RESUMO
Chromosome instability (CIN) consists of high rates of structural and numerical chromosome abnormalities and is a well-known hallmark of cancer. Aluminum is added to many industrial products of frequent use. Yet, it has no known physiological role and is a suspected human carcinogen. Here, we show that V79 cells, a well-established model for the evaluation of candidate chemical carcinogens in regulatory toxicology, when cultured in presence of aluminum-in the form of aluminum chloride (AlCl3) and at concentrations in the range of those measured in human tissues-incorporate the metal in a dose-dependent manner, predominantly accumulating it in the perinuclear region. Intracellular aluminum accumulation rapidly leads to a dose-dependent increase in DNA double strand breaks (DSB), in chromosome numerical abnormalities (aneuploidy) and to proliferation arrest in the G2/M phase of the cell cycle. During mitosis, V79 cells exposed to aluminum assemble abnormal multipolar mitotic spindles and appear to cluster supernumerary centrosomes, possibly explaining why they accumulate chromosome segregation errors and damage. We postulate that chronic aluminum absorption favors CIN in mammalian cells, thus promoting carcinogenesis.
Assuntos
Cloreto de Alumínio , Instabilidade Cromossômica/efeitos dos fármacos , Cromossomos de Mamíferos/metabolismo , Quebras de DNA de Cadeia Dupla , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Alumínio/farmacocinética , Alumínio/toxicidade , Cloreto de Alumínio/farmacocinética , Cloreto de Alumínio/toxicidade , Animais , Linhagem Celular , Centrômero/metabolismo , CricetulusRESUMO
A sufficient quantitative understanding of aluminium (Al) toxicokinetics (TK) in man is still lacking, although highly desirable for risk assessment of Al exposure. Baseline exposure and the risk of contamination severely limit the feasibility of TK studies administering the naturally occurring isotope 27Al, both in animals and man. These limitations are absent in studies with 26Al as a tracer, but tissue data are limited to animal studies. A TK model capable of inter-species translation to make valid predictions of Al levels in humans-especially in toxicological relevant tissues like bone and brain-is urgently needed. Here, we present: (i) a curated dataset which comprises all eligible studies with single doses of 26Al tracer administered as citrate or chloride salts orally and/or intravenously to rats and humans, including ultra-long-term kinetic profiles for plasma, blood, liver, spleen, muscle, bone, brain, kidney, and urine up to 150 weeks; and (ii) the development of a physiology-based (PB) model for Al TK after intravenous and oral administration of aqueous Al citrate and Al chloride solutions in rats and humans. Based on the comprehensive curated 26Al dataset, we estimated substance-dependent parameters within a non-linear mixed-effect modelling context. The model fitted the heterogeneous 26Al data very well and was successfully validated against datasets in rats and humans. The presented PBTK model for Al, based on the most extensive and diverse dataset of Al exposure to date, constitutes a major advancement in the field, thereby paving the way towards a more quantitative risk assessment in humans.
Assuntos
Cloreto de Alumínio/toxicidade , Ácido Cítrico/toxicidade , Modelos Biológicos , Administração Intravenosa , Administração Oral , Adulto , Cloreto de Alumínio/administração & dosagem , Cloreto de Alumínio/farmacocinética , Animais , Ácido Cítrico/administração & dosagem , Ácido Cítrico/farmacocinética , Conjuntos de Dados como Assunto , Feminino , Humanos , Masculino , Dinâmica não Linear , Ratos , Medição de Risco , Especificidade da Espécie , Distribuição Tecidual , ToxicocinéticaRESUMO
The present study was designed to investigate the nephroprotective effect of bromelain against oxidative stress stimulated by aluminium chloride in rats. Rats were grouped as follows; group one was used as control while groups 2, 3 and 4 were treated orally with bromelain (250â¯mg/kg, daily), aluminium chloride (AlCl3; 34â¯mg/kg BW, every other day) and bromelain plus AlCl3 for 30 days, respectively. Administration of AlCl3 caused a significant reduction in rats' body and kidney weights, and increased Al accumulation in kidney tissue. Also, AlCl3 treatment elevated thiobarbituric acid reactive substances, hydrogen peroxide, kidney functions biomarkers levels and lactate dehydrogenase activity. While enzymatic (SOD, CAT, GPx, GR, GST) and non-enzymatic (GSH) antioxidants, protein content, and alkaline phosphatase activity were significantly decreased. In addition, significant alterations in lipid and protein profiles were detected. Furthermore, histopathological and immunohistochemical variations were seen in kidney sections supporting the obtained biochemical changes. Otherwise, rats supplemented with bromelain singly declined lipid peroxidation and improved most of the studied parameters. Moreover, rats pretreated with bromelain followed by AlCl3 intoxication showed significant alleviation in lipid peroxidation, antioxidant status and biochemical indices with respect to AlCl3 treated group. Conclusively, bromelain has beneficial protective effects and has the capability to counteract the toxic influence of AlCl3. So, bromelain might represent a novel approach in the therapy of metal toxicity because of its antioxidant and chelating properties.
Assuntos
Injúria Renal Aguda/tratamento farmacológico , Cloreto de Alumínio/toxicidade , Bromelaínas/uso terapêutico , Substâncias Protetoras/uso terapêutico , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Fosfatase Alcalina/metabolismo , Cloreto de Alumínio/farmacocinética , Animais , Bromelaínas/farmacologia , Glutationa/metabolismo , Peróxido de Hidrogênio/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , L-Lactato Desidrogenase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Ratos Wistar , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
Although aluminum chronic neurotoxicity is well documented, there are no well-established experimental protocols of Al exposure. In the current study, toxic effects of sub-chronic Al exposure have been evaluated in outbreed male rats (gastrointestinal administration). Forty animals were used: 10 were administered with AlCl3 water solution (2 mg/kg Al per day) for 1 month, 10 received the same concentration of AlCl3 for 3 month, and 20 (10 per observation period) saline as control. After 30 and 90 days, the animals underwent behavioral tests: open field, passive avoidance, extrapolation escape task, and grip strength. At the end of the study, the blood, liver, kidney, and brain were excised for analytical and morphological studies. The Al content was measured by inductively coupled plasma mass-spectrometry. Essential trace elements-Co, Cr, Cu, Fe, Mg, Mn, Mo, Se, and Zn-were measured in whole blood samples. Although no morphological changes were observed in the brain, liver, or kidney for both exposure terms, dose-dependent Al accumulation and behavioral differences (increased locomotor activity after 30 days) between treatment and control groups were indicated. Moreover, for 30 days exposure, strong positive correlation between Al content in the brain and blood for individual animals was established, which surprisingly disappeared by the third month. This may indicate neural barrier adaptation to the Al exposure or the saturation of Al transport into the brain. Notably, we could not see a clear neurodegeneration process after rather prolonged sub-chronic Al exposure, so probably longer exposure periods are required.