Simultaneous effects of aluminum exposure on the homeostasis of essential metal content in rat brain and perturbation of gut microbiota.

The theory of the brain-gut axis has confirmed that gut microbiota and metabolites are involved in the progression of neurodegenerative diseases through multiple pathways. However, few studies have highlighted the role of gut microbiota in cognitive impairment induced by aluminum (Al) exposure and its correlations with the homeostasis of essential metal content in the brain. To explore the relationship between alterations in the content of essential metals in the brain and relative abundance changes in gut microbiota induced by Al exposure, the Al, zinc (Zn), copper (Cu), iron (Fe), chromium (Cr), manganese (Mn), and cobalt (Co) content level in the hippocampus, olfactory bulb, and midbrain tissue were measured by inductively coupled plasma mass spectrometry (ICP-MS) methods after Al maltolate was intraperitoneally injected every other day for exposed groups. Then the unsupervised principal coordinates analysis (PCoA) and linear discriminant analysis effect size (LEfSe) were used to analyze the relative abundance of the gut microbiota community and the structure of the gut microbiome. Finally, the correlations between gut microbiota composition and essential metal content in the different exposure groups were explored by using the Pearson correlation coefficient method. Based on the results, we indicated that the content of Al in the hippocampus, olfactory bulb, and midbrain tissue was increased and then decreased with the increasing exposure duration, with peaks occurring between 14 and 30 days. Concomitantly, Al-exposure decreased the Zn, Fe, and Mn levels in these tissues. 16 S rRNA gene sequencing results indicated that significant differences in the intestinal microbial community structure at the phylum, family, and genus levels were found in the Day 90 exposed group compared with the Day 7 exposed group. Ten enriched species in the exposed group were identified as markers at the three levels. Furthermore, ten bacteria at the genus level were identified to have a significantly strong correlation (r = 0.70-0.90) with Fe, Zn, Mn, and Co.

Involvement of Mitophagy in Primary Cultured Rat Neurons Treated with Nanoalumina.

The aim of this study was to explore the influence of the neurotoxicity of nanoalumina on primarily cultured neurons. Normal control, particle size control, aluminum, micron-alumina, and nanoalumina at 50-nm and 13-nm particle sizes were included as subjects to evaluate the level of apoptosis, necrosis, and autophagy in primarily cultured neurons and further explore the mitophagy induced by nanoalumina. The results demonstrated that nanoalumina could induce neuronal cell apoptosis, necrosis, and autophagy, among which autophagy was the most notable. When the autophagy inhibitor was added to the nanoalumina-treated group, it significantly downregulated the protein expression levels of Beclin-1 and LC3II/LC3. Observation under a transmission electron microscope and a fluorescence microscope revealed mitophagy characteristics induced by nanoalumina. Additionally, the neurotoxicological effects induced by nanoalumina were more significant than those induced by aluminum and in a particle size-dependent manner.

Necrostatin-1 Relieves Learning and Memory Deficits in a Zebrafish Model of Alzheimer's Disease Induced by Aluminum.

Aluminum (Al) is considered one of the environmental risk factors for Alzheimer's disease (AD). The present study aims to establish a zebrafish AD model induced by Al and explore if necrostation-1 (Nec-1), a specific inhibitor of necroptosis, is effective in relieving learning and memory deficits in the zebrafish AD models. We treated adult zebrafish with aluminum trichloride at various doses for 1 month, followed by a T-maze test to evaluate learning and memory performance. Al concentration, levels of acetylcholine (Ach), and AD-related protein and gene expression in the brain tissue were evaluated in the zebrafish AD models. Our results demonstrated that in the brain tissue of Al-treated zebrafish, Al accumulated, Ach levels decreased, and AD-related genes and proteins increased. As a result, the learning and memory performance of Al-treated zebrafish was impaired. This suggested that a zebrafish AD model was established. To test the effect of Nec-1 on the zebrafish AD model, we added Nec-1 into the culture medium of the Al-treated adult zebrafish. The results demonstrated that Nec-1 could relive the learning and memory deficits, enhance Ach levels and the numbers of neural cells, and impact necroptosis-related gene expression. We concluded that Nec-1 could reverse Al-induced learning and memory impairment and had potential theoretical value in the zebrafish AD model.

Neurodevelopmental toxicity of alumina nanoparticles to zebrafish larvae: Toxic effects of particle sizes and ions.

The aim of this study was to explore the mechanism of neurodevelopmental toxicity of alumina nanoparticles (AlNPs) on zebrafish larvae, specifically, the toxic effects of AlNPs of different particle sizes and of dissolved aluminum ions. AlNPs with sizes of 13 nm (13 nm-Al) and 50 nm (50 nm-Al) were used as the main research objects; while nanocarbon particles with sizes of 13 nm (13 nm-C) and 50 nm (50 nm-C) as particle-size controls; and an aluminum chloride solution (Al3+) as an ion control. Zebrafish embryos were exposed to different treatments from 6 h post-fertilization (hpf) to 168 hpf. Deformities were observed at different time points. Neurodevelopmental behavior tests were carried out, and oxidative stress responses and transcriptional alterations in autophagy-related genes were assessed. Malformations occurred in the 13 nm-Al, 50 nm-Al, and Al3+ treated groups at different developmental stages of zebrafish larval, but no malformations were observed in the 13 nm-C or 50 nm-C groups. In addition, the average speed, distance travelled and thigmotaxis in zebrafish larvae decreased in the AlNPs treated group, and the effects were related to the particle sizes. Furthermore, increases in the oxidative stress response and autophagy-related genes expression were also related to the particle sizes of AlNPs as well. In conclusion, the mechanism underlying the neurodevelopmental toxicity of AlNPs on zebrafish larvae mainly depended on the size of the nanoparticles, and dissolved Al3+ also contributes to the toxic effects.

Increased aluminum and lithium and decreased zinc levels in plasma is related to cognitive impairment in workers at an aluminum factory in China: A cross-sectional study.

BACKGROUND: Previous studies have shown that multiple imbalances of metal ions in the brain are closely associated with the neurodegenerative disorders. Our studies have shown that long-term working exposure to aluminum induces increased plasma aluminum levels and causes cognitive impairment in workers at aluminum factories. OBJECTIVE: To explore the levels of nine metals in plasma and the effect on cognitive function among in-service workers. METHODS: In this cross-sectional study, cognitive function was assessed using the Montreal Cognitive Assessment (MoCA), which included seven subitems: executive/visuospatial abilities; naming; attention and calculation; language; abstract; recall; and orientation. The plasma levels of nine kinds of metals were measured by inductively coupled plasma-mass spectrometry (ICP-MS). A multivariate generalized linear regression model and Bayesian kernel machine regression (BKMR) were selected to estimate the relationship between metal plasma level and MoCA scores with adjustment for confounders. RESULTS: One hundred and eighty-seven workers participated in this study. In the multivariable generalized linear model, among these nine metals studied, five were related to the MoCA score: aluminum, lithium, cobalt, zinc and chromium. In the BKMR model, a significantly negative correlation between the plasma aluminum, lithium and the total MoCA score was observed. Moreover, for subitems on the MoCA scale, the plasma levels of lithium, aluminum, and zinc had a significant correlation with the executive/visuospatial abilities, naming, and orientation abilities, respectively. The log-transformation concentrations of plasma aluminum and lithium were negatively correlated with the executive/visuospatial abilities and naming abilities, respectively. The log-transformation plasma zinc concentration was positively correlated with orientation abilities. CONCLUSION: Based on the results, we determined that increased aluminum and lithium and decreased zinc levels in plasma were associated with the incidence of mild cognitive impairment (MCI) in workers at a Chinese aluminum plant.

Involvement of Mitophagy in Aluminum Oxide Nanoparticle-Induced Impairment of Learning and Memory in Mice.

Aluminum oxide nanoparticles (nano-aluminum) have been known to be widespread in the environment for decades. Exposure to nano-aluminum may impair learning and memory, but the potential mechanism has not yet been elucidated. In neurons, efficient clearance of damaged mitochondria through mitophagy plays an important role in mitochondrial energy supply, neuronal survival, and health. However, abnormal mitophagy induces accumulation of damaged mitochondria, which induces cellular dysfunction, contributing to the impairment of learning and memory. It is currently unclear whether nano-aluminum interferes with the function of nerve cells through mitophagy, leading to learning and memory disorders. Institute of Cancer Research (ICR) female mice were randomly divided into four groups, and treated with normal saline (control) and 50 nm nano-aluminum at concentrations of 25, 50, and 75 mg/kg for 30 days. Our results showed that exposure to nano-aluminum impaired the spatial learning and memory of mice. Superoxide dismutase levels decreased, whereas the levels of malondialdehyde increased. Moreover, there were significant pathological changes in the ultra-structure and function of mitochondria. Finally, expression of autophagy-related proteins LC3-II and Beclin-1 was upregulated and p62 expression decreased, but the expression of apoptotic and necrosis-related proteins had no significant difference among groups. Our results suggest that learning and memory impairment induced by nano-aluminum could be related to mitophagy.