{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T02:42:13Z","timestamp":1792204933150,"version":"4.4.0"},"reference-count":59,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T00:00:00Z","timestamp":1697414400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Millions of people around the world are exposed to elevated levels of arsenic through food or drinking water. Epidemiological studies have linked chronic arsenic exposure to an increased risk of several cancers, cardiovascular disease, central nervous system neuropathies, and genotoxic as well as immunotoxic effects. In addition to the induction of oxidative stress and inhibition of DNA repair processes, epigenetic effects, including altered DNA methylation patterns resulting in aberrant gene expression, may contribute to carcinogenicity. However, the underlying mechanisms by which chronic micromolar concentrations of arsenite affect the methylation status of DNA are not fully understood. In this study, human HepG2 hepatocarcinoma cells were treated with 0.5\u201310 \u03bcM sodium arsenite for 24 h, 10, or 20 days. During these periods, the effects on global DNA methylation, cell cycle phase distribution, and gene expression were investigated. While no impact on DNA methylation was seen after short-term exposure, global hypomethylation was observed at both long-term exposure periods, with concomitant induction of the DNA methyltransferase genes DNMT1 and DNMT3B, while DNMT3A was slightly down-regulated. Pronounced time- and concentration-dependent effects were also seen in the case of genes involved in DNA damage response and repair, inflammation, oxidative stress response, and metal homeostasis. These results suggest that chronic low-dose arsenite exposure can lead to global hypomethylation. As an underlying mechanism, the consistent down-regulation of DNA methyltransferase genes could be excluded; alternatively, interactions at the protein level could play an important role.<\/jats:p>","DOI":"10.3390\/ijms242015238","type":"journal-article","created":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T10:06:36Z","timestamp":1697450796000},"page":"15238","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Effect of Long-Term Low-Dose Arsenic Exposure on DNA Methylation and Gene Expression in Human Liver Cells"],"prefix":"10.3390","volume":"24","author":[{"given":"Sandra","family":"St\u00f6\u00dfer","sequence":"first","affiliation":[{"name":"Department of Food Chemistry and Toxicology, Institute of Applied Biosciences (IAB), Karlsruhe Institute of Technology (KIT), 76131 Karlsruhe, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatjana","family":"Lumpp","sequence":"additional","affiliation":[{"name":"Department of Food Chemistry and Toxicology, Institute of Applied Biosciences (IAB), Karlsruhe Institute of Technology (KIT), 76131 Karlsruhe, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franziska","family":"Fischer","sequence":"additional","affiliation":[{"name":"Department of Food Chemistry and Toxicology, Institute of Applied Biosciences (IAB), Karlsruhe Institute of Technology (KIT), 76131 Karlsruhe, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Gunesch","sequence":"additional","affiliation":[{"name":"Department of Food Chemistry and Toxicology, Institute of Applied Biosciences (IAB), Karlsruhe Institute of Technology (KIT), 76131 Karlsruhe, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Schumacher","sequence":"additional","affiliation":[{"name":"Department of Food Chemistry and Toxicology, Institute of Applied Biosciences (IAB), Karlsruhe Institute of Technology (KIT), 76131 Karlsruhe, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3826-3319","authenticated-orcid":false,"given":"Andrea","family":"Hartwig","sequence":"additional","affiliation":[{"name":"Department of Food Chemistry and Toxicology, Institute of Applied Biosciences (IAB), Karlsruhe Institute of Technology (KIT), 76131 Karlsruhe, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.yrtph.2018.09.010","article-title":"A review on arsenic carcinogenesis: Epidemiology, metabolism, genotoxicity and epigenetic changes","volume":"99","author":"Zhou","year":"2018","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Huang, H.W., Lee, C.H., and Yu, H.S. (2019). Arsenic-Induced Carcinogenesis and Immune Dysregulation. Int. J. Environ. Res. Public Health, 16.","DOI":"10.3390\/ijerph16152746"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"115299","DOI":"10.1016\/j.taap.2020.115299","article-title":"Balance between the toxicity and anticancer activity of arsenic trioxide in treatment of acute promyelocytic leukemia","volume":"409","author":"Wang","year":"2020","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_4","unstructured":"IARC (2012). Arsenic, metals, fibres, and dusts. IARC Monogr. Eval. Carcinog. Risks Hum., 100, 11\u2013465."},{"key":"ref_5","first-page":"49","article-title":"Arsenic and arsenic compounds (with the exception of arsine). MAK Value Documentation","volume":"Volume 21","author":"Greim","year":"2002","journal-title":"The MAK-Collection for Occupational Health and Safety. Part I: MAK Value Documentations"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.mrfmmm.2003.07.009","article-title":"Mechanism of arsenic carcinogenesis: An integrated approach","volume":"533","author":"Rossman","year":"2003","journal-title":"Mutat. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1002\/1098-2744(200102)30:2<79::AID-MC1016>3.0.CO;2-F","article-title":"Genetic events associated with arsenic-induced malignant transformation: Applications of cDNA microarray technology","volume":"30","author":"Chen","year":"2001","journal-title":"Mol. Carcinog."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Speer, R.M., Nandi, S.P., Cooper, K.L., Zhou, X., Yu, H., Guo, Y., Hudson, L.G., Alexandrov, L.B., and Liu, K.J. (2023). Arsenic is a potent co-mutagen of ultraviolet light. bioRxiv, preprint.","DOI":"10.1101\/2023.02.22.529578"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Riedmann, C., Ma, Y., Melikishvili, M., Godfrey, S.G., Zhang, Z., Chen, K.C., Rouchka, E.C., and Fondufe-Mittendorf, Y.N. (2015). Inorganic Arsenic-induced cellular transformation is coupled with genome wide changes in chromatin structure, transcriptome and splicing patterns. BMC Genom., 16.","DOI":"10.1186\/s12864-015-1295-9"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1196\/annals.1454.028","article-title":"Arsenic-induced aberrant gene expression in fetal mouse primary liver-cell cultures","volume":"1140","author":"Liu","year":"2008","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"87","DOI":"10.2217\/epi.09.45","article-title":"Effects of arsenic exposure on DNA methylation and epigenetic gene regulation","volume":"2","author":"Reichard","year":"2010","journal-title":"Epigenomics"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Zhang, W., and Xu, J. (2017). DNA methyltransferases and their roles in tumorigenesis. Biomark. Res., 5.","DOI":"10.1186\/s40364-017-0081-z"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Del Castillo Falconi, V.M., Torres-Arciga, K., Matus-Ortega, G., Diaz-Chavez, J., and Herrera, L.A. (2022). DNA Methyltransferases: From Evolution to Clinical Applications. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23168994"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1002\/tox.23026","article-title":"Inorganic arsenic-mediated upregulation of AS3MT promotes proliferation of nonsmall cell lung cancer cells by regulating cell cycle genes","volume":"36","author":"Sun","year":"2021","journal-title":"Environ. Toxicol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"111752","DOI":"10.1016\/j.ecoenv.2020.111752","article-title":"Different mechanisms of arsenic related signaling in cellular proliferation, apoptosis and neo-plastic transformation","volume":"208","author":"Medda","year":"2021","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2745","DOI":"10.1007\/s00204-015-1621-7","article-title":"Use of high-throughput RT-qPCR to assess modulations of gene expression profiles related to genomic stability and interactions by cadmium","volume":"90","author":"Fischer","year":"2016","journal-title":"Arch. Toxicol."},{"key":"ref_17","first-page":"171","article-title":"Arsenic and inorganic arsenic compounds (with the exception of arsenic hydride and its salts). BAT Value Documentation","volume":"Volume 4","author":"Drexler","year":"2003","journal-title":"The MAK-Collection for Occupational Health and Safety. Part II: BAT Value Documentations"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/s12199-011-0247-5","article-title":"Arsenic speciation analysis of urine samples from individuals living in an arsenic-contaminated area in Bangladesh","volume":"17","author":"Hata","year":"2012","journal-title":"Environ. Health Prev. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"10907","DOI":"10.1073\/pnas.94.20.10907","article-title":"Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression","volume":"94","author":"Zhao","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2811","DOI":"10.1093\/jn\/131.11.2811","article-title":"Intracellular S-adenosylhomocysteine concentrations predict global DNA hypomethylation in tissues of methyl-deficient cystathionine beta-synthase heterozygous mice","volume":"131","author":"Caudill","year":"2001","journal-title":"J. Nutr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"120090","DOI":"10.1016\/j.envpol.2022.120090","article-title":"As3MT-mediated SAM consumption, which inhibits the methylation of histones and LINE1, is involved in arsenic-induced male reproductive damage","volume":"313","author":"Wu","year":"2022","journal-title":"Environ. Pollut."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.taap.2004.05.004","article-title":"Interindividual variation in the metabolism of arsenic in cultured primary human hepatocytes","volume":"201","author":"Drobna","year":"2004","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1021\/tx060076u","article-title":"shRNA silencing of AS3MT expression minimizes arsenic methylation capacity of HepG2 cells","volume":"19","author":"Drobna","year":"2006","journal-title":"Chem. Res. Toxicol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1007\/s00204-011-0710-5","article-title":"Analysis of arsenic metabolites in HepG2 and AS3MT-transfected cells","volume":"85","author":"Watanabe","year":"2011","journal-title":"Arch. Toxicol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/ijc.10911","article-title":"Very low concentrations of arsenite suppress poly(ADP-ribosyl)ation in mammalian cells","volume":"104","author":"Hartwig","year":"2003","journal-title":"Int. J. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1080\/10623320390233391","article-title":"Modulation of the arsenic effects on cytotoxicity, viability, and cell cycle in porcine endothelial cells by selenium","volume":"10","author":"Yeh","year":"2003","journal-title":"Endothelium"},{"key":"ref_27","first-page":"121","article-title":"Toxicity of Arsenic (III) on Isolated Liver Mitochondria: A New Mechanistic Approach","volume":"12","author":"Hosseini","year":"2013","journal-title":"Iran. J. Pharm. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1177\/1091581816645797","article-title":"In Vivo and In Vitro Arsenic Exposition Induces Oxidative Stress in Anterior Pituitary Gland","volume":"35","author":"Ronchetti","year":"2016","journal-title":"Int. J. Toxicol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2113","DOI":"10.18632\/aging.203930","article-title":"Human endothelial cells promote arsenic-transformed lung epithelial cells to induce tumor growth and angiogenesis through interleukin-8 induction","volume":"14","author":"Zhao","year":"2022","journal-title":"Aging"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1016\/j.taap.2013.06.017","article-title":"Involvement of HIF-2alpha-mediated inflammation in arsenite-induced transformation of human bronchial epithelial cells","volume":"272","author":"Xu","year":"2013","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1016\/j.bbamcr.2012.01.005","article-title":"The taste of heavy metals: Gene regulation by MTF-1","volume":"1823","author":"Guenther","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.7150\/jca.56777","article-title":"The correlation and role analysis of SLC30A1 and SLC30A10 in cervical carcinoma","volume":"13","author":"Zhang","year":"2022","journal-title":"J. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"104925","DOI":"10.1016\/j.tiv.2020.104925","article-title":"Chronic and acute arsenic exposure enhance EGFR expression via distinct molecular mechanisms","volume":"67","author":"Kim","year":"2020","journal-title":"Toxicol. In Vitro"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1093\/carcin\/bgh295","article-title":"Arsenite induces prominent mitotic arrest via inhibition of G2 checkpoint activation in CGL-2 cells","volume":"26","author":"Yih","year":"2005","journal-title":"Carcinogenesis"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3969","DOI":"10.1007\/s13277-015-3040-z","article-title":"Arsenic trioxide inhibits growth of human chondrosarcoma cells through G2\/M arrest and apoptosis as well as autophagy","volume":"36","author":"Jiao","year":"2015","journal-title":"Tumour Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"39","DOI":"10.18632\/genesandcancer.185","article-title":"Chronic low dose arsenic exposure preferentially perturbs mitotic phase of the cell cycle","volume":"10","author":"Ganapathy","year":"2019","journal-title":"Genes. Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1002\/ijc.10968","article-title":"Decreased DNA repair gene expression among individuals exposed to arsenic in United States drinking water","volume":"104","author":"Andrew","year":"2003","journal-title":"Int. J. Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1039\/c2mt20120h","article-title":"Environmental arsenic exposure and DNA methylation of the tumor suppressor gene p16 and the DNA repair gene MLH1: Effect of arsenic metabolism and genotype","volume":"4","author":"Hossain","year":"2012","journal-title":"Metallomics"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2272","DOI":"10.1093\/hmg\/ddm179","article-title":"Role of the Dnmt3 family in de novo methylation of imprinted and repetitive sequences during male germ cell development in the mouse","volume":"16","author":"Kato","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/S0092-8674(00)81656-6","article-title":"DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development","volume":"99","author":"Okano","year":"1999","journal-title":"Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1146\/annurev.biochem.74.010904.153721","article-title":"Eukaryotic cytosine methyltransferases","volume":"74","author":"Goll","year":"2005","journal-title":"Annu. Rev. Biochem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/S0070-2153(04)60003-2","article-title":"Structure and function of eukaryotic DNA methyltransferases","volume":"60","author":"Chen","year":"2004","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"17986","DOI":"10.1074\/jbc.M413246200","article-title":"Inactivation of Dnmt3b in mouse embryonic fibroblasts results in DNA hypomethylation, chromosomal instability, and spontaneous immortalization","volume":"280","author":"Dodge","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/nn.2514","article-title":"Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons","volume":"13","author":"Feng","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1158\/0008-5472.CAN-05-1980","article-title":"De novo CpG island methylation in human cancer cells","volume":"66","author":"Jair","year":"2006","journal-title":"Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"12253","DOI":"10.1073\/pnas.2037852100","article-title":"Predicting aberrant CpG island methylation","volume":"100","author":"Feltus","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.taap.2004.11.017","article-title":"Molecular events associated with arsenic-induced malignant transformation of human prostatic epithelial cells: Aberrant genomic DNA methylation and K-ras oncogene activation","volume":"206","author":"Waterland","year":"2005","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.humpath.2005.10.013","article-title":"Arsenic trioxide inhibits DNA methyltransferase and restores methylation-silenced genes in human liver cancer cells","volume":"37","author":"Cui","year":"2006","journal-title":"Hum. Pathol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"41474","DOI":"10.1038\/srep41474","article-title":"Genome-wide DNA methylation reprogramming in response to inorganic arsenic links inhibition of CTCF binding, DNMT expression and cellular transformation","volume":"7","author":"Rea","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.freeradbiomed.2012.11.009","article-title":"Metal interaction with redox regulation: An integrating concept in metal carcinogenesis?","volume":"55","author":"Hartwig","year":"2013","journal-title":"Free Radic. Biol. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.dnarep.2006.08.008","article-title":"Impact of arsenite and its methylated metabolites on PARP-1 activity, PARP-1 gene expression and poly(ADP-ribosyl)ation in cultured human cells","volume":"6","author":"Walter","year":"2007","journal-title":"DNA Repair"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"22855","DOI":"10.1074\/jbc.M111.232926","article-title":"Arsenite interacts selectively with zinc finger proteins containing C3H1 or C4 motifs","volume":"286","author":"Zhou","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1016\/j.dnarep.2003.09.001","article-title":"Arsenite and its biomethylated metabolites interfere with the formation and repair of stable BPDE-induced DNA adducts in human cells and impair XPAzf and Fpg","volume":"2","author":"Schwerdtle","year":"2003","journal-title":"DNA Repair"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1021\/tx7003135","article-title":"Monomethylarsonous acid destroys a tetrathiolate zinc finger much more efficiently than inorganic arsenite: Mechanistic considerations and consequences for DNA repair inhibition","volume":"21","author":"Piatek","year":"2008","journal-title":"Chem. Res. Toxicol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.semcancer.2021.05.009","article-title":"Arsenic co-carcinogenesis: Inhibition of DNA repair and interaction with zinc finger proteins","volume":"76","author":"Zhou","year":"2021","journal-title":"Semin. Cancer Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1002\/cbic.201000195","article-title":"Structure and function of mammalian DNA methyltransferases","volume":"12","author":"Jurkowska","year":"2011","journal-title":"Chembiochem"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"10000","DOI":"10.1021\/bi8011725","article-title":"CXXC domain of human DNMT1 is essential for enzymatic activity","volume":"47","author":"Pradhan","year":"2008","journal-title":"Biochemistry"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e54147","DOI":"10.15252\/embr.202154147","article-title":"Developmental arsenic exposure impairs cognition, directly targets DNMT3A, and reduces DNA methylation","volume":"23","author":"Yan","year":"2022","journal-title":"EMBO Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/20\/15238\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:07:52Z","timestamp":1760130472000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/20\/15238"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,16]]},"references-count":59,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["ijms242015238"],"URL":"https:\/\/doi.org\/10.3390\/ijms242015238","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,16]]}}}