Changes in elemental homeostasis and gene expression profile under subchronic hydroxide intoxication with aluminum

Introduction. Aluminum hydroxide (Al(OH)₃) is widely used in industry and medicine, but its toxic properties when it ingested are of concern. According to various authors, aluminum can affect the homeostasis of essential elements and other cellular functions. The present study is devoted to the study of the dose-dependent toxic effect of aluminum hydroxide on changes in the concentration of essential elements in the organs of laboratory animals and the expression profile of genes involved in pathogenesis.Materials and methods. The study was conducted on female white outbred rats weighing 180–200 g, which were orally administered aluminum hydroxide (Al(OH)3) at doses of 0.015 mg/kg, 0.15 mg/kg, and 1.5 mg/kg for 28 days. Analysis of liver and kidney tissue for the content of aluminum and essential elements (calcium, magnesium, iron) was carried out using atomic absorption spectrometry. The expression of metallothionein genes (Mt1a, Mt2a, Mt3) and zinc transporter genes (ZIP) was studied using the real-time PCR method. Statistical analysis was performed using the Bootstrap method and the Holm-Bonferroni correction (p<0.05).Results. The results of this study demonstrated a dose-dependent increase in aluminum content in the kidneys and liver in rats, with the most pronounced changes recorded at doses of 0.015 mg/kg and 1.5 mg/kg. Significant changes in the concentrations of calcium, magnesium, and iron in the kidneys were also revealed. The experiment showed oral administration of aluminum hydroxide to lead to a decrease in the levels of magnesium and iron in the liver in rats. The expression of metallothionein genes and the ZIP gene in the kidneys in rats also showed a significant suppression at low doses of aluminum hydroxide, with a maximum increase in expression at a dose of 1.5 mg/kg. Mt1a and Mt2a gene expression was decreased by aluminum hydroxide administration. The correlation between magnesium levels and ZIP gene expression highlights the influence of trace elements on metabolic processes and renal defense mechanisms.Limitations. Our study faces several limitations. First, molecular genetic markers may not fully reflect the diversity of body responses. Second, individual differences may significantly affect the results. Finally, extrapolation of data to humans is difficult due to differences in species-specific metabolic features.Conclusion. The study showed that aluminum hydroxide causes dose-dependent toxic effects by disrupting trace element homeostasis and altering gene expression, including metallothioneins and ZIP. These results highlight the need for further research to understand the mechanisms of intoxication and develop preventive strategies to protect the body.Compliance with ethical standards. The study was approved by the local ethics committee of the Ufa Research Institute of Occupational Medicine and Human Ecology of Rospotrebnadzor (protocol No.02–04 of 18.04.2024), and was conducted in accordance with the European Convention for the Protection of Vertebrate Animals Used for Experiments or for Other Scientific Purposes.Contribution: Usmanova E.N. – study concept and design, material collection and data processing, chemical analysis, writing the text; Karimov D.O. – study concept and design, editing, statistical processing;Daukaev R.A. – material collection and data processing, literature data collection; Valova Ya.V. – genetic analysis, editing; Smolyankin D.A. – study design, seeding, material collection; Karimov D.D. – animal care; Adieva G.F. – literature data collection and results processing. All authors are responsible for the integrity of all parts of the manuscript and approval of the manuscript final version.Conflict of interest. The authors declare no conflict of interest.Acknowledgment. The study was carried out within the framework of the industry research program of the Federal Service for Supervision in Protection of the Rights of Consumer and Man Wellbeing for 2021–2025 “Scientific substantiation of the national system for ensuring sanitary and epidemiological well-being, managing health risks and improving the quality of life of the population of Russia”, R & D “Experimental substantiation of highly sensitive markers of the impact of toxic metals on the body and the development of preventive measures”, registration No. 223122100004-3.Received: October 17, 2024 / Accepted: December 3, 2024 / Published: April 30, 2025

aluminum, essential elements, gene expression, toxicity, homeostasis