Maurizio Perazzolo

Aluminium toxicity and metal speciation: established data and open questions

Histopathological findings in humans and extensive toxicological investigation in vivo and in vitro point to an unambiguous neurotoxic potency of AI(III). Experimental toxicology with aqueous AI(III) is very difficult owing to the complex and somewhat uncontrollable aqueous chemistry of the metal centre in the neutral range. The choice of neutral, hydrolytically stable synthetic toxins makes possible both the control of metal speciation and of analytical metal concentration down to about 1 mM in neutral buffered solutions. The employment of less stable complexes like Al2(citrate)2(H2O)6 and AI(lactate)3 or of ordinary salts is unavoidably complicated by the precipitation of Al(OH)3 under the same conditions. In spite of this, the choice of a carefully designed protocol, based on ensuring well defined steps, enables one to successfully control the analytical metal concentration down to 10 μM AI(III). The control of the metal speciation at these concentration levels remains an open question.

Aluminum(III) influences the permeability of the blood-brain barrier to [14C]sucrose in rats

To determine the influence of the metal coordination sphere on the permeability of the blood-brain barrier (BBB), rats were injected intraperitoneally with aluminum lactate (Al(lact)3), aluminum acetylacetonate (Al(acac)3), aluminum maltolate (Al(malt)3) at pH 7.5, or with physiological saline. Two h after each treatment, [14C]sucrose physiological saline solution was injected in animals, and the radioactivity was measured in 5 brain regions (cerebral cortex, mesencephalon, diencephalon, medulla-pons, cerebellum). Radioactivity was significantly elevated in brains from animals treated with Al(malt)3 (hydrolytically stable and hydrophilic), and with Al(acac)3 (hydrolytically stable and lipophilic) but not with Al(lact)3. Time-course study carried out at 2, 4 and 24 h with different aluminum compounds showed a persistent radioactivity 24 h after treatment only in the brain from animals treated with Al(acac)3. Morin stain localized AlIII only in neurons from animals treated with Al(acac)3. These findings indicate that AlIII alters the BBB function in the rat either permanently or transiently depending on the physiochemical properties of the metal coordination sphere. Implications of these results, in terms of AlIII as a potential toxic factor in humans, are considered and discussed.

Different effects of aluminum upon carbonic anhydrases and Na+/K+-ATPase activities in rat.

Aluminum (Al(III)) is a well established toxicant implicated as an etiological factor in several neuropathies. In this paper we report results regarding opposite effects produced by Al(III) on the activity of two enzymes utilized as models. While sodium-potassium ATP-ase (Na/K-ATPase) is strongly activated by Al(III) in a dose-effect dependent way, on the contrary, carbonic anhydrase (CA) is remarkably inhibited. The relevance of the metal speciation together with the enzymatic structural modification demonstrated by circular dichroism measurements could explain the observed modified enzymatic activities. In addition, a new experimental protocol for the preparation of Al(III) solutions at physiological pH useful in the standardization of Al(III) experimental toxicology is also proposed and discussed.

Tris acetylacetonate aluminium(III) induces osmotic fragility and acanthocyte formation in suspended erythrocytes.

Tris acetylacetonate aluminium(III) (Al(acac)3), dissolved in water, is effective in producing osmotic fragility in suspended erythrocytes in the concentration range of 0.034-0.34 mmol/l. Water solutions of Tris maltolate aluminium(III) (Al(malt)3) and aluminium lactate (Al(lac)3) are also effective but the dose-response behavior is less pronounced. Moreover, only Al(acac)3 induces a prominent generation of acanthocytes. The stronger effects of Al(acac)3 on membrane stability are attributed to the greater solubility of this complex in the cell membrane.

Effects of aluminum speciation on murine neuroblastoma cells

Murine neuroblastoma cells behave differently in the presence of Al(acac)3 [acac = 2,4-pentanedionate; acetylacetonate] or Al(malt)3 [malt = 3-hydroxy, 2-methyl, 4-pyronate; maltolate] with respect to Al(lac)3 [lac = 2-hydroxypropionate; lactate]. Thus, a remarkable cytotoxic effect was observed in the first case; on the contrary, an evident cytostatic and neuritogenic effect was produced by aqueous Al(lac)3. The hydrolytically stable complexes Al(acac)3 and Al(malt)3 were both toxic in the concentration range of 0.10-0.30 and 0.10-0.50 mM, respectively, over 24 h. In contrast with this behavior Al(lac)3 displayed a potent cytostatic activity with induction of neurites at 0.2-10 mM. Al(OH)3 manifested biological effects comparable to those exhibited by Al(lac)3. AlPO4 was also cytostatic and led to a morphological differentiation of the neuroblastoma cells, qualitatively different from that elicited by Al(lac)3. The morphological effects induced by Al(lac)3, Al(OH)3, and AlPO4 were irreversible.

N-Octanol/Water Partition Coefficients of the Acetylacetonate and Maltolate Complexes of Al(III), Cr(III) and Fe(III) and of Aluminum Lactate

Abstract The n-octanol/water partition coefficients of the neutral complexes M(acac)3 (M = Al, Cr and Fe; acac = actylacetonate) and M(malt)3 (M = Al and Cr; malt = 3-hydroxy-2-methyl-4-pironate) put into evidence the importance of the residual lipophilic-hydrophilic character of the metal-coordinated ligand in determining the lipophilicity of M(acac)3 and the hydrophilicity of M(malt)3. Aluminum lactate was also investigated and it results to be very hydrophilic.

A long-term toxicological investigation on the effect of tris(maltolate)aluminum(III) in rabbits

The toxicity of iv injected hydrophilic aluminum complex tris(maltolate)aluminum(III) was studied in New Zealand white rabbits for a period of time ranging from 5 to 63 wk. Animals were injected 3–5 times a week with 1 mL of 7.5 mM Al(malt)3 and one rabbit with a dose 10 times higher after 14 wk of treatment. Autopical examination was performed on all animals. Chemoclinical analysis (glucose, urea, creatinine, cholesterol, bilirubin, alanin aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyltransferase, LDH, CK, total protein, triglycerides, and Ca2+) gave no variation in treated animals with respect to the control. The toxicological data show a moderate systemic general toxicity at doses far higher than those used in similar previous experiments using Al(acac)3 (acac=2,4 pentanedionate), a hydrolytically stable and more lipophilic aluminum(III) complex (1). The diversity of behavior is discussed in terms of metal speciation as well as respect to the thermodynamic and kinetic properties of the two complexes in aqueous solution. The toxicological model presented here emphasizes that neutral, water compatible aluminum(III) complexes are to be considered as promising tools for toxicological experiments providing biological models of human pathologies.

Gallium distribution in several human brain areas

Gallium is an element of increasing biological interest: It is involved in problems related to environmental pollution (Ga compounds are used in electronics industry) and to clinical treatments (Ga radionuclides are employed to detect neoplastic lesions). Moreover, since its chemical behavior is similar to that of aluminum, gallium could play a role in the health effects attributed to this element.Data on naturally occurring Ga levels in human samples from healthy subjects are scanty; regarding the brain, the only reliable values available in the literature were published by Hamilton in 1972/73. In this work, the gallium distribution in several human brain areas, evaluated by radiochemical neutron activation analysis (RNAA), was found to be dishomogeneous. The element concentration determined in dry samples was, in any case, lower than the ppb level.