in offspring beginning on day 10 postnatal; combined gestation and lactation exposure led to the biggest weight differential at weaning (23%). For neurobehavioral measures obtained at weaning, forelimb grasp strength was influenced by gestation high Al exposure, whereas negative geotaxis was influenced by lactation exposure, and hindlimb grasp and temperature sensitivity were influenced by both gestation and lactation exposure. Pup liver and brain manganese (Mn) and liver iron (Fe) concentrations at weaning were lower after high Al lactation exposure than in controls. Pup brain and liver Al concentrations were similar among the groups. These data show that mice are susceptible to neurodevelopmental effects of high maternal dietary Al intake during both gestation and lactation, and that high maternal intake can result in altered essential trace element metabolism in the offspring.

Studies in mice have suggested that both dietary Al excess and dietary Mn deficiency promote oxidative tissue damage. To determine if these factors can interact to produce functional nervous system damage, female mice (N = 10-12 per group) were fed diets with control or low Mn (35 or 3 micrograms Mn/g diet) and/or control or high Al (25 or 1000 micrograms Al/g diet, Al as Al lactate) content for a 90-day period. No overt signs of neurotoxicity were observed in any group. Excess Al produced a threefold Al accumulation in both liver and brain, a slight acceleration of growth, decreased motor activity, decreased grip strength, and decreased startle responsiveness. Manganese deprivation led to liver, brain, and femur Mn depletion and reduced liver MnSOD activity but no neurobehavioral changes. No interactive effects between Al excess and Mn deficiency were observed. Neither Al excess nor Mn deficiency altered brain or liver lipid peroxidation measures. This study suggests that (1) subchronic dietary Al at doses of 1000 micrograms Al/g diet produces elevated brain Al and altered neurobehavioral indices in adult mice; (2) brain lipid peroxidation is not altered by this treatment; (3) dietary Mn deficiency does not influence Al neurotoxicity in adult mice.

Excessive dietary aluminum (Al) has been proposed to be a factor contributing to several neurological disorders in humans. Six 8-week-old female Swiss Webster mice were fed for 10 weeks purified diets containing 100 (control, 100 Al), 500 (500 Al) or 1000 (1000 Al) micrograms Al/g diet. Brain and liver lipid peroxidation was determined by evaluating the production of 2-thiobarbituric acid reactive substances (TBARS) in brain and liver homogenates in the presence or absence of 50 microM ferrous iron. TBARS production in the absence of iron in brain homogenates from mice fed the 1000 Al diet was higher (30%) than that in the 100 Al control group (3.1 vs. 2.4 nmol TBARS/mg protein). The addition of ferrous iron increased TBARS production in brain homogenates from all 3 dietary groups. The iron-induced TBARS production was 26% higher in the 1000 Al brain homogenates than in the 100 Al group (4.9 vs. 3.9 nmol TBARS/mg protein). Brain TBARS production in the presence and absence of iron was similar between the 100 and 500 Al groups. TBARS production in liver homogenates measured either with or without iron was similar for the 3 groups. These results show that, in mice, dietary Al intoxication leads to increased brain TBARS production, suggesting that enhanced lipid peroxidation may be one possible mechanism underlying the neurological damage associated with increased tissue Al.

One of the possible mechanisms that has been proposed to underlie the deleterious effects of excess aluminum on brain function is an impairment in the normal formation of the cytoskeletal network. Based on recent reports that aluminum can promote the in-vitro polymerization of purified tubulin, in the present study we characterized the effects of high dietary aluminum on in-vitro microtubule formation in brain supernatants. Mice were fed diets containing aluminum 25-1000 micrograms/g for up to 10 weeks. Tubulin polymerization in high-speed brain supernatants was not found to be affected by dietary aluminum. However, we observed that the addition of aluminum in vitro stimulated microtubule assembly in brain supernatants from mice fed control diets, as had been previously reported. Thus, impaired brain microtubule function is not an early general biochemical lesion in aluminum toxicosis.

Aluminum (Al) as aluminum lactate in a purified diet was fed to adult female Swiss-Webster mice over a six week period. Comparison groups were: controls (CON), 25 micrograms Al/g diet; low Al (LO), 500 micrograms Al/g diet; high Al (HI), 1000 micrograms Al/g diet; and pair fed (PF) 25 micrograms Al/g diet pair fed to HI group. Weights, food intake and toxic signs were recorded at 3-day intervals and activity levels were measured during a 24-hr session during week 5 using an automated apparatus. Food intake was not reduced overall in Al-treated groups but they demonstrated a cyclic pattern of food intake. Mean weight gain over the 6-week period in the HI (0.5 g) and PF(0.1 g) groups was somewhat less than that in the CON (2.3 g) and LO (2.0 g) groups. No neurotoxic signs were recorded in any group, but a dose dependent increase in localized fur loss was seen. Overall activity level was 20% lower in HI than CON groups, with vertical movement more affected than horizontal movement. HI mice were less active during the diurnal period of peak activity than CON mice and their activity periods were also somewhat shorter (130 vs. 200 min). Activity of LO and PF mice did not differ significantly from controls, although PF activity levels were more variable. These data demonstrate that short term feeding of aluminum at levels within an order of magnitude of estimated human intake can influence neurobehavioral function as indexed by motor activity.

The present study demonstrated aluminum-induced neurotoxicity in mouse dams and developmental retardation in their offspring following oral exposure to several dose levels during gestation and lactation. Female mice fed aluminum lactate (AL) at levels of 500 or 1000 ppm in their diet from Day 0 gestation to Day 21 postpartum were compared to mice which received a 100 ppm aluminum diet either ad libitum or pair-fed to the 1000 ppm AL group. Dams receiving the 500 and 1000 ppm AL diets showed signs of neurotoxicity beginning at Days 12-15 postpartum and showed significant weight loss. Offspring showed dose-dependent decreases in body weight (F = 6.47, p less than 0.001), crown-rump length (F = 7.37, p less than 0.0001), and ponderal index (F = 6.90, p less than 0.0002), at birth and preweaning. Absolute and relative liver and spleen weights were lower in pups from the high AL groups compared to controls (F = 3.34, p less than 0.025 and F = 15.54, p less than 0.001, respectively). Neurobehavioral development was somewhat delayed in aluminum-treated pups, but not in their pair-fed controls (F = 5.52, p less than 0.005). In addition to showing oral toxicity of excess AL during development dose-dependent toxic effects of parenteral aluminum exposure were demonstrated in pregnant mice which were injected subcutaneously with aluminum lactate solution at 10, 20, or 40 mg Al/kg body wt on Days 3, 5, 7, 9, 12, 13, and 15 of gestation. Maternal spleen and liver weights were significantly increased in aluminum treated animals (p less than 0.001 and p less than 0.05, respectively). Fetal crown-rump lengths were significantly reduced in the 20 mg/kg aluminum group (F = 9.79, p less than 0.001).

Female, adult Swiss-Webster mice were fed, during gestation and subsequent lactation, diets containing either 25 (control), 500 or 1,000 micrograms Al/g diet in the form of Al lactate, followed by challenge with Listeria monocytogenes. Mice in the groups fed 1,000 and 500 micrograms Al/g had significantly lowered resistance to bacterial infection when compared to control animals (p less than 0.025). The animals given 1,000 micrograms Al/g also had higher concentrations of liver Al (p less than 0.05) than controls. Pups derived from these dams showed no differences in mortality rates or Al tissue levels. In contrast, nonpregnant animals fed 1,000 micrograms Al/g for 6 weeks had a slight decrease in mortality rate when compared to control animals. Dose-related changes in tissue Al levels were not observed in these adult, virgin mice. Finally, adult nonpregnant mice were injected subcutaneously with PBS only, or with 1, 5 or 10 mg of Al (in the form of Al lactate) per kilogram body weight followed by bacterial challenge. Animals which received 5 mg Al/kg had lower mortality rates to L. monocytogenes when compared to other treatment groups (p less than 0.025). This data suggests that Al has the potential to influence host resistance to bacterial infection depending on the physiological state of the host; it provides additional evidence for the role of Al as an environmental toxin.

Aluminum (Al) as Al lactate in a purified diet (25, 500 or 1000 micrograms Al/g diet) was fed to Swiss-Webster mice from conception through weaning. Weights, food intake and toxic signs were recorded at regular intervals and pregnancy outcome evaluated. Pups were assessed for growth, neurobehavioral development and toxic signs prior to weaning. Offspring were also evaluated with a multi-item neurobehavioral test battery immediately after weaning and again after a 2-week period during which they were all fed control (25 micrograms/g Al) diet. No maternal or reproductive toxicity was detected and there were no group differences in pup mortality, growth, toxic signs, or neurobehavioral development prior to weaning, with the exception of poor performance in a climbing test in the 1000 micrograms Al/g diet group. Parameters significantly affected by Al in the postweaning neurobehavioral testing were foot splay, forelimb and hindlimb grip strengths, and thermal sensitivity. Negative geotaxis was inconsistently affected and startle responses were not affected. These results show that maternal dietary exposure to excess Al during gestation and lactation which do not produce maternal toxicity can result in persistent neurobehavioral deficits in weanling mice.