Proteomic profiling of blood plasma in chronic experimental exposure to aluminum oxide as a tool for predicting adverse effects from critical human organs and systems

Abstract

Introduction. Highly informative research methods, which include proteomic profiling, make it possible to predict the development of negative effects on the part of critical human organs and systems at the earliest stages of their formation. In combination with toxicological studies, these methods allow changes in the protein profile of blood plasma, identified in the experiment on biological models, to be extrapolated to humans. Determination of the expression, functional characteristics and tissue identity of altered proteins and peptides provides clarification of the mechanisms of homeostasis disorders at the cellular and molecular level associated with exposure to chemicals. The purpose of the work is to identify and evaluate changes in the proteomic profile of blood plasma during experimental exposure to aluminum oxide in order to predict negative effects on the part of critical human organs and systems. Materials and methods. When modelling inhalation exposure to aluminum oxide at a dose of 0.0025 mg/(kg·day), equivalent to the dose in natural exposure conditions with an annual averaging period, and taking into account interspecies dose transfer, in an experiment on Wistar rats, the content of this metal in urine and a comparative analysis of the proteomic profile of the blood plasma of exposed and unexposed individuals was carried out. Using the methods of statistical and bioinformatic analysis, the data obtained in the experiment were extrapolated to humans in order to predict negative effects on the part of critical organs and systems during chronic aerogenic exposure to aluminum. Results. With chronic inhalation intake of aluminum oxide at a dose of 0.0025 mg/(kg·day) in animals of the experimental group, the content of aluminum in the urine was 3.5 times higher than that in the control group. As a result of densitometric measurement and comparative analysis of proteomic maps of blood plasma of exposed and unexposed animals, 13 protein spots were found, the intensity of which significantly differs between groups, which was proved to be related to the aluminum content in the urine. When comparing the mass spectra of these protein spots, 8 proteins were identified that coincided with the proteins of the library mass spectrum (Actin-binding Rho-activating protein; Aldehyde dehydrogenase, cytosol 1; Apolipoprotein A-I; Sec22b protein transporting vesicles; Elongation factor 1-γ; Neurosecretory protein Vgf; Pumilio homologue 3; Teneurin-2). As a result of bioinformatics analysis, there were determined genes encoding the identified proteins, their participation in biological processes (cellular and metabolic processes, biological regulation processes) and tissues of organs in which they have an increased expression (liver, brain, heart, muscles, small intestine, spleen, uterus, testicles, adrenal glands). In humans, orthologues of established genes have been identified, which makes it possible to use the proteins identified in the experiment as markers of negative responses and to suggest the development of diseases of the cardiovascular system, liver, and brain under conditions of long-term aerogenic exposure to aluminum oxide. Limitations. The conducted study on Wistar rats simulated only chronic inhalation exposure to aluminum oxide. Conclusion. The transformation of the proteomic profile of blood plasma was established in an experiment on a biological model with chronic inhalation exposure to aluminum oxide at a dose of 0.0025 mg/(kg·day). Extrapolation of the data obtained and the detection of orthologous genes in humans suggests the development of negative effects in the form of diseases of the cardiovascular system, liver and brain with chronic inhalation intake of aluminum oxide into the body. The data obtained expand the theoretical understanding of the mechanisms of the toxic action of chemicals, including aluminum oxide compounds, at the cellular and molecular level to predict the negative effects of critical human organs and systems. Compliance with ethical standards. The study was approved by the local ethics committee of the Federal Research Center for Medical and Preventive Technologies of Public Health Risk Management of Rospotrebnadzor (minutes of the meeting No. 2 dated 11.02.2021), conducted in accordance with the generally accepted scientific principles of the Helsinki Declaration of the World Medical Association (ed. 2013).