https://orcid.org/0009-0002-3803-4444
Abstract
As an element with metalloid properties, arsenic is pervasively present in the environment and is recognized as a potent carcinogen. Consequently, the issue of human arsenic exposure has become a significant concern within the global public health sector. Numerous studies have indicated that arsenic induces cellular senescence through various mechanisms, including triggering epigenetic alterations, inducing the senescence-associated secretory phenotype (SASP), promoting telomere shortening, and causing mitochondrial dysfunction. This article collates and summarizes the latest research advancements on the involvement of cellular senescence in arsenic toxicity and explores the mechanisms of arsenic-induced toxicity. This study aims to provide new perspectives and directions for future research on arsenic toxicity and the development of prevention and treatment strategies.
Introduction
Metallic arsenic is widely distributed in air, water and soil and can enter the human body by a variety of routes, sources and exposures. Food and drinking water are the main routes of exposure to arsenic, especially in areas where groundwater naturally contains high concentrations of arsenic. Arsenic can also enter the body through the respiratory tract, and skin contact with arsenic-contaminated soil, water or other substances can also lead to arsenic absorption. Both long-term and acute arsenic exposure can pose serious health risks to humans. It is not only a potential carcinogen but also closely associated with various health conditions, including cardiovascular diseases (such as hypertension and atherosclerosis), neurological disorders, gastrointestinal issues, liver and kidney diseases, impaired sexual health, and dermal lesions. 1 Long-term exposure to inorganic arsenic has become an urgent environmental public health issue, with over 220 million people worldwide affected by its harmful effects. Cell senescence is a process in which cells cease to divide and undergo characteristic phenotypic changes, a state that can be triggered by several factors. These include intrinsic elements, such as oxidative stress and alterations in gene expression, and extrinsic factors like radiation, heavy metals, and chemotherapy. These factors lead to changes in cellular biomarkers or induce the secretion of various cytokines through different mechanisms, ultimately affecting the normal function of cells and inducing cell death.2
Based on the inducing factors of cellular senescence, it can be broadly categorized into several types, including telomere shortening-initiated senescence, epigenetic-induced cellular aging, senescence-associated secretory phenotype (SASP)-induced senescence, mitochondrial dysfunction-induced cellular senescence, and oxidative stress-induced cellular senescence. The characteristic manifestations of cellular senescence are diverse, including the production of SASP, enlargement of cell size, high expression of proteins such as P16 and P21, and enhanced activity of senescence-associated β-galactosidase (SA-β-gal). Current extensive research indicates that cellular senescence is involved in the pathogenesis and progression of many diseases, including cancer, cardiovascular diseases, diabetes, and neurodegenerative disorders.3 Previous studies have revealed a close link between arsenic poisoning and cellular senescence, such as arsenic’s ability to enhance SA-β-gal activity, upregulate the expression of genes like p53, p21, and p16 INK 4a, and promote SASP secretion. However, our understanding of the deeper mechanisms of arsenic-induced cellular senescence and effective preventive measures remains limited, which has become a major reason for the slow progress in arsenic poisoning prevention and treatment in recent years.4 Recent research has shown that arsenic can induce cellular senescence through multiple pathways, including triggering epigenetic changes, inducing SASP production, shortening telomere length, and causing mitochondrial dysfunction (Fig. 1). This article aims to systematically summarize recent research advancements on the role and mechanisms of cellular senescence in arsenic-induced cellular damage or dysfunction and provide an in-depth analysis of the molecular mechanisms during arsenic-induced cellular senescence, thereby offering new strategies and insights for the prevention and treatment of arsenic poisoning.
Multiple pathways of arsenic-induced cellular senescence. Arsenic can induce cellular senescence through multiple pathways, including triggering epigenetic changes, inducing SASP production, shortening telomere length, and causing mitochondrial dysfunction. Figure was created with BioRender.com.
Arsenic exposure induces SASP which contributes to the aging process
Exposure to inorganic arsenic is widely associated with the development of cancers in multiple organs. However, the specific molecular mechanisms remain to be fully elucidated. Cellular senescence, as a common cellular biological phenomenon, is characterized by irreversible cell cycle arrest and alterations in the senescence-associated cellular phenotype, accompanied by a significant increase in the expression of senescence-related genes and proteins.5 SASP is a group of cytokines and chemokines with pro-inflammatory and tissue-remodeling functions, which has been shown to play a key role in the development and metastasis of cancer and is closely associated with poor patient prognosis.6 During inorganic arsenic-induced cellular senescence, the expression levels of SASP factors are significantly increased, which is associated with various mechanisms (Fig. 2).7
Multiple signaling pathways for SASP secretion induced by arsenic. The expression levels of SASP factors are significantly increased during arsenic-induced cellular senescence, which is associated with various mechanisms, including GATA 4-NFκB signaling pathway, ERK/CEBPB signaling pathway, and p38 and JNK signaling pathways. Figure was created with BioRender.com.
Arsenic can release SASP in chondrocytes via the GATA 4-NFκB signaling pathway
Cellular senescence is a stress response process regulated by the tumor suppressor proteins p53 and p16(INK4a), marking a permanent halt in the cell cycle. The transcription factor GATA4 serves as a modulator of cellular senescence and the production of the senescence-associated secretory phenotype (SASP), initiating SASP by activating the NF-κB signaling pathway, thereby triggering the cell to enter a senescent state. Stable expression of GATA4 in senescent cells is crucial for the activation of SASP.8 Under normal physiological conditions, GATA4 stability is regulated by p62-mediated selective autophagy. However, during senescence, the inhibitory effect of this autophagic pathway is diminished, leading to persistent accumulation of GATA4. The accumulation of GATA4 further activates NF-κB, promoting the production of SASP and intensifying cellular senescence.8
In a study focusing on bone progenitor cells in aged mice, it was observed that the expression levels of the GATA4 protein were significantly increased in mouse tissues treated with senescence-inducing agents and showed an increasing trend in various tissues of both naturally aged mice and humans. Particularly in the bone progenitor cells of aged mice, elevated expression levels of GATA4, NF-κB, and SASP were closely associated with enhanced support for osteoclastogenesis.9 In addition, another study provided evidence that arsenic exposure can induce an increase in GATA4 protein expression, phosphorylation of NF-κB, and SASP production, changes that can trigger the cellular senescence process in human chondrocytes and rat cartilage.10 These findings reveal the key role of GATA4 in regulating the senescence of bone progenitor cells and the activation of SASP and suggest a potential mechanism by which arsenic exposure may promote chondrocyte senescence and degenerative changes in bone tissue through activation of the GATA4-NF-κB-SASP signaling pathway. With your proficiency in medical English, you can assist in translating this passage into a format suitable for publication in professional medical journals.
Arsenic induces cell senescence through p38 and JNK signaling pathways
Numerous studies have highlighted the critical role of phosphorylation of p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) in the process of chondrocyte senescence.11,12 p38MAPK is an emerging DNA damage response modulator associated with the SASP.13 In normal human fibroblasts, various senescence-inducing stimuli activate the stress-activated kinase p38MAPK, and the inhibition of p38MAPK significantly reduces the secretion of most SASP factors.13 Another study indicated that p38 MAPK plays a key role in p53-induced senescence of human tumor cells14 and replicative senescence of chondrocytes,15 suggesting that p38 MAPK is necessary and sufficient for the formation of SASP, making the p38 signaling pathway an attractive target for therapeutic interventions in human aging, age-related degenerative diseases, and cell-level senescence-related diseases.16 In research exploring the role of p38 and JNK signaling in arsenic-induced chondrocyte senescence, it was found that arsenic induces the phosphorylation of p38 and JNK in chondrocytes in a dose-dependent manner. Treatment of chondrocytes with a p38 inhibitor significantly reverses the increase in p38 phosphorylation and p16 protein expression induced by arsenic exposure. Similarly, pretreatment of chondrocytes with the JNK inhibitor SP 600125 significantly reversed the increase in JNK phosphorylation and p53 and p21 protein expression induced by arsenic exposure. These results suggest that arsenic promotes chondrocyte senescence by activating p38- and JNK-dependent signaling pathways.10
Arsenic may modulate SASP secretion through the activation of the ERK/CEBPB signaling pathway
Mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) signaling pathways play crucial roles in regulating key biological processes such as cell proliferation, differentiation, migration, senescence, and apoptosis.17 In the field of cellular senescence research, substantial evidence indicates that the ERK signaling pathway is involved in the regulation of the cellular senescence process.18 In-depth studies have found that the ERK signaling pathway exerts its control over cellular senescence by activating the transcription factor CCAAT/enhancer-binding protein β (CEBPB).19–21 Although there is currently no direct evidence definitively confirming the involvement of arsenic in skin cell senescence through the ERK/CEBPB signaling pathway, multiple studies have confirmed that arsenic can activate the ERK signaling pathway.4 One study investigated the role of autophagy in arsenite-induced urothelial cell carcinogenesis and found that autophagy induced by arsenite exposure is mediated by oxidative stress, which functions by modulating the activation of PTEN, p70S6K, and ERK1/2 signaling pathways.22 In addition, research has suggested that the ERK/CEBPB signaling pathway may be involved in the process of skin cell senescence induced by low doses of arsenic through the modulation of oxidative stress responses. As a potential intervention factor, Kaji-Ichigoside has been found to alleviate arsenic-induced skin cell senescence by downregulating the ERK/CEBPB signaling pathway and regulating the balance between oxidation and antioxidants.4
Mitochondrial dysfunction associated with cell senescence after arsenic exposure
Arsenic is a genotoxic mutagen that induces genomic instability through mechanisms involving various biological processes. Studies at both the animal and cellular levels suggest that inorganic arsenic exposure is associated with increased production of reactive oxygen species (ROS), causing mitochondrial DNA damage and disruption of mitochondrial membrane integrity, leading to mitochondrial dysfunction. Mitochondria are highly sensitive to oxidative stress caused by multiple factors, and dysfunction resulting from mitochondrial DNA mutations is considered to be related to the pathogenesis of various diseases. Mitochondrial dysfunction has been shown to play a crucial role in the apoptosis of mammalian cells.23 The mutagenic effects of arsenic are primarily achieved through mitochondrial damage. Recent research has revealed that inorganic arsenic disrupts mitochondrial function by depolarizing the mitochondrial membrane potential (MMP) and promoting the release of cytochrome c from the mitochondrial membrane into the cytoplasm.24,25 Excessive ROS is associated with the formation of ternary complexes induced by As2O3.26 The accumulation of hydrogen peroxide (H2O2) further leads to a decrease in mitochondrial membrane potential, triggering the release of cytochrome c and activation of the caspase cascade.27 In addition, the levels of mitochondrial apoptosis markers (such as bax, bid, and bim) change, and the expression of various inflammatory markers (including IL-6, TNF-α, IL-1β, and IFN-γ) is also affected.26 Mitochondrial damage also produces a large number of superoxide anions, which react with nitric oxide to form highly reactive peroxynitrites. In vitro studies have shown that under conditions of inorganic phosphate deficiency, arsenic can affect mitochondrial oxidation and may function by stimulating the activity of mitochondrial ATPase.28
A hallmark of cellular senescence is significant changes in mitochondrial dynamics and organization. In senescent tissues and cells, typical manifestations of mitochondrial dysfunction include a decrease in the respiratory capacity of individual mitochondria and a reduction in the mitochondrial membrane potential (MMP) at steady-state levels. The aging process is closely associated with the impairment of mitochondrial dynamics.29 In various cellular senescence models, phenomena such as elongation, enlargement, and excessive fusion of mitochondria have been observed.30–34 During arsenic poisoning, a decrease in MMP is accompanied by an increase in the production of reactive oxygen species (ROS) and the occurrence of DNA breaks.26 Mitochondrial DNA (mtDNA) encodes 13 proteins crucial for the electron transport chain, genes for 12S, and 16S rRNA and 22 transfer RNAs.29 Damage to the mtDNA replication system and/or mtDNA repair mechanisms can severely affect mitochondrial function. mtDNA damage, mtDNA mutations, or deletions are associated with the occurrence of various mitochondrial diseases.35,36 In a study on cells treated with arsenic, abnormal mitochondrial function was observed following arsenic exposure, which included mitochondrial dysfunction, mtDNA depletion, and mtDNA deletion induction. Depletion of mtDNA may lead to cellular senescence, especially in situations related to high levels of ROS,37 and these results are consistent with the DNA damage and genotoxic effects observed after arsenic exposure.38
Arsenic exposure leads to telomere shortening and accelerates cell senescence
Telomere shortening is influenced by genetic, epigenetic, and environmental factors that cause oxidative damage and replicative stress, including various telomere diseases, electromagnetic radiation, physiological stress, lifestyle factors, and carcinogens such as arsenic. Long-term exposure to arsenic has been shown to induce oxidative stress responses, leading to DNA damage and genomic instability, which in turn promotes telomere shortening.39 The relationship between arsenic exposure and telomere length has been extensively explored in numerous experimental and observational studies, with research indicating that the impact of arsenic exposure on telomere length is influenced by factors such as the dose, duration, age, and DNA repair capacity of arsenic exposure.40,41
In vitro experimental studies have revealed the potential effects of arsenic on telomerase activity and telomere length, which may exhibit dose-dependent characteristics. At lower concentrations, arsenic exposure may increase telomerase activity, thereby maintaining or extending telomere length and promoting cell proliferation. However, at higher concentrations, arsenic exposure may inhibit telomerase activity, shorten telomeres, and induce cell apoptosis.42 However, the relationship between arsenic exposure and telomere length has shown inconsistent results across different studies (Table 1). A study on the effects of arsenic on telomeres and telomerase in HL-60 and HaCaT cells showed that low concentrations of arsenic can increase telomerase activity, thus promoting cell proliferation by maintaining or extending telomere length. High concentrations of arsenic decrease telomerase activity, shorten telomeres, and induce cell apoptosis.42 Telomeres and telomerase play dual roles in tumorigenesis and replicative senescence.43 In immortalized cells, telomerase activity and telomere stability help maintain genomic stability and prevent chromosomal abnormalities, thereby supporting unlimited cell proliferation. However, in non-immortalized cells, inhibition of telomerase activity and shortening of telomeres may lead to apoptosis or promote fusion of chromosome ends, which may trigger the initiation of the cancerous process. Although lengthening telomeres can avoid replicative senescence of cells and achieve cell immortalization, if the cells have DNA damage, telomere lengthening may lead to erroneous DNA replication, which in turn leads to the formation of immortalized cells with genomic instability, i.e. malignant proliferation or tumorigenesis.
Relationship between arsenic exposure and telomere length in multiple experimental and observational studies.
| Country | Research sample | Modes of arsenic exposure | Source of Arsenic | Primary endpoint event | Reference |
|---|---|---|---|---|---|
| India | 60 arsenic-exposed individuals with and without skin lesions and 60 unexposed control individuals were included | Drinking water | 30–620 mg/L | A significant increase in non-telomerase telomere length was observed in the skin lesions group | 44 |
| India | 528 arsenic-exposed patients with skin basal cell carcinoma and 533 healthy controls | Drinking water | >1.32 μg /L | Arsenic exposure was statistically significantly associated with telomere length in cases and controls exposed to levels >1.32 μg/L | 39 |
| Bangladesh | 476 children between the ages of five and seven | Drinking water (water, urine) | The urinary arsenic concentration in children was 3.67–1261.54 μg /L | Inverse relationship between urinary arsenic concentration and leukocyte relative telomere length | 45 |
| Sweden | 202 women | Drinking water (water, urine) | 3.5–200 μg/L | Urinary arsenic levels were positively correlated with telomerase reverse transcriptase expression | 46 |
| Italy | 241 healthy individuals in four areas known to be affected by natural or anthropogenic arsenic contamination | Drinking water | Urine samples were tested for iAs, MMA, and DMA. | Significant inverse trend between leukocyte telomerase length and urinary arsenic concentration | 40 |
| Country | Research sample | Modes of arsenic exposure | Source of Arsenic | Primary endpoint event | Reference |
|---|---|---|---|---|---|
| India | 60 arsenic-exposed individuals with and without skin lesions and 60 unexposed control individuals were included | Drinking water | 30–620 mg/L | A significant increase in non-telomerase telomere length was observed in the skin lesions group | 44 |
| India | 528 arsenic-exposed patients with skin basal cell carcinoma and 533 healthy controls | Drinking water | >1.32 μg /L | Arsenic exposure was statistically significantly associated with telomere length in cases and controls exposed to levels >1.32 μg/L | 39 |
| Bangladesh | 476 children between the ages of five and seven | Drinking water (water, urine) | The urinary arsenic concentration in children was 3.67–1261.54 μg /L | Inverse relationship between urinary arsenic concentration and leukocyte relative telomere length | 45 |
| Sweden | 202 women | Drinking water (water, urine) | 3.5–200 μg/L | Urinary arsenic levels were positively correlated with telomerase reverse transcriptase expression | 46 |
| Italy | 241 healthy individuals in four areas known to be affected by natural or anthropogenic arsenic contamination | Drinking water | Urine samples were tested for iAs, MMA, and DMA. | Significant inverse trend between leukocyte telomerase length and urinary arsenic concentration | 40 |
Relationship between arsenic exposure and telomere length in multiple experimental and observational studies.
| Country | Research sample | Modes of arsenic exposure | Source of Arsenic | Primary endpoint event | Reference |
|---|---|---|---|---|---|
| India | 60 arsenic-exposed individuals with and without skin lesions and 60 unexposed control individuals were included | Drinking water | 30–620 mg/L | A significant increase in non-telomerase telomere length was observed in the skin lesions group | 44 |
| India | 528 arsenic-exposed patients with skin basal cell carcinoma and 533 healthy controls | Drinking water | >1.32 μg /L | Arsenic exposure was statistically significantly associated with telomere length in cases and controls exposed to levels >1.32 μg/L | 39 |
| Bangladesh | 476 children between the ages of five and seven | Drinking water (water, urine) | The urinary arsenic concentration in children was 3.67–1261.54 μg /L | Inverse relationship between urinary arsenic concentration and leukocyte relative telomere length | 45 |
| Sweden | 202 women | Drinking water (water, urine) | 3.5–200 μg/L | Urinary arsenic levels were positively correlated with telomerase reverse transcriptase expression | 46 |
| Italy | 241 healthy individuals in four areas known to be affected by natural or anthropogenic arsenic contamination | Drinking water | Urine samples were tested for iAs, MMA, and DMA. | Significant inverse trend between leukocyte telomerase length and urinary arsenic concentration | 40 |
| Country | Research sample | Modes of arsenic exposure | Source of Arsenic | Primary endpoint event | Reference |
|---|---|---|---|---|---|
| India | 60 arsenic-exposed individuals with and without skin lesions and 60 unexposed control individuals were included | Drinking water | 30–620 mg/L | A significant increase in non-telomerase telomere length was observed in the skin lesions group | 44 |
| India | 528 arsenic-exposed patients with skin basal cell carcinoma and 533 healthy controls | Drinking water | >1.32 μg /L | Arsenic exposure was statistically significantly associated with telomere length in cases and controls exposed to levels >1.32 μg/L | 39 |
| Bangladesh | 476 children between the ages of five and seven | Drinking water (water, urine) | The urinary arsenic concentration in children was 3.67–1261.54 μg /L | Inverse relationship between urinary arsenic concentration and leukocyte relative telomere length | 45 |
| Sweden | 202 women | Drinking water (water, urine) | 3.5–200 μg/L | Urinary arsenic levels were positively correlated with telomerase reverse transcriptase expression | 46 |
| Italy | 241 healthy individuals in four areas known to be affected by natural or anthropogenic arsenic contamination | Drinking water | Urine samples were tested for iAs, MMA, and DMA. | Significant inverse trend between leukocyte telomerase length and urinary arsenic concentration | 40 |
Epigenetic changes induced by arsenic exposure induce cell senescence
Extensive research in vitro, in vivo, and in animal models has established a close association between arsenic exposure and various epigenetic modifications, which represent a significant mechanism of arsenic carcinogenesis47 (Fig. 3). These modifications include DNA methylation, histone alterations, changes in miRNA and lncRNA expression, mRNA modifications, and alternative splicing. These epigenetic modifications play a pivotal role in the regulation of gene expression and, consequently, in the toxicity and carcinogenicity of arsenic.48 Notably, these senescence-associated epigenetic changes are involved in the modulation of the aging process and may lead to the development and progression of various diseases closely related to aging.
Arsenic exposure induces cell senescence through epigenetic changes triggered by its biotransformation. Arsenic biotransformation refers to the reduction of pentavalent arsenic (AsV) to trivalent arsenic (AsIII) in vivo, which is then methylated to DMA and MMA, resulting in epigenetic changes and finally inducing cell senescence. Figure was created with BioRender.com.
Prolonged arsenic exposure induces aberrant DNA methylation and promotes cellular senescence
In the human body, the primary detoxification pathway for arsenic involves a methylation process catalyzed by methyltransferases, where S-adenosylmethionine (SAM) serves as the key methyl donor in the formation of the methylated arsenic metabolites: monomethyl arsenic acid (MMA) and dimethyl arsenic acid (DMA). Notably, the arsenic methyltransferases share the same methyl donor, SAM, with DNA methyltransferases (DNMT1 and DNMT3a) responsible for DNA methylation. Prolonged arsenic exposure may lead to the depletion of SAM, further inhibiting the expression of DNMT1 and DNMT3a,49 thereby disrupting the maintenance of methylated cytosine on DNA and inducing a phenomenon of global DNA hypomethylation.50 Multiple in vitro experiments have confirmed that arsenic can induce global or gene-specific DNA hypomethylation in various cell lines.48 For example, under conditions of long-term low-level arsenic exposure (continuous exposure to 5 μM arsenate for 16 weeks), the normal human prostate epithelial cell line RWPE-1 underwent malignant transformation and acquired a malignant phenotype characterized by DNA hypomethylation, with SAM levels exhibiting a rapid and sustained decline during arsenic-induced cell malignant transformation.50,51 At the population level, studies comparing the abnormal methylation frequency of the death-associated protein kinase (DAPK) gene promoter in urothelial carcinoma samples from arsenic-contaminated and non-contaminated areas using methylation-specific polymerase chain reaction (MSP) technology have indicated that arsenic exposure may induce hypermethylation of the DAPK gene promoter in urothelial carcinoma, leading to the inactivation of DAPK function.50 Integrating the results from in vitro, animal experiments, and population studies, arsenic exposure has been confirmed to alter the overall DNA methylation patterns. Although the precise mechanisms remain to be further explored, various factors related to arsenic metabolism, whether through direct action or indirect influence, may lead to abnormal changes in DNA methylation levels during arsenic-induced malignant transformation processes.52
DNA methylation, as a critical epigenetic modification mechanism, plays an indispensable role in the molecular pathways of physiological functional decline associated with aging and the development of tumors. Cancer, a disease intimately linked to aging, is characterized by the common occurrence of global DNA hypomethylation during the aging process.16 In normal cells, alongside global DNA hypomethylation, there is aberrant hypermethylation of specific gene regions. In contrast to normal cells, the hypermethylation of abnormal gene regions in cancer cells contributes to the maintenance of continuous self-renewal capabilities and the preservation of an embryonic-like state.16 Additionally, research has indicated that during the aging process, there is a general decline in the methylation levels of genomic DNA, leading to the loss of epigenetic information.53 Under conditions of high-dose and prolonged arsenic exposure, global or local DNA hypomethylation has been observed in several cell lines, which may be associated with the induction of cellular senescence and tumor development. Arsenic-induced changes in DNA methylation levels not only affect cellular gene expression patterns, inducing senescence, but may also interfere with normal cellular proliferation and apoptosis processes, thus promoting tumorigenesis and tumor progression.
Arsenic exposure affects cellular senescence through various histone modifications
Chromatin exists within the cell nucleus as nucleosome units composed of a histone octamer around which DNA is wrapped. The N-terminal tails of histones protrude from the nucleosome surface and serve as primary targets for various epigenetic modifications. These modifications include methylation, acetylation, phosphorylation, and SUMOylation, which together constitute a complex regulatory network and play a crucial role in the precise regulation of gene expression.54 Particularly during the biological process of aging, dynamic changes in acetylation and methylation modifications are closely associated with a decline in cellular function.55 Histone acetylation is generally associated with a relaxed state of chromatin and enhanced gene transcription activity, whereas methylation can be either activating (e.g.H3K4me2/3) or repressive (e.g.H3K9me2/3, H3K27me3) depending on the specific residue and degree of methylation.54
Histone methylation is a critical epigenetic modification that predominantly occurs on the lysine (K) or arginine (R) residues of histone proteins H3 and H4. This process is catalyzed by specific enzymes known as histone methyltransferases (HMTs). Among the numerous potential methylation sites on histones, H3K4 and H3K9 are two widely studied modification sites.54 In the human non-small-cell lung cancer cell line A549, studies have shown that exposure to inorganic trivalent arsenic leads to an increase in the dimethylation of H3K9 (H3K9me2) and a decrease in the trimethylation of H3K27 (H3K27me3), both of which are known markers of gene silencing. Concurrently, arsenic exposure is also accompanied by an overall increase in the trimethylation of H3K4 (H3K4me3), an epigenetic mark associated with gene activation.56–58 H3K4 methylation is closely related to the aging process in various cell types and plays a significant role in regulating gene transcription, thereby affecting cellular senescence. In a cross-sectional study of 63 male steelworkers, a positive correlation was found between the expression levels of H3K4 dimethylation (H3K4me2) in peripheral blood leukocytes and the level of arsenic exposure.59
Histone acetylation is generally associated with a relaxed state of chromatin, thereby facilitating the assembly of the transcription complex and the progression of transcriptional activity. In contrast, the activity of histone deacetylases (HDACs) tightens the chromatin structure by removing acetyl groups, subsequently inhibiting gene transcription. This dynamic equilibrium between acetylation and deacetylation is reversible and is crucial for maintaining cellular function and identity.54 The acetylation of lysine 16 on histone H4 (H4K16ac) is a modification of significant biological importance. H4K16ac is involved not only in regulating nucleosome-level interactions but also impacts the interconnections between chromatin fibers, exerting a decisive influence on the higher-order three-dimensional structure and function of chromatin.60 Recent studies have reported that arsenic exposure within a certain concentration range (0.2–10 μM) leads to a significant decrease in H4K16ac at the genomic level,61–63 a hallmark of most cancers.60 In addition, research has found that a hypoacetylated state of histones can regulate chromatin structure, inducing cellular differentiation and senescence processes.64
Arsenic exposure affects cell senescence by modulating the regulation of various non-coding RNAs
Non-coding RNAs (ncRNAs) are a class of RNA molecules with significant regulatory functions, including long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs). Among them, miRNAs have garnered widespread attention in research on aging and related diseases. miRNAs participate in multiple key processes of tumorigenesis by negatively regulating gene expression, including transcriptional regulation, cell proliferation, apoptosis, and epithelial-mesenchymal transition (EMT).65,66 Arsenic exposure exerts multifaceted effects on the expression patterns of miRNAs, and skin lesions, as an early clinical manifestation of arsenic toxicity, are closely associated with subsequent cancer risk.67 Recent studies have revealed significant changes in miRNA expression in skin tissue due to chronic arsenic exposure.68–70 For instance, miR-21, miR-145, miR-155, and miR-191 are upregulated in the plasma of individuals with damaged skin.71 In a study from West Bengal, plasma miRNA microarray analysis identified 145 unique miRNAs that were upregulated in arsenic-exposed individuals with skin lesions, including precancerous and cancerous changes, with increased levels of miR-21, miR-23a, miR-619, miR-126, and miR-3613, whereas miR-1282 and miR-4530 levels decreased.72,73 p53, a tumor suppressor protein, is a key transcriptional activator of miRNAs in the miR-34 family.74 miR-34a promotes senescence of endothelial and colon cancer cells by targeting the E2F pathway.75 In addition, miR-34a can induce cellular senescence by inhibiting the expression of silent mating type information regulator 2 homolog 1 (SIRT1), a protein with complex roles in the aging process. Other miRNAs, such as miR-22 and miR-217, also contribute to the induction of senescence by suppressing SIRT1 expression.76–78 Concurrently, certain miRNAs like miR-25 and miR-30d directly target the 3′ untranslated region (3′UTR) of p53 mRNA, reducing p53 levels and thereby inhibiting p53-mediated cell survival and senescence responses.79 In HeLa cells and fibroblasts, miR-519 promotes the transition to a senescent state by reducing the expression of proteins crucial for DNA repair and calcium ion metabolism and increasing the expression levels of p53 and p21.80–82
Conclusion
Taken together with the results of current studies in cells and animal models, arsenic exposure has been confirmed to promote cellular senescence through various mechanisms, including inducing epigenetic changes, activating SASP, accelerating telomere shortening, and causing mitochondrial dysfunction. These aging-related biological processes are closely related to the occurrence and development of various diseases, such as cancer, cardiovascular disease, diabetes, and neurodegenerative diseases. Therefore, prevention and mitigation of arsenic-induced cellular senescence may be an effective strategy to reduce the structural damage and dysfunction of cells caused by arsenic toxicity. However, it is worth noting that some molecular mechanisms in arsenic-induced cellular senescence may intersect and influence each other, and the specific action pathways of these mechanisms have not been fully studied and verified. Future studies are needed to deeply explore the mechanism of cellular senescence in arsenic toxicity to provide a scientific basis for the development of new prevention and treatment strategies to reduce the harm of arsenic toxicity to human health more effectively.
Author contributions
Yun Gu & Ying Qiu: Writing—original draft. Yujian Li: Writing review & editing. Weihua Wen & Ying Yang: Writing—review & editing, Supervision.
Funding
This review was supported by the following projects and departments: National Natural Science Foundation of China (802060591), Key Specialties of Yunnan Province, Yunnan Famous Doctors Project (YNWR-MY-2018-012), and Yunnan Medical leading Talents Support Program (L-2018016).
Conflict of interest statement: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Data availability
No data was used for the research described in the article.
