Influence of dietary factors on aluminium absorption and retention in the brain and bone of rats

Young adult male Sprague-Dawley rats were treated by gavage for 10 weeks (3-times weekly) with aluminium 100 mg/kg b.wt. in the form of Al-hydroxide (Novalucol), Al-citrate, Al-hydroxide together with citric acid or with tap water (controls). Male rats aged 13 months were gavaged for 11 weeks 3-times a weak with black currant soup (0.8 ml/kg b.wt.) stored 19 days in either aluminium or stainless steel saucepans. The brain cortex, bone and blood (young adults only) of each rat were analysed for Al using graphite furnace atomic absorption spectroscopy. The rats treated with Al-citrate and in particular rats treated with Al-hydroxide + citric acid showed a significant increase of Al concentrations in all the tissues studied. In the latter group the mean Al concentrations were elevated at 0.039 micrograms Al/g wet weight (controls 0.005 micrograms/g) 0.092 micrograms/g (0.016 micrograms/g) and 26.6 micrograms/g (0.22 micrograms/g) in the blood, brain and bone, respectively. After treatment with Al-hydroxide alone only the bone showed a moderate increase of Al-concentration. No significant differences were found in the brain and bone Al levels of the rats given fruit soup from aluminium saucepans (containing 17 mg Al/l) or stainless steel saucepans (0.4 mg Al/l).     

Developmental toxicity evaluation of oral aluminum in rats: influence of citrate

To evaluate the influence of citrate on the potential developmental toxicity of high doses of aluminum (133 mg/kg/day), three groups of pregnant Sprague-Dawley rats were given by gavage aluminum hydroxide (384 mg/kg/day), aluminum citrate (1064 mg/kg/day), or aluminum hydroxide (384 mg/kg/day) concurrent with citric acid (62 mg/kg/day) on gestational days 6 through 15. Control animals received distilled water. At termination on gestation day 20, live fetuses were examined for external, visceral, and skeletal alterations. There were no significant differences between controls and Al-treated rats on pre- or postimplantation loss, number of live fetuses per litter, or sex ratio. Fetal body weight was significantly reduced in the group treated with Al(OH)3 and citric acid. Although no increases in the incidence of malformations were observed, the incidence of skeletal variations was significantly increased in the group given Al(OH)3 concurrent with citric acid. In summary, although the administration of citric acid did not modify the lack of embryotoxicity and teratogenicity of Al(OH)3 in rats, some signs of maternal toxicity and fetotoxicity could be observed in this group.     

Toxicity and aluminium concentration in bone following dietary administration of two sodium aluminium phosphate formulations in rats

The effects of dietary administration of the basic sodium aluminium phosphates, KASAL and KASAL II, were examined in male rats. Aluminium levels in bone were determined in order to estimate the possible aluminium deposition by these compounds. Groups of 25 male Sprague-Dawley rats were fed control diet or diets containing 30,000 ppm KASAL, 7000 or 30,000 ppm KASAL II, or 14,470 ppm aluminium hydroxide for 28 days. The mean daily aluminium doses were calculated to be 5, 141, 67, 288 or 302 mg/kg body weight/day, respectively. Neither form of KASAL induced detectable toxicity. No adverse treatment-related clinical signs were observed. Body weights and food consumptions were similar in treated and control groups. No toxicologically significant changes were observed in haematology, clinical chemistry parameters or organ weights. No treatment-related changes were observed at autopsy or in histopathological examination of collected tissues. Femurs collected at autopsy under conditions free of aluminium contamination showed no significant deposition of aluminium after dietary administration of KASAL, KASAL II or aluminium hydroxide. All aluminium values in bone were less than 1 ppm and most values were not quantifiable. Thus, dietary administration of up to 30,000 ppm of either of the basic sodium aluminium phosphate formulations caused neither toxicity nor significant deposition of aluminium in femur.     

Distribution of aluminium following intraperitoneal injection of aluminium lactate in the rat

An animal experiment was performed to evaluate the absorption and distribution of aluminium in serum and tissues of normal rats. The animals were intraperitoneally injected with an aluminium lactate solution at a pH adjusted to 7.0. Before starting, a short preliminary study was carried out in order to verify the validity of the treatment with aluminium lactate instead of aluminium chloride at endogenous pH 3.4. Thirty-one rats were used in the main experiment, divided in four groups. In treated animals, the total Al-administered dose was 75.6 mg during 78 days of treatment. Furthermore, to evaluate the influence of the parathyroid hormone on Al absorption and/or distribution, 200 USP/rat of parathyroid hormone extract (PTH) were also administered during the last 5 days of the experiment. Aluminium content in serum, tibia, rib, brain, liver, muscle, kidney and spleen was determined. Calcium analysis in serum and bone was also performed. The highest concentrations of aluminium were found in liver and spleen, whereas the lowest level was found in the brain. The PTH effect on Al absorption was evident in brain and bone.     

大鼠亚慢性铬染毒引起的肾损害

30只Wistar♂大鼠ip K_2Cr_2O_7 1.06mgCr~(6+)/kg,每周5次,连续12wk。肾脏出现明显的形态和功能异常,早期肾小管上皮细胞出现变性,尿中N-乙酰-β-D-氨基葡萄糖苷酶(NAG)、溶菌酶(LZM)和蛋白质的含量分别在染毒d2,3和5wk时显著增加;晚期肾小管上皮细胞出现广泛变性和坏死,尿中碱性磷酸酶(ALP)、γ-谷氨酰移换酶(γ-GT)和葡萄糖的含量分别在染毒d6,10和10wk时明显增加,GFR在染毒7wk开始下降。尿铬主要以低分子铬结合物(LW-Cr,5000道尔顿)形式排出。尿铬与肾损害程度显著相关,尿LZM、尿蛋白和GFR出现异常的尿铬临界浓度分别为5.90,7.57和9.36μg/mg肌酐。肾脏铬的蓄积则以高分子铬结合物(HM-Cr,65000道尔顿)和与尿铬相似的LM-Cr两种形式存在,主要蓄积在肾皮质。肾铬与肾损害相关密切,尿LZM和尿蛋白出现异常的肾皮质铬临界浓度分别为36.7ppm和41.8ppm。     

Beta-alanyl-L-histidinato zinc prevents the toxic effect of aluminium on bone metabolism in weanling rats

The preventive effect of beta-alanyl-L-histidinato zinc (AHZ) on the toxic action of aluminium on bone metabolism was investigated in the femoral diaphysis of weanling rats. Aluminium chloride (5.0, 10.0 and 20.0 mumol A1/100 g body weight) was orally administered for 3 days. The dose of 10.0 and 20.0 mumol A1/100 g caused a significant increase in serum calcium concentration and bone acid phosphatase activity, while bone alkaline phosphatase activity and calcium content were not altered significantly. Moreover, the bone DNA content was significantly decreased by the doses of 10.0 and 20.0 mumol A1/100 g. Meanwhile, the increase in serum calcium concentration caused by the administration of aluminium (20 mumol/100 g) was completely prevented by the simultaneous administration of AHZ (1.0 and 2.5 mg/100 g) for 3 days, although AHZ alone did not have any effect. Also, the effects of aluminium (20.0 mumol/100 g) to increase bone acid phosphatase activity and to decrease the bone DNA content were completely blocked by the simultaneous administration of AHZ (1.0 and 2.5 mg/100 g). AHZ (1.0 and 2.5 mg/100 g) alone had the effect to increase bone DNA content but not bone acid phosphatase activity. The present study indicates that AHZ can prevent the revelation of the toxic effect of aluminium on bone metabolism in rats.     

Long-term effects of postnatal aluminium exposure on acetylcholinesterase activity and biogenic amine neurotransmitters in rat brain

The long-term effects of early postnatal exposure to aluminium on acetyl choline esterase (AChE) activity and on biogenic amines were studied in different brain regions. The subjects were eight days old male Wistar rat pups. They were grouped into normal control and aluminium exposed groups. For aluminium exposure, the pups were gastric intubated with aluminium chloride (40 mg/Kg body weight) for two weeks. Control rats were given equal volumes of distilled water. After the treatment, they were rehabilitated for forty days. On the sixtieth day, the rats from both the groups were sacrificed and AChE activity, levels of dopamine, noradrenaline and serotonin were estimated in the cerebral cortex, hippocampus, septum, brainstem and striatum. In the aluminium exposed group: the AChE activity was significantly decreased in the hippocampus, septum, striatum and brainstem; serotonin levels were reduced by 20% in the cortex, hippocampus, septum and striatum; in brain stem, the serotonin level was decreased by 40%. A 60% reduction in noradrenaline levels was observed in the striatum whereas it was reduced by 25% in other regions except in hippocampus. Though dopamine levels were not altered in the cortex, septum and brainstem, they were reduced by 40% in the striatum. The study documents the long-term consequences of exposure to aluminium during the developmental periods.     

Hepatic clearance and retention of aluminium: studies in the isolated perfused rat liver

Aluminium (Al) exposure can result in Al accumulation in the liver and this metal can be toxic to the hepatic tissue at high concentrations. In the present study the model of the isolated perfused rat liver was used to investigate the hepatic handling of Al. Livers from male Wistar rats were perfused in a recirculating system for 240 min. The liver function remained unchanged at perfusate concentrations of Al ranging from 4.9 to 1530.0 μ/1. At higher Al levels of 6535.3–16 694.9 μ/1 signs of toxicity towards isolated perfused livers were observed as indicated by an increased release of the enzymes AST and ALT into the perfusate, a pronounced reduction of bile flow rate and a 50% suppression of oxygen consumption. The hepatic Al clearance was low and decreased with increasing concentrations of Al in the perfusate from 4.3 + 0.6 μ/min per g liver at a nominal Al concentration of 9.1 μ/l in control perfusate to 0.04 ± 0.02μl/min per g liver at the highest concentration group. There was almost a linear dose dependent retention of Al in the liver with 4.9–635.7 μ Al/1 perfusate while at higher concentrations Al levels in this organ increased disproportionally. It is concluded that by using the isolated perfused rat changes of liver functions occur only at very high Al concentrations in the perfusate and that only negligible amounts of Al are eliminated by the liver.     

Nephrotoxicities of Aluminium and/or Cadmium-Metallothionein in Rats: Creatinine Excretion and Metabolism of Selected Essential Metals

Abstract: The effects of exposure to aluminium (Al) and cadmium (Cd) on urinary creatinine and protein excretion, and the concentrations of calcium, magnesium and copper in kidney and urine were studied in 32 male adult Wistar rats. The animals were divided into 8 groups, groups 1–4 given a calcium-deficient diet (0.01%, i.e. 0.01 g calcium/100 g diet weight) and groups 5–8 a calcium-adequate diet (0.9%) for 6 weeks. Single daily intraperitoneal injections of AlCl₃ (10.8 mg Al/kg body weight, per day) were done on 6 consecutive days to groups 3, 4, 7 and 8 during the last week of the experiment. One single intraperitoneal injection of cadmium-metallothionein (Cd-MT, 0.4 mg Cd/kg) was administered 12 hr before the final Al dose to groups 2, 4, 6, and 8 and the rats were sacrificed 47 hr after the Cd-MT injection. The rate of creatinine clearance was significantly lower in rats injected intraperitoneally with either Cd-MT or Al, and the concentrations of magnesium and calcium in urine were lower in rats administered both Al and Cd-MT as compared to those in control groups. Histological examination showed that Al was toxic to the kidney tubule cells of rats, however, an adequate supply of calcium in food protected to some extent the renal tubules from Al toxicity as indicated by a higher creatinine clearance, and there was also less tubule damage as shown by histological examination. The copper concentrations in kidney tissue were lower in groups treated with either Al or Cd-MT. The above results indicate that: (1) Al administered by intraperitoneal injection is nephrotoxic in rats; (2) food deficient in calcium increases the vulnerability of the kidney to Al-induced toxicity; (3) the decreased creatinine clearance in Cd-MT-injected rats may explain the low calcium excretion in urine observed in these rats.     

Retention of aluminium in the tissues of rats after the discontinuation of oral exposure to aluminium

Two studies were conducted to determine whether the aluminium deposited in the bones, muscles and kidneys of young growing rats fed diets supplemented with A1(OH)₃ (989 or 1070 μg A1/g diet) for 16 days was retained after the A1(OH)₃ was removed from the diets. Al levels in the tissues of test rats decreased significantly (P 0.01) 3 days after withdrawal of the Al(OH)₃ from the diet, and 7 days after withdrawal the tissue concentrations of A1 were similar in the test and control animals. Ingestion of A1 had no effect on tissue levels of phosphorus, calcium, magnesium, zinc or iron.     

Effects of various aluminium compounds given orally to mice on Al tissue distribution and tissue concentrations of essential elements

To evaluate the risk of gastrointestinal long-term aluminium (Al) exposure, aluminium distribution and the levels of the following essential elements: Ca, Mg, Zn, Cu, and Fe in tissue were studied. Aluminium was administered in drinking water as aluminium chloride, dihydroxyaluminium sodium carbonate or aluminium hydroxide. Mice (strain Pzh:SFIS) were exposed to a total dose of 700 mg Al in long-term treatment (for each Al compound n = 15). Concentrations of Al, Ca, Mg, Zn, Cu, and Fe in stomach, kidneys, bone and liver were analyzed by atomic absorption spectrometry. After AlCl3 treatment, aluminium was found to accumulate in all tested tissues. A significant decrease in Fe concentration in liver and Zn in kidneys was observed in comparison to concentrations of these elements in the control group. In the Al(OH)3-treated group, accumulation of aluminium was observed in bone only and decline of Fe concentration in stomach and Cu in liver and kidney. In the NaAl(OH)2CO3-treated group the increase in Al concentration was significant in bone; there was no change in concentration of essential elements in the examined tissues. The observed aluminium accumulation was not accompanied by changes in Ca and Mg concentration except for bone. This study showed that oral administration as a route of Al exposure can result in diverging accumulation of aluminium in tissues, the concentration depending on the chemical form.     

Lack of Maternal and Developmental Toxicity in Mice Given High Doses of Aluminium Hydroxide and Ascorbic Acid During Gestation

The present study was conducted to assess if the concurrent ingestion of high doses of aluminium hydroxide and ascorbic acid might result in maternal and developmental toxicity in mice. Three groups of pregnant Swiss mice were given by gavage daily doses of aluminium hydroxide (300 mg/kg), ascorbic acid (85 mg/kg), or aluminium hydroxide (300 mg/kg) concurrent with ascorbic acid 85 (mg/kg) on gestational days 6-15. A fourth group of animals received distilled water and served as control group. Dams were killed on gestation day 18 and foetuses were examined for external, internal, and skeletal abnormalities. The reproductive data did not show embryotoxic or foetotoxic effects in any group. No gross, internal, or skeletal malformations or variations related to the different treatments were found. There were no significant differences between control and treated groups on the aluminium levels in maternal liver and bone as well as in whole body foetuses, whereas aluminium concentrations were significantly higher in placenta and kidney of dams receiving aluminium hydroxide and aluminium hydroxide plus ascorbic acid than in those from the control group. Although in this study aluminium hydroxide was given at doses higher than those usually consumed by pregnant women, no signs of maternal or developmental toxicity were observed when the compound was given alone or concurrently with high doses of ascorbic acid.     

Acute acid exposure of rainbow trout,Salmo gairdneri Richardson: Effects of aluminium and calcium on ion balance and haematology

Rainbow trout, acclimated to low environmental calcium (38 μEq/1) were acutely exposed to either acid water (pH 4.1) or acid water with aluminium (350 μg/1) for 3.5 h. The exposure to Al in acid water provoked a massive whole body ion loss of sodium, chloride and potassium which was twice as high as in fish exposed to acid water. It is demonstrated that the branchial ion loss increased, while the urinary ion loss remained the same in acid + Al conditions compared to control conditions. The presence of higher ambient Ca-levels (190 μEq/1) had no moderating effect on the toxicity of Al to the ion balance. Plasma ion levels and plasma osmolality declined in Al-exposed fish, indicating a possible disturbance of the osmotic equilibrium between the intracellular and extracellular compartments. This phenomenon could also give rise to a swelling of the red blood cells, thus explaining the observed higher haematocrit value in Al-exposed trout.     

慢性神经痛大鼠鞘内联合应用吗啡和氯胺酮在脊髓上水平的抗伤害性作用及对吗啡耐受的影响

目的研究鞘内联合应用吗啡和氯胺酮对慢性神经痛大鼠的抗伤害作用机制及对吗啡耐受的影响。方法 40只Wistar大鼠,体质量220～260 g,制备坐骨神经结扎模型并进行鞘内置管,随机分为5组(n=8):B组为空白对照组;C组鞘内注射0.9%盐水10μL;K组鞘内注射氯胺酮50μg;M组鞘内注射吗啡20μg;KM组鞘内注射吗啡10μg和氯胺酮25μg。坐骨神经结扎术后第4天开始鞘内给药,每日1次,连续7 d。用药7d后处死大鼠,取大脑皮质、海马、脑干组织,硝酸还原酶法测定NO浓度和NOS活性。结果与B组比较,C和K组脑干NO浓度升高,M组皮质、海马、脑干中NO浓度均升高;与C组比较,M组皮质、海马NO浓度升高,KM组海马、脑干中NO浓度降低;与M组比较,KM组皮质、海马、脑干NO浓度均降低(P<0.05或0.01)。与B组比较,C、K和M组皮质、海马、脑干中NOS活性均升高;与C和M组比较,KM组皮质、海马、脑干中NOS活性均降低(P<0.05或0.01)。结论神经病理性痛大鼠鞘内联合应用吗啡和氯胺酮可在脊髓上水平产生抗伤害性作用,并可抑制吗啡耐受的形成,这可能与大脑皮质、海马、脑干的NO水平和NOS活性有关。     

Cholinergic system under aluminium toxicity in rat brain

The present investigation envisages the toxic effects of aluminium on the cholinergic system of male albino rat brain. Aluminium toxicity (LD(50)/24 h) evaluated as per Probit method was found to be 700 mg/kg body weight. One-fifth of lethal dose was taken as the sublethal dose. For acute dose studies, rats were given a single lethal dose of aluminium acetate orally for one day only and for chronic dose studies, the rats were administered with sublethal dose of aluminium acetate once in a day for 25 days continuously. The two constituents of the cholinergic system viz. acetylcholine and acetylcholinesterase were determined in selected regions of rat brain such as cerebral cortex, hippocampus, hypothalamus, cerebellum, and pons-medulla at selected time intervals/days under acute and chronic treatment with aluminium. The results revealed that while acetylcholinesterase activity was inhibited, acetylcholine level was elevated differentially in all the above mentioned areas of brain under aluminium toxicity, exhibiting area-specific response. All these changes in the cholinergic system were subsequently manifested in the behavior of rat exhibiting the symptoms such as adipsia, aphagia, hypokinesia, fatigue, seizures, etc. Restoration of the cholinergic system and overt behavior of rat to the near normal levels under chronic treatment indicated the onset of either detoxification mechanisms or development of tolerance to aluminium toxicity in the animal which was not probably so efficient under acute treatment.     

Differential responses of certain brain phosphoesterases to aluminium in dietary protein adequacy and inadequacy.

The aluminium-induced neurotoxic consequences include, among other factors, dephosphorylation, phosphorylation as well as hyperphosphorylation of specific macromolecules. Accordingly, activities of phosphoesterases were measured in different regions of rat brain, maintained with either adequate or inadequate protein diet, following aluminium exposure. Male Wistar rats weighing 80-100 g were treated with aluminium chloride at a dose of 15% of the LD50 for 4 weeks. In different regions of the brain of aluminium-exposed rats, significant variation in both phosphomonoesterase and phosphodiesterase activities have been recorded. These alterations were found to be varied when the rats were subjected to dietary protein insufficiency. These findings demonstrate the specificity of aluminium on different phosphoesterases. These regional variations may be attributed to the accumulated level of aluminium or may be due to cellular localization of these enzymes and linked to whether the enzymes are compartmentalized with different aluminium hydration species.     

Compartmental model for aluminium biokinetics

An open compartmental model for describing aluminium biokinetics is presented with a central compartment consisting of transferrin- and citrate-bound aluminium in blood plasma and interstitial fluid, and three peripheral compartments for organs, muscles and bones and the gastro-intestinal tract. The rate constants describing the transport of aluminium are normalized to an estimated plasma volume and do not depend on the size of the individual. Effects due to changes in compartmental sizes or to transport characteristics are described. The model is applied to biokinetics studies of a volunteer after i.v. administration and of Sprague-Dawley rats with different iron status and with nephrectomization after p.o. administration of 26Al.     

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD): results of a 13-week oral toxicity study in rats.

Rats were given 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at dosages of 0, 0.001, 0.01, 0.1, or 1.0 μg/kg, 5 days/wk for 13 wk. Doses of 1.0 μg TCDD/kg/day caused some mortality, inactivity, decreased body weights and food consumption, icterus, increased serum bilirubin and alkaline phosphatase, pathomorphologic changes in the liver, lymphoid depletion of the thymus and other lymphoid organs, increased urinary excretion of porphyrins and delta-aminolevulinic acid, and minimal alterations of some hematopoietic components. Morphological evidence of a functional suppression of the reproductive organs was consistent with either a direct toxic effect of this dose of TCDD, or an indirect toxic effect associated with the poor physical condition of these rats. Doses of 0.1 μg TCDD/kg/day caused decreased body weights and food consumption, and slight degrees of liver degeneration and lymphoid depletion. Other effects seen only in females given this dose level included increases in urinary excretion of coproporphyrin and delta-aminolevulinic acid and increases in serum alkaline phosphatase and bilirubin. Effects seen only in males given this dose level included a depression of some hematologic parameters (packed cell volume, red blood cells, and hemoglobin). In rats given 0.01 or 0.001 μg TCDD/kg/day, all parameters were essentially unaffected, except for a slight increase in the mean liver-to-body-weight ratio in rats given 0.01 μg TCDD/kg/day. This slight increase in relative liver weight was not considered of any toxicological significance. These data indicate that no discernible ill effects occurred in rats given 0.01 or 0.001 μg TCDD/kg 5 days/wk for 13 wk.     

Effect of aluminium hydroxide and glycopyrrhonium on the absorption of ethambutol and alcohol in man.

1 The effect of aluminium hydroxide and/or of glycopyrrhonium on the absorption of a single oral 50 mg/kg dose of ethambutol (EMB) was investigated on thirteen tuberculous in-patients and on two groups of healthy volunteers with six subjects each. The EMB concentrations in serum and 10+h urine were measured by colorimetry. 2 In order to assess gastric emptying the healthy volunteers ingested ethanol, either 0.5 g/kg in 10% solution or 0.8 g/kg in 20% solution, simultaneously with the drug, and breath alcohol levels were measured repetitively. 3 Aluminium hydroxide significantly lowered the serum EMB levels of the patients during the first 4 h after the EMB intake. No consistent effect was found in the first student experiment, whereas in the second experiment aluminium hydroxide and glycopyrrhonium, alone or in combination, clearly retarded the EMB absorption. 4 Repeated breath alcohol analysis proved unsuitable to indicate the time course of gastric emptying in these circumstances.     

Effects of retinoic acid on rat bone

The effects of retinoic acid on rat bones were investigated. Fifteen adult male Sprague-Dawley rats were given various oral doses of retinoic acid (0-20 mg/kg body weight/day, 5 days/wk) and were killed after various treatment periods (1-17 wk). Histological and microradiographic examination of the bones showed the presence of lesions, the development of which was dependent on the dose and the duration of treatment. These lesions were characterized by a dissolution of bone matrix, leaving only fibrils, by osteocytic osteolysis and by an increase in osteoclastic resorption.