Assessment of cellular senescence potential of PM2.5 using 3D human lung fibroblast spheroids in vitro model.

Background: Epidemiological studies demonstrate that particulate matter 2.5 (PM2.5) exposure closely related to chronic respiratory diseases. Cellular senescence plays an important role in many diseases. However, it is not fully clear whether PM2.5 exposure could induce cellular senescence in the human lung. In this study, we generated a three-dimensional (3D) spheroid model using isolated primary human lung fibroblasts (HLFs) to investigate the effects of PM2.5 on cellular senescence at the 3D level. Methods: 3D spheroids were exposed to 25-100 µg/ml of PM2.5 in order to evaluate the impact on cellular senescence. SA-ß-galactosidase activity, cell proliferation, and the expression of key genes and proteins were detected. Results: Exposure of the HLF spheroids to PM2.5 yielded a more sensitive cytotoxicity than 2D HLF cell culture. Importantly, PM2.5 exposure induced the rapid progression of cellular senescence in 3D HLF spheroids, with a dramatically increased SA-ß-Gal activity. In exploiting the mechanism underlying the effect of PM2.5 on senescence, we found a significant increase of DNA damage, upregulation of p21 protein levels, and suppression of cell proliferation in PM2.5-treated HLF spheroids. Moreover, PM2.5 exposure created a significant inflammatory response, which may be at least partially associated with the activation of TGF-ß1/Smad3 axis and HMGB1 pathway. Conclusions: Our results indicate that PM2.5 could induce DNA damage, inflammation, and cellular senescence in 3D HLF spheroids, which may provide a new evidence for PM2.5 toxicity based on a 3D model which has been shown to be more in vivo-like in their phenotype and physiology than 2D cultures.

Inhibition of demethylase by IOX1 modulates chromatin accessibility to enhance NSCLC radiation sensitivity through attenuated PIF1.

Chromatin accessibility is a critical determinant of gene transcriptional expression and regulated by histones modification. However, the potential for manipulating chromatin accessibility to regulate radiation sensitivity remains unclear. Our findings demonstrated that the histone demethylase inhibitor, 5-carboxy-8-hydroxyquinoline (IOX1), could enhance the radiosensitivity of non-small cell lung cancer (NSCLC) in vitro and in vivo. Mechanistically, IOX1 treatment reduced chromatin accessibility in the promoter region of DNA damage repair genes, leading to decreased DNA repair efficiency and elevated DNA damage induced by γ irradiation. Notably, IOX1 treatment significantly reduced both chromatin accessibility and the transcription of phytochrome interacting factor 1 (PIF1), a key player in telomere maintenance. Inhibition of PIF1 delayed radiation-induced DNA and telomeric DNA damage repair, as well as increased radiosensitivity of NSCLC in vitro and in vivo. Further study indicated that the above process was regulated by a reduction of transcription factor myc-associated zinc finger protein (MAZ) binding to the distal intergenic region of the PIF1. Taken together, IOX1-mediated demethylase inactivation reduced chromatin accessibility, leading to elevated telomere damage which is partly due to PIF1 inhibition, thereby enhancing NSCLC radiosensitivity.

Remodeling of Chromatin Accessibility Regulates the Radiological Responses of NSCLC A549 Cells to High-LET Carbon Ions.

Carbon-ion radiation therapy (CIRT) may offer remarkable advantages in cancer treatment with its unique physical and biological characteristics. However, the underlying epigenetic regulatory mechanisms of cancer response to CIRT remain to be identified. In this study, we showed consistent but different degrees of biological effects induced in NSCLC A549 cells by carbon ions of different LET. The genome-wide chromatin accessibility and transcriptional profiles of carbon ion-treated A549 cells were performed using transposase-accessible chromatin sequencing (ATAC-seq) and RNA-seq, respectively, and further gene regulatory network analysis was performed by integrating the two sets of genomic data. Alterations in chromatin accessibility by carbon ions of different LET predominantly occurred in intron, distal intergenic and promoter regions of differential chromatin accessibility regions. The transcriptional changes were mainly regulated by proximal chromatin accessibility. Notably, CCCTC-binding factor (CTCF) was identified as a key transcription factor in the cellular response to carbon ions. The target genes regulated by CTCF in response to carbon ions were found to be closely associated with the LET of carbon ions, particularly in the regulation of gene transcription within the DNA replication- and metabolism-related signaling pathways. This study provides a regulatory profile of genes involved in key signaling pathways and highlighted key regulatory elements in NSCLC A549 cells during CIRT, which expands our understanding of the epigenetic mechanisms of carbon ion-induced biological effects and reveals an important role for LET in the regulation of changes in chromatin accessibility, although further research is needed.

POT1 involved in telomeric DNA damage repair and genomic stability of cervical cancer cells in response to radiation.

Though telomeres play a crucial role in maintaining genomic stability in cancer cells and have emerged as attractive therapeutic targets in anticancer therapy, the relationship between telomere dysfunction and genomic instability induced by irradiation is still unclear. In this study, we identified that protection of telomeres 1 (POT1), a single-stranded DNA (ssDNA)-binding protein, was upregulated in γ-irradiated HeLa cells and in cancer patients who exhibit radiation tolerance. Knockdown of POT1 delayed the repair of radiation-induced telomeric DNA damage which was associated with enhanced H3K9 trimethylation and enhanced the radiosensitivity of HeLa cells. The depletion of POT1 also resulted in significant genomic instability, by showing a significant increase in end-to-end chromosomal fusions, and the formation of anaphase bridges and micronuclei. Furthermore, knockdown of POT1 disturbed telomerase recruitment to telomere, and POT1 could interact with phosphorylated ATM (p-ATM) and POT1 depletion decreased the levels of p-ATM induced by irradiation, suggesting that POT1 could regulate the telomerase recruitment to telomeres to repair irradiation-induced telomeric DNA damage of HeLa cells through interactions with p-ATM. The enhancement of radiosensitivity in cancer cells can be achieved through the combination of POT1 and telomerase inhibitors, presenting a potential approach for radiotherapy in cancer treatment.

Directed evolution of TetR for constructing sensitive and broad-spectrum tetracycline antibiotics whole-cell biosensor.

Antibiotic abuse is the main reason for the drug resistance of pathogenic bacteria, posing a potential health risk. Antibiotic surveillance is critical for preventing antibiotic contamination. This study aimed to develop a sensitive and broad-spectrum whole-cell biosensor for tetracycline antibiotics (TCs) detection. Wild-type TCs-responsive biosensor was constructed by introducing a tetracycline operon into a sfGFP reporter plasmid. Using error-prone PCR, mutation libraries containing approximately 107 variants of the tetracycline repressor (TetR) gene were generated. The tigecycline-senstive mutants were isolated using high-throughput flow cytometric sorting. After 2 rounds of directed evolution, a mutant epS2-22 of TerR was isolated and assembled as a TCs biosensor. The epS2-22 biosensor was more sensitive and broad-spectrum than the wild-type biosensors. The detection limits of the epS2-22 biosensor for seven TCs were 4- to 62-fold lower than the wild-type biosensor (no response to tigecycline). Meanwhile, the epS2-22 biosensor had a shorter detection time and a stronger signal output than the wild type. In addition, the evolved epS2-22 biosensor showed excellent performance in detecting low traces of TCs in environmental water. These results suggest that directed evolution is a powerful tool for developing high-performance whole-cell biosensors, and the evolved epS2-22 biosensors have the potential for wider applications in real-world TCs detection.

Connexin26 Modulates Radiation-Induced Skin Damage by Regulating Chemokine CCL27 through MAPK Signaling.

Connexin26 (Cx26) plays an important role in ionizing radiation-induced damage, and CC chemokine ligand 27 (CCL27) regulates the skin immune response. However, the relationship between Cx26 and CCL27 in radiation-induced skin damage is unclear. After X-ray irradiation, clonogenic survival and micronucleus formation were assessed in immortalized human keratinocytes (HaCaT). Proteins in the mitogen activated protein kinase (MAPK) signaling pathway and CCL27-related proteins were detected by immunoblotting. HaCaTCx26-/- cells were constructed to verify the effects of Cx26 on CCL27 secretion. A mouse model was established to examine the expression of CCL27 and skin inflammation in vivo. The degree of skin injury induced by 6 MV of X rays was closely related to CCL27. The phosphorylation of ERK, p38 and NF-κB was significantly increased in irradiated cells. The secretion of CCL27 was significantly decreased in HaCaT wild-type cells relative to HaCaTCx26-/- cells. Whereas cell survival fractions decreased, and the micronuclei formation rate increased as a function of increasing X-ray dose in HaCaT cells, the opposite trend occurred in HaCaTCx26-/- cells. Our findings show that Cx26 likely plays a role in the activation of the MAPK and NF-κB/COX-2 signaling pathways and regulates the secretion of CCL27 in keratinocytes after X-ray radiation-induced skin damage.

The developmental toxicity of PM2.5 on the early stages of fetal lung with human lung bud tip progenitor organoids.

Exposure to air pollution has been proven to be associated with impaired fetal lung development. However, due to the lack of reliable human source models, it is still challenging to deeply understand the human fetal lung development under PM2.5 exposure. Here, we utilized human embryonic stem cell (hESC) line H9 to generate lung bud tip progenitor organoids (LPOs), a process that mimics early stages of fetal lung development including definitive endoderm (DE) formation, anterior foregut endoderm (AFE) differentiation and lung progenitor cell specification, to evaluate potential pulmonary developmental toxicity of PM2.5. We demonstrated that PM2.5 exposure the entire LPOs induction from hESCs significantly affected cellular proliferation of LPOs, and altered the expression of lung progenitor cell markers NKX2.1, SOX2 and SOX9, which are canonically defined subsequently proximal-distal airways specification. To explore the dynamic influences of PM2.5 exposure at different stages of LPOs specification, we also found that PM2.5 exposure significantly affected the expression of several transcriptional factors that are important for the differentiation of DE and AFE. Mechanistically, we suggested PM2.5-induced developmental toxicity to LPOs was partially linked with the Wnt/ß-catenin signaling pathway. Therefore, our findings further emphasize the substantial health risks in the development of respiratory system associated with prenatal exposure to PM2.5.

Prenatal triclosan exposure impairs mammalian lung branching morphogenesis through activating Bmp4 signaling.

Triclosan (TCS) is a commonly used antibacterial agent present in personal care and household products. Recently, there have been increasing concerns about the association between children's health and TCS exposure during gestation, but the toxicological effects of TCS exposure on embryonic lung development remain undetermined. In this study, through using an ex vivo lung explant culture system, we found that prenatal exposure to TCS resulted in impaired lung branching morphogenesis and altered proximal-distal airway patterning. These TCS-induced dysplasias are accompanied by significantly reduced proliferation and increased apoptosis within the developing lung, as a consequence of activated Bmp4 signaling. Inhibition of Bmp4 signaling by Noggin partially rescues the lung branching morphogenesis and cellular defects in TCS-exposed lung explants. In addition, we provided in vivo evidence that administration of TCS during gestation leads to compromised branching formation and enlarged airspace in the lung of offspring. Thus, this study provides novel toxicological information on TCS and indicated a strong/possible association between TCS exposure during pregnancy and lung dysplasia in offspring.

Aging of Nanoplastics Significantly Affects Protein Corona Composition Thus Enhancing Macrophage Uptake.

Nanoplastics (NPs), as emerging contaminants, have attracted increasing attention for their effects on human exposure and potential health risks. The protein corona formed on the surface of NPs affects the biological activity and fate of the NPs in vivo. However, how environmental aging, an inevitable process once NPs enter the environment, affects the formation of protein corona on NPs is still unclear. This study investigated the changes in the compositions of protein corona formed on photo-aged polystyrene (PS) NPs in human bronchoalveolar lavage fluid (BALF), corresponding to the inhalation exposure pathway. The results demonstrated that both the species and abundance of proteins in the BALF protein corona on the surface of PS NPs were altered by aging. In addition, the aged PS NPs are more hydrophilic and less electronegative than the pristine PS NPs; hence, there is an increased sorption of more negatively charged hydrophilic proteins. Moreover, aging-induced alterations in BALF protein corona enhanced the uptake of aged PS NPs by lung macrophages J774A.1 through phagocytosis and clathrin-mediated endocytosis. These findings highlight the importance of environmental aging processes in the biosafety assessment of nanoplastics.

Directly Evolved AlkS-Based Biosensor Platform for Monitoring and High-Throughput Screening of Alkane Production.

Biosynthetic alkane using acyl-ACP aldehyde reductase (AAR) and aldehyde-deformylating oxygenase (ADO) from cyanobacteria is considered a promising alternative for the production of biofuels and chemical feedstocks. However, the lack of suitable screening methods to improve the catalytic efficiency of AAR and ADO has hindered further improvements in alkane production. Herein, a novel alkane biosensor was developed based on transcriptional factor AlkS by directed evolution, which shows sensitive dynamic response curves for exogenous long-chain alkanes as well as in situ monitoring of endogenously produced alkanes. The evolved biosensor enables high-throughput screening of alkane-producing strains from the AAR and ADO mutant library, which led to a 13-fold increase in the production of long-chain alkanes, including a 22-fold increase of C15. This study is the first to improve the alkane production through biosensors, which provides a good reference for the establishment of microbial cell factories for alkane production.

Microcystin-LR-induced nuclear translocation of cGAS promotes mutagenesis in human hepatocytes by impeding homologous recombination repair.

Microcystin-LR (MC-LR) has been recognized as a typical hepatotoxic cyclic peptides produced by cyanobacteria. Nowadays, due to the frequent occurrence of cyanobacterial blooms, the underlying hepatotoxic mechanism of MC-LR has become the focus of attention. In our present work, the mutagenic effect of MC-LR on human normal hepatic (HL-7702) cells regulated by cGAS was mainly studied. Here, we showed that exposure to MC-LR for 1-4 days could activate the cGAS-STING signaling pathway and then trigger immune response in HL-7702 cells. Notably, relative to the treatment with 1 µM MC-LR for 1-3 days, it was observed that when HL-7702 cells were exposed to 1 µM MC-LR for 4 days, the mutation frequency at the Hprt locus was remarkably increased. In addition, cGAS in HL-7702 cells was also found to complete the nuclear translocation after 4-day exposure. Moreover, co-immunoprecipitation and homologous recombination (HR)-directed DSB repair assay were applied to show that homologous recombination repair was inhibited after 4-day exposure. However, the intervention of the nuclear translocation of cGAS by transfecting BLK overexpression plasmid restored homologous recombination repair and reduced the mutation frequency at the Hprt locus in HL-7702 cells exposed to MC-LR. Our study unveiled the distinct roles of cGAS in the cytoplasm and nucleus of human hepatocytes as well as potential mutagenic mechanism under the early and late stage of exposure to MC-LR, and provided a novel insight into the prevention and control measures about the hazards of cGAS-targeted MC-LR.

Ambient PM2.5 exposure causes cellular senescence via DNA damage, micronuclei formation, and cGAS activation.

Ambient PM2.5 is one of the environmental risk factors and was correlated with senescence-related diseases based on the epidemiologic investigation. However, little is known about senescence induced by PM2.5 as well as the underlying mechanisms. In this study, we demonstrated that PM2.5 exposure aggravated cellular senescence in vivo and in vitro, and disrupted micronuclei (MN) played a vital role in this process. Our results suggested that the nuclear envelope (NE) of PM2.5-induced MN was ruptured. Subsequently, cGAS was found to localize to approximately 80% of the disrupted MN but few for intact MN. Upon examination of cGAMP and SA-ß-Gal, the cGAS-STING pathway was found activated and related to cellular senescence induced by PM2.5. Taken together, we reported a novel finding that PM2.5 exposure causes cellular senescence via DNA damage, MN formation, and cGAS activation. These results revealed the potential toxicity of PM2.5 and its related mechanisms in cellular senescence.

Selenomethionine mitigate PM2.5-induced cellular senescence in the lung via attenuating inflammatory response mediated by cGAS/STING/NF-κB pathway.

Particulate matter 2.5 (PM2.5) is a widely known atmospheric pollutant which can induce the aging-related pulmonary diseases such as acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD) and interstitial pulmonary fibrosis (IPF). In recent years, with the increasing atmospheric pollution, airborne fine PM2.5, which is an integral part of air pollutants, has become a thorny problem. Hence, this study focused on the effect of PM2.5 on cellular senescence in the lung, identifying which inflammatory pathway mediated PM2.5-induced cellular senescence and how to play a protective role against this issue. Our data suggested that PM2.5 induced time- and concentration-dependent increasement in the senescence of A549 cells. Using an inhibitor of cGAS (PF-06928215) and an inhibitor of NF-κB (BAY 11-7082), it was revealed that PM2.5-induced senescence was regulated by inflammatory response, which was closely related to the cGAS/STING/NF-κB pathway activated by DNA damage. Moreover, our study also showed that the pretreatment with selenomethionine (Se-Met) could inhibit inflammatory response and prevent cellular senescence by hindering cGAS/STING/NF-κB pathway in A549 cells exposed to PM2.5. Furthermore, in vivo C57BL/6J mice model demonstrated that aging of mouse lung tissue caused by PM2.5 was attenuated by decreasing cGAS expression after Se-Met treatment. Our findings indicated that selenium made a defense capability for PM2.5-induced cellular senescence in the lung, which provided a novel insight for resisting the harm of PM2.5 to human health.

Advances in neural organoid systems and their application in neurotoxicity testing of environmental chemicals.

Due to the complex structure and function of central nervous system (CNS), human CNS in vitro modeling is still a great challenge. Neurotoxicity testing of environmental chemicals mainly depends on the traditional animal models, which have various limitations such as species differences, expensive and time-consuming. Meanwhile, in vitro two-dimensional (2D) cultured cells or three-dimensional (3D) cultured neurospheres cannot fully simulate complex 3D structure of neural tissues. Recent advancements in neural organoid systems provides excellent models for the testing of environmental chemicals that affect the development of human CNS. Neural organoids derived from hPSCs not only can simulate the process of CNS development, including early stage neural tube formation, neuroepithelium differentiation and regional specification, but also its 3D structure, thus can be used to evaluate the effect of chemicals on differentiation and morphogenesis. Here, we provide a review of recent progress in the methods of culturing neural organoids and their applications in neurotoxicity testing of environmental chemicals. We conclude by highlighting challenge and future directions in neurotoxicity testing based on neural organoids.

Ecotoxicity Risk of Low-Dose Methylmercury Exposure to Caenorhabditis elegans: Multigenerational Toxicity and Population Discrepancy.

Methylmercury (MeHg) is a common organic form of mercury in water, which has been linked to several forms of biological toxicity. However, studies on the ecotoxicity risk of long-term exposure to low-dose MeHg are insufficient for the assessment of environmental safety. In the present study, the effects of MeHg on multiple generations (P0-F3) and population of Caenorhabditis elegans were investigated under long-term, low-dose exposure. We investigated the multigenerational toxicity of MeHg by analyzing reproductive and developmental indicators. According to our results, exposure to 100 nM MeHg had little effect on the parental generation (P0) but caused serious reproductive toxicity in the offspring (F1-F3), and the effect of MeHg was aggravated with each passing generation. The genes related to apoptosis and DNA damage were upregulated in the F3 generation. Pearson correlation analysis showed that the changes in these genes were closely related to the apoptosis of gonadal cells. Furthermore, chronic exposure to MeHg (from 100 to 1000 nM group) caused a sharp decline in population size and triggered the "bag of worms" phenotype. Genes related to vulvar development were downregulated in the F3 generation after treatment with 100 nM MeHg. These data suggest that long-term low-dose MeHg exposure adversely affected C. elegans and its offspring and triggered multigenerational toxicity and population discrepancy.

Ceramide mediates radiation-induced germ cell apoptosis via regulating mitochondria function and MAPK factors in Caenorhabditis elegans.

Studies about radiation damage in vivo are very significant for healthy risk assessment as well as cancer radiotherapy. Ceramide as a second messenger has been found to be related to radiation-induced apoptosis. However, the detailed mechanisms in living systems are still not fully understood. In the present study, the effects of ceramide in gamma radiation-induced response were investigated using Caenorhabditis elegans. Our results indicated that ceramide was required for gamma radiation-induced whole-body germ cell apoptosis by the production of radical oxygen species and decrease of mitochondrial transmembrane potential. Using genetic ceramide synthase-related mutated strains and exogenous C16-ceramide, we illustrated that ceramide could regulate DNA damage response (DDR) pathway to mediate radiation-induced germ cell apoptosis. Moreover, ceramide was found to function epistatic to pmk-1 and mpk-1 in MAPK pathway to promote radiation-induced apoptosis in Caenorhabditis elegans. These results demonstrated ceramide could potentially mediated gamma radiation-induced apoptosis through regulating mitochondrial function, DDR pathway and MAPK pathway.

Mutagenicity of 7-ketocholesterol in CHO cells: The role of lipid peroxidation.

As an important cholesterol oxide, 7-ketocholesterol plays a deleterious role in the occurrence of cancer. Although the fact had been proved that 7-ketocholesterol could induce several biological phenomena, including apoptosis, DNA damage, et al., this issue whether 7-ketocholesterol led to mutagenesis in mammalian cells remains largely unexplored. Here, we investigated the major role of lipid peroxidation in the genotoxic response to 7-ketocholesterol in chinese hamster ovary (CHO) cells. The results showed that 7-ketocholesterol induced gene mutation and DNA double-strand breaks (DSBs) in concentration- and time-dependent manner. After CHO cells were treated with 25 µM 7-ketocholesterol for 48 h, the mutation frequency at hprt gene loci and the level of γ-H2AX protein were both significantly increased. Exposure to 7-ketocholesterol resulted in a concentration-dependent increase in the apoptotic rate and the protein expression of cleaved caspase-3 and -7 in CHO cells. Moreover, a significant increase of superoxide dismutase (SOD) activity and content of malondialdehyde (MDA) was also observed. Using a inhibitor of lipid peroxidation (butylated hydroxytoluene), it was found to remarkably inhibit the genotoxicity and MDA levels caused by 7-ketocholesterol. These findings indicated that lipid peroxidation was involved in the mutagenic process of 7-ketocholesterol in CHO cells.

Silver nanoparticle-activated COX2/PGE2 axis involves alteration of lung cellular senescence in vitro and in vivo.

Silver nanoparticles (AgNPs) are widely used as antimicrobial agents and resulted in their accumulation in environment. The purpose of this study was to investigate the detailed molecular mechanisms underlying AgNP-induced lung cellular senescence which has been proposed as a pathogenic driver of chronic lung disease. Herein, we demonstrate that exposure to AgNPs elevates multiple senescence biomarkers in lung cells, with cell cycle arrest in the G2/M phase, and potently activates genes of the senescence-associated secretory phenotype (SASP) in human fetal lung fibroblast cell line MRC5. Fluorescence-based assay also reveals that apoptosis induced by AgNPs is associated with senescence. Furthermore, we show that AgNPs cause premature senescence through an increase in transcription factor nuclear factor kappa B (NF-κB), cyclooxygenase-2 (COX2) expression and over-production of prostaglandin E2 (PGE2) in lung cells. Inhibition of COX2 reduces AgNPs-induced senescence to a normal level. Moreover, AgNPs also induce upregulation of COX2 and accelerate lung cellular senescence in vivo and cause mild fibrosis in the lung tissue of mice. Taken together, our studies support a critical role of AgNPs in the induction of lung cellular senescence via the upregulation of the COX2/PGE2 intracrine pathway, and suggest the adverse effects to the human respiratory system.

Effects of ionic strength on physicochemical properties and toxicity of silver nanoparticles.

In the environment, silver nanoparticles (AgNPs) undergo a number of potential transformations, such as aggregation, dissolution, and redox reactions. However, the transformation in ionic strength condition, as well as their related toxicity was not quite clear, especially in the in vivo system. In the present study, we comprehensively evaluated three different characteristics (ddH2O, EPA water and K+ medium (KM)) mediated changes in the physical morphology of AgNPs and the alteration of the toxicity to Caenorhabditis elegans (C. elegans). Our results showed besides the changes of AgNPs behavior such as the transformation of morphological, with the transmission electron microscopy we found for the first time that smaller nanoparticles (<5 nm) appeared around the pristine AgNPs after incubation in EPA or KM for 5 days. Together with these changes, the toxicity of AgNPs to C. elegans changed significantly, showing that a higher ionic strength medium resulted in greater toxicity to C. elegans, as measured by germ cell apoptosis, brood size and lifespan. More importantly, our results indicated that the higher toxicity of AgNPs to C. elegans reproduction was probably related to the appearance of the smaller-size AgNPs in higher ionic strength media. These findings highlight that toxicity assessments for the release of nanomaterial to the environment need to be improved to assess environmental safety more accurately.

Involvement of telomerase activity inhibition and telomere dysfunction in silver nanoparticles anticancer effects.

AIM: To investigate the possible mechanisms of telomerase and telomere underlying the anticancer effects of silver nanoparticles (AgNPs). MATERIALS & METHODS: 25nm polyvinylpyrrolidone-coated AgNPs were used. The telomerase activity and telomere function were evaluated. The anticancer effects of AgNPs were gauged with cell viability assay under different statement of telomerase and telomere. RESULTS & CONCLUSION: AgNPs could inhibit telomerase activity and lead to telomere shortening and dysfunction. Overexpression of telomerase attenuated the anticancer activity of AgNPs, whereas downregulation of telomerase activity or dysfunction of the telomere enhanced the cytotoxicity of AgNPs in HeLa cells. Our findings provided strong evidence that the anticancer effects of AgNPs were mediated via interference with the telomerase/telomere.