Industrial production activities result in the emission of a wide range of chemical compounds into the environment, many of which are potentially hazardous to human health. Long-term, continuous exposure to these compounds, including combined exposure, is a major risk factor for adverse health outcomes. Steelworks adversely affect urban and industrial areas, primarily through emissions of dust and gas mixtures. These emissions have a complex chemical composition and may interact synergistically or additively, thereby amplifying their adverse effects on human health [1].

Aluminum production is associated with the simultaneous atmospheric emission of three specific pollutants: aluminum oxide, hydrofluoride, and benzo[a]pyrene. These substances exert a pronounced multisystem toxic effect on the human body, primarily affecting the respiratory, nervous, musculoskeletal, and immune systems. This contributes to additional health and demographic losses through increased morbidity and reduced life expectancy. Numerous adverse health effects associated with exposure to these airborne pollutants have been observed in exposed populations [2]. This hygienic problem underscores the need to develop and implement targeted technologies and medical-preventive programs at both the individual and population levels, aimed at reducing the health risks associated with exposure to airborne aluminum oxide, hydrofluoride, and benzo[a]pyrene [3].

Accordingly, some of the intensively investigated subjects are proactive identification and in-depth analysis of risks associated with exposure to airborne pollutants, and improvement of the predictive capacity of methods for early diagnosis and prevention of adverse health effects [3, 4]. Ensuring the high reliability and objectivity of the results requires development and deployment of modern biotechnologies [5]. Currently, proteomic analysis is a central component of the cluster of omics technologies that underpin the study of physiological and pathological processes at the cellular and molecular levels. Characterization of changes in the protein composition of biological fluids and matrices, such as plasma, serum, and urine, enables the prediction of adverse outcomes at their early stages, before cellular, tissue, or organ-system damage becomes clinically apparent [6].

Therefore, a detailed understanding of the molecular mechanisms underlying the toxicity of chemicals, including oxidative stress-inducing air pollutants such as aluminum oxide, hydrofluoride, and benzo[a]pyrene, is required to enhance the predictive potential of biomarker-based diagnostics. A particularly important area of investigation is the disruption of intracellular signaling pathways that trigger cascades of oxidative-stress reactions and mitochondrial toxicity, as such alterations underlie the pleiotropic oxidative-stress effects of the airborne pollutants studied.

This study aimed to systematically review the literature on how combined exposure to airborne pollutants induces oxidative stress and alters the proteomic profile through structure-dependent molecular mechanisms.

Methods

The review included studies from eLIBRARY, PubMed, Google Scholar, Web of Science, and Scopus that investigated cellular, molecular, and related systemic disorders in the human body induced by pollutants that cause oxidative stress, with aluminum oxide, hydrofluoride, and benzo[a]pyrene used as examples of such pollutants. The search was based on keywords "target proteins,"  "aluminum," "fluorine," "benzo[a]pyrene," "molecular mechanisms," "proteomic profile," "oxidative stress," and "adverse effects." We included original research articles and reviews published between 2015 and 2026, as well as earlier studies where necessary. We excluded papers whose full text was inaccessible, works addressing irrelevant topics, conference abstracts, and studies that did not examine cellular, molecular, or related systemic disorders in the human body caused by oxidative stress–inducing pollutants. Ultimately, 33 publications were selected from 206 initially identified sources and formed the basis of this review.

Cellular and molecular disorders induced by aluminum oxide, hydrofluoride, and benzo[a]pyrene in the human body

Proteomic tests are widely used to investigate the molecular mechanisms underlying the effects of chemicals and to identify the molecular events triggering adverse effects at early stages of their emergence [7]. The data from such tests are essential for mapping key events across adverse outcome pathways, enabling timely detection of the transition from disturbed homeostasis to a developing pathological process [8]. Identification of these transitions provides deeper insight into the molecular mechanisms of the adverse effects of chemicals, including oxidative stress-inducing pollutants such as aluminum oxide, hydrofluoride, and benzo[a]pyrene [7, 8].

Aluminum (Al) is present in the human body but has no known essential biological function. Al³⁺ ions, like other metal cations, interact with carboxyl and phosphate groups of macromolecules, including proteins, DNA, and RNA, as well as with low-molecular-weight ligands, thereby disrupting their structure and function. Aluminum ions may activate molecular and cellular mechanisms underlying oxidative stress, cytotoxicity, genotoxicity, proinflammatory effects, protein and enzyme dysfunction, metabolic disturbances, disruption of membranes and microtubules, and necrosis or apoptosis. These toxic effects are mediated primarily by pronounced pro-oxidant activity, which induces oxidative stress through free-radical-mediated damage and oxidative modification of cellular proteins and lipids [9]. Aluminum can also inhibit key antioxidant enzymes, such as superoxide dismutase and glutathione peroxidase, thereby weakening endogenous antioxidant defenses and exacerbating oxidative damage [10].

The effects of aluminum ions on hepatocytes include inhibition of ATP production and glycolysis, as well as disruption of tricarboxylic acid cycle function. Consequently, lipid peroxidation and oxidative modification of proteins are activated, driving a metabolic shift toward lipogenesis in tissues. As the principal ATP-generating pathways become impaired, metabolic flux is redirected toward lipid synthesis, indicating mitochondrial dysfunction. The resulting energy deficit increases cellular vulnerability to oxidative damage and activates cell death mechanisms [11]. Particular attention should be paid to the apoptotic cascade involving c-Jun N-terminal kinase (JNK). Activation of this cascade can initiate programmed cell death, which may explain the ability of aluminum ions to induce apoptosis [12].

In addition to its direct cytotoxic and proapoptotic effects, aluminum can induce an inflammatory response. Exposure has been associated with increased levels of the proinflammatory cytokines IL-1β and TNF-α, upregulated TNF-α gene expression, and elevated levels of the macrophage inflammatory protein MIP-1α. Oxidative stress, which activates inflammatory signaling pathways, appears to be the key driver of these effects. Consequently, leukocytes are recruited to the damaged region and secrete cytokines and chemokines. Thus, aluminum may trigger chronic low-grade inflammation, contributing to tissue damage and acting as a pathogenetic link in the development of adverse effects [13].

The toxicity of fluoride is attributable to its high chemical and biological reactivity. Studies using radioactive isotopes have shown that the distribution of fluoride in tissue depends on the transmembrane pH gradient. In most tissues, fluoride concentrations are 10−50% lower than in blood plasma. Equilibrium between plasma and highly vascularized organs, such as the heart, lungs, and liver, is reached more rapidly than in poorly vascularized tissues [14].

The effects of fluoride ions on physiological functions and cellular metabolism depend on the cell type, the fluoride concentration in the body, and the duration of exposure. In bone tissue and teeth, micromolar concentrations of fluoride stimulate cell proliferation, whereas millimolar concentrations inhibit proliferation and induce apoptosis, indicating a dose-dependent effect [15]. Fluoride ions can increase the production of superoxide anion radicals in osteoblast mitochondria while simultaneously reducing cellular oxygen utilization and slowing down the synthesis of superoxide dismutase, catalase, and glutathione peroxidase. This imbalance promotes the accumulation of free radicals, the development of oxidative stress, and damage to cellular structures [16].

Mitochondrial cytotoxicity plays a particularly important role in the pathogenesis of fluoride toxicity. It reduces mitochondrial transmembrane potential and promotes opening of the mitochondrial permeability transition pore [17]. These changes lead to swelling of the mitochondrial matrix, rupture of the outer mitochondrial membrane, and release of cytochrome c from the intermembrane space into the cytosol. The resulting impairment of the respiratory chain suppresses ATP synthesis and promotes the generation of reactive oxygen species (ROS), thereby exacerbating oxidative damage. In addition, fluoride ions disrupt the barrier properties of mitochondrial membranes, thereby inducing apoptosis in various tissues [14, 18].

Prolonged exposure to fluoride compounds is a significant risk factor for the development of cardiometabolic disorders, including hypertension and dyslipidemia [19]. Fluoride may alter the concentrations of hormones involved in thyroid regulation (TSH, T3, and T4). The direction and magnitude of these changes are complex and depend on the duration of exposure. Because thyroid hormones are key regulators of basal metabolism and redox homeostasis, imbalance of those can impair energy metabolism, thereby contributing to the development of systemic disorders and reducing the body's adaptive capacity [20].

Benz[a]pyrene, owing to its cytotoxic and mutagenic properties, is one of the best-studied polycyclic aromatic hydrocarbons. The compound is lipophilic and therefore tends to accumulate in adipose tissue. Its metabolic activation occurs primarily in the liver, where the enzymes responsible for its biotransformation are most highly expressed. This process generates reactive intermediates that covalently bind to DNA, proteins, and lipids, initiating intracellular damage [21]. Benz[a]pyrene and its metabolites transcriptionally repress MSH2, MSH6, and EXO1, genes involved in DNA repair, thereby promoting an aging phenotype associated with the accumulation of oxidative damage [22].

In addition to its direct genotoxic effects, benzo[a]pyrene induces oxidative stress, disrupts the regulation of cell proliferation, and interferes with key signaling pathways [22]. These effects lead to alterations in the gene expression profile, which are ultimately realized in full at the proteome level. Exposure to benzo[a]pyrene causes extensive cellular changes, including cytoskeletal remodeling, activation of proteolytic systems, and dysregulation of MAPK signaling pathways [23]. Studies confirm that cellular responses to benzo[a]pyrene are dose-dependent, reflecting multilevel rearrangements of signaling cascades involving post-transcriptional, post-translational, and epigenetic regulatory mechanisms [24].

Known mechanisms of combined toxicity of aluminum oxide, benz[a]pyrene, and hydrofluoride

Assessment of the combined effects of chemicals co-occurring in the environment is one of the major challenges in modern hygiene and toxicology, as, under real-world conditions, populations are continuously exposed to a broad spectrum of airborne chemicals. Moreover, certain effects may emerge only from the combined action of several substances rather than from exposure to any single substance alone. The study of the patterns of combined action of multiple chemicals, together with the analysis and characterization of their combined toxicity, forms the basis of methodological approaches to assessing public health risks associated with multicomponent chemical pollution of the environment [25].

The combined effect of benzo[a]pyrene and aluminum oxide is particularly harmful, with the nervous system being the most vulnerable target. Benzo[a]pyrene can cause direct damage to nerve cells and induce neuroinflammation, whereas aluminum is recognized as a neurotoxicant that can accumulate in brain tissue and cause disorders of varying severity, ranging from cognitive impairment to neurodegeneration [26, 27]. Experimental data demonstrate that combined exposure produces classic signs of neuronal apoptosis: a pyknotic nuclear membrane with condensed chromatin at the periphery, widened intercellular spaces, and apoptotic bodies. These changes are more severe upon simultaneous exposure to both compounds than with either compound alone, indicating synergistic toxicity toward the central nervous system [28].

When aluminum and fluoride enter the body simultaneously, they can interact to form stable AlF₃ and AlF₄⁻complexes. Owing to their structural similarity to phosphate groups, these complexes may mimic phosphate and thereby cross biological barriers, distribute to various organs and tissues, and interfere with key cellular processes. The stability and bioavailability of these complexes depend on pH and on the initial concentrations of the constituent ions [29]. Their effects are most pronounced in bone tissue, as demonstrated by several in vitro experiments. In one study, osteoblasts were cultured in a medium containing NaF and AlCl₃, revealing a synergistic interaction between the two compounds. This interaction enhanced the expression of Runx2 and Osterix, key transcription factors involved in early osteogenesis and subsequent bone mineralization [30]. In addition to directly damaging osteoblasts, aluminum and fluoride exert a substantial combined effect on bone resorption. In primary cultures of bone marrow macrophages, AlF₄⁻has been shown to activate G proteins, thereby triggering intracellular signaling cascades that may enhance RANKL-mediated osteoclastogenesis. Because RANKL is a key cytokine stimulating osteoclast formation and activity, its overexpression in response to AlF₄⁻ may promote increased bone resorption and bone loss [29, 31].

In the available literature, information on the combined action of fluoride and benzo[a]pyrene remains limited. Quantum chemical modeling suggests that fluorine substitution destabilizes key carbocation intermediates formed during the metabolic activation of benzo[a]pyrene. This molecular mechanism may explain the observed decrease in its carcinogenic potential upon exposure to fluorine compounds [32].

Little information is available in the literature on the combined molecular effects of elevated concentrations of aluminum, fluoride, and benz[a]pyrene in the body. Nevertheless, a theoretical analysis incorporating the aforementioned molecular mechanisms of action of these three airborne pollutants suggests that their effects may be additive or synergistic, mediated by the induction of systemic oxidative stress. Such interactions may cause profound alterations in intracellular structures, damage to key proteins, and disruption of cellular integrity, thereby increasing the risk of tissue injury in various organs and systems.

CONCLUSION

A review of the literature has shown that the toxic effects of aluminum oxide, hydrofluoride, and benzo[a]pyrene are primarily realized through the induction of oxidative stress. At the molecular and cellular levels, aluminum ions inhibit antioxidant enzymes and induce mitochondrial dysfunction. In turn, fluoride ions enhance the production of reactive oxygen species and disrupt the respiratory chain. Benzo[a]pyrene forms reactive metabolites and impairs the repair of mismatched DNA bases. Moreover, these substances exert synergistic effects in a body, thereby exacerbating the adverse effects observed with each substance acting alone.

Proteomic analysis enables the detection of early signs of adverse effects and pathological processes, thereby expanding the possibilities for predicting and preventing health risks. An analytical synthesis of the available data, using aluminum oxide, hydrofluoride, and benzo[a]pyrene as examples, justifies the need for further in-depth investigation of the molecular mechanisms underlying the toxic effects of airborne pollutants. Such research will facilitate the introduction of integrative approaches for the assessment of health risks in populations chronically exposed to these airborne chemical pollutants.