{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T19:33:56Z","timestamp":1792956836449,"version":"4.5.0"},"reference-count":115,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T00:00:00Z","timestamp":1791676800000},"content-version":"vor","delay-in-days":10,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001409","name":"Department of Science and Technology, Ministry of Science and Technology, India","doi-asserted-by":"publisher","award":["SR\/WOS\u2010A\/LS\u2010444\/2018 (G)"],"award-info":[{"award-number":["SR\/WOS\u2010A\/LS\u2010444\/2018 (G)"]}],"id":[{"id":"10.13039\/501100001409","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Biochem &amp;amp; Molecular Tox"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>In light of the increasing exposure to folate and its unresolved relationship with skin cancer, experimental studies are warranted to better understand and define its role in skin carcinogenesis. The present study evaluated the effects of folic acid supplementation on cutaneous squamous cell carcinoma (cSCC) in mice and explored the underlying mechanisms. A two\u2010stage skin carcinogenesis model was employed using 7,12\u2010dimethylbenz[a]anthracene (DMBA) and 12\u2010O\u2010tetradecanoyl phorbol\u201013\u2010acetate (TPA) as initiator and tumor promoter respectively. LACA mice were orally supplemented with folic acid (FA) at doses of 1 or 2\u2009mg\/kg body weight and divided into six groups: control, DMBA\/TPA, FA1(1\u2009mg\/kg) + DMBA\/TPA, FA2(2\u2009mg\/kg) + DMBA\/TPA, FA1 and FA2 groups. Supplementation began 4 weeks prior to tumor induction and continued for twenty weeks. Histopathological analysis confirmed cSCC development. During the early stages, papilloma incidence was higher in FA1\u2009+\u2009DMBA\/TPA and FA2\u2009+\u2009DMBA\/TPA groups in comparison to DMBA\/TPA group. However, by the end of the treatment period, lesion incidence reached 100% in all groups, with a greater total lesion count and lesion burden observed in the supplemented groups its indicating pro\u2010carcinogenic effects. Enhanced cellular proliferation in these groups was evident from histomorphometric assessments and increased expression of proliferating cell nuclear antigen and folate transporters. Increase in tumorigenesis was also associated with enhanced activity of serum lactate dehydrogenase, oxidative DNA damage and inhibition in expression of MGMT gene. However, no noteworthy difference was observed between two levels of supplementation. These findings suggest that folic acid supplementation may promote skin tumorigenesis through increased proliferation, enhanced DNA damage, and impaired DNA repair mechanisms.<\/jats:p>","DOI":"10.1002\/jbt.71117","type":"journal-article","created":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T13:27:03Z","timestamp":1791725223000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pro\u2010Carcinogenic Implications of Folic Acid Supplementation During Chemically Induced Cutaneous Squamous Cell Carcinoma in Mice"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4051-4113","authenticated-orcid":false,"given":"Neha Arora","family":"Chugh","sequence":"first","affiliation":[{"name":"Department of Biophysics, Basic Medical Sciences Block\u2010II Panjab University, South Campus Chandigarh India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shashi","family":"Bala","sequence":"additional","affiliation":[{"name":"Department of Biophysics, Basic Medical Sciences Block\u2010II Panjab University, South Campus Chandigarh India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7296-9705","authenticated-orcid":false,"given":"Tuhin","family":"Mallick","sequence":"additional","affiliation":[{"name":"Department of Biophysics, Basic Medical Sciences Block\u2010II Panjab University, South Campus Chandigarh India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7522-412X","authenticated-orcid":false,"given":"Ashwani","family":"Koul","sequence":"additional","affiliation":[{"name":"Department of Biophysics, Basic Medical Sciences Block\u2010II Panjab University, South Campus Chandigarh India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,11]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2023.105457"},{"key":"e_1_2_9_3_1","article-title":"Membrane Transporters and Folate Homeostasis: Intestinal Absorption and Transport Into Systemic Compartments and Tissues","volume":"13","author":"Zhao R.","year":"2011","journal-title":"Expert Reviews in Molecular Medicine"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/foods12081612"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu3030370"},{"key":"e_1_2_9_6_1","article-title":"Global Heterogeneity in Folic Acid Fortification Policies and Implications for Prevention of Neural Tube Defects and Stroke: A Systematic Review","volume":"66","author":"Quinn M.","year":"2023","journal-title":"Clinical Medicine"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/MEG.0b013e328306ccdb"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-814639-2.00032-0"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1177\/03000605231223064"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26051967"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.7189\/jogh.16.04102"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/em.20025"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40495-016-0046-1"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0084635"},{"key":"e_1_2_9_15_1","first-page":"115","article-title":"The Role of Folic Acid in Carcinogenesis, Diagnosis, and Treatment of Cancer","volume":"1","author":"Rashedi J.","year":"2018","journal-title":"International Journal of Biomedicine and Public Health"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules26123731"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.31083\/IJVNR26221"},{"key":"e_1_2_9_18_1","first-page":"3198S","article-title":"Folate and Carcinogenesis: Evidence, Mechanisms, and Implications","volume":"134","author":"Kim Y. I.","year":"2004","journal-title":"Journal of Nutrition"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25179339"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgl156"},{"key":"e_1_2_9_21_1","first-page":"1","article-title":"Original Paper Association of Methylenetetrahydrofolate Reductase Gene Polymorphisms With Basal Cell Carcinoma Development","volume":"28","author":"W\u00f3dz\u2010Naskiewicz K.","year":"2011","journal-title":"Advances in Dermatology and Allergology\/Post?py Dermatologii i Alergologii"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.3945\/ajcn.2009.28319"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.28038"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.3945\/ajcn.115.109041"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.11872"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.5021\/ad.2014.26.5.570"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.22061"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.3945\/ajcn.112.057562"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/mutage\/gead007"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.10798"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canep.2018.06.006"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jphotobiol.2010.02.003"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-94-007-2199-9_10"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25021046"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)62001-7"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2014.155"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13668-018-0237-y"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/nqaa259"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu15214699"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1080\/19390211.2017.1322659"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2017.171074"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2009.120"},{"key":"e_1_2_9_43_1","first-page":"215","article-title":"Ethanolic Neem Leaf Extract Protects Against N\u2010Methyl\u2010N\u2019\u2010Nitro\u2010N\u2010Nitrosoguanidine\u2010Induced Gastric Carcinogenesis in Wistar Rats","volume":"4","author":"Subapriya R.","year":"2003","journal-title":"Asian Pacific Journal of Cancer Prevention: APJCP"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/ptr.3280"},{"key":"e_1_2_9_45_1","unstructured":"L. G.Humanson1961. Animal Tissue Technique 2nd Edition. San Francisco CA: W.H. Freeman and Company."},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/9.11.1959"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1024\/0300-9831\/a000597"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-091302-2.50010-4"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/11.5.1475"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/131.1.21"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)52451-6"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0902072106"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2006.095463"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.3322\/canjclin.56.5.254"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amsu.2022.104170"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1002\/mnfr.200600191"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.EPI-07-2557"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.EPI-07-2952"},{"key":"e_1_2_9_59_1","first-page":"13","article-title":"Histopathological Variants of Cutaneous Squamous Cell Carcinoma: A Review","volume":"210813","author":"Yanofsky V. R.","year":"2011","journal-title":"Journal of Skin Cancer"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells12010064"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.5021\/ad.22.175"},{"key":"e_1_2_9_62_1","first-page":"6","article-title":"Tumor Infiltrating Lymphocytes in Cutaneous Squamous Cell Carcinoma","volume":"13","author":"Loo L. Y.","year":"2026","journal-title":"Current Oncology (Toronto, Ont.)"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2009.05.008"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgp019"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.1093\/aob\/mcq243"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12903-019-0928-9"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.acthis.2016.05.002"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chroma.2019.06.008"},{"key":"e_1_2_9_69_1","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000019755"},{"key":"e_1_2_9_70_1","doi-asserted-by":"publisher","DOI":"10.3727\/096504011X12970940207724"},{"key":"e_1_2_9_71_1","doi-asserted-by":"publisher","DOI":"10.4254\/wjh.v8.i29.1222"},{"key":"e_1_2_9_72_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12018-024-09296-1"},{"key":"e_1_2_9_73_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0083-6729(08)00405-6"},{"key":"e_1_2_9_74_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdv250"},{"key":"e_1_2_9_75_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2021.12.003"},{"key":"e_1_2_9_76_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.9651"},{"key":"e_1_2_9_77_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.708214"},{"key":"e_1_2_9_78_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-019-1123-1"},{"key":"e_1_2_9_79_1","first-page":"2169","article-title":"Reduced Folate Carrier Gene Expression in Childhood Acute Lymphoblastic Leukemia: Relationship to Immunophenotype and Ploidy","volume":"4","author":"Zhang L.","year":"1998","journal-title":"Clinical Cancer Research: An Official Journal of the American Association for Cancer Research"},{"key":"e_1_2_9_80_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-04-0116"},{"key":"e_1_2_9_81_1","first-page":"621","article-title":"Mechanisms of Methotrexate Resistance in Osteosarcoma","volume":"5","author":"Guo W.","year":"1999","journal-title":"Clinical Cancer Research: An Official Journal of the American Association for Cancer Research"},{"key":"e_1_2_9_82_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-007-9046-2"},{"key":"e_1_2_9_83_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0021820"},{"key":"e_1_2_9_84_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-026-07993-7"},{"key":"e_1_2_9_85_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.843369"},{"key":"e_1_2_9_86_1","doi-asserted-by":"publisher","DOI":"10.1002\/cac2.70008"},{"key":"e_1_2_9_87_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12263-013-0369-z"},{"key":"e_1_2_9_88_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-08-101210-9.00005-6"},{"key":"e_1_2_9_89_1","first-page":"5434","article-title":"Effects of Dietary Folate on Intestinal Tumorigenesis in the apcMin Mouse","volume":"60","author":"Song J.","year":"2000","journal-title":"Cancer Research"},{"key":"e_1_2_9_90_1","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/88.2.448"},{"key":"e_1_2_9_91_1","doi-asserted-by":"publisher","DOI":"10.3945\/jn.115.211185"},{"key":"e_1_2_9_92_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00385.2005"},{"key":"e_1_2_9_93_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu11102353"},{"key":"e_1_2_9_94_1","unstructured":"National Institute of Health. Office of Dietary Supplements Folate Fact Sheet for Health Professionals."},{"key":"e_1_2_9_95_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19040970"},{"key":"e_1_2_9_96_1","doi-asserted-by":"publisher","DOI":"10.1080\/10590500902885684"},{"key":"e_1_2_9_97_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2020.101724"},{"key":"e_1_2_9_98_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrestox.2c00258"},{"key":"e_1_2_9_99_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41421-022-00512-0"},{"key":"e_1_2_9_100_1","doi-asserted-by":"publisher","DOI":"10.3390\/cimb44040097"},{"key":"e_1_2_9_101_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfq371"},{"key":"e_1_2_9_102_1","doi-asserted-by":"publisher","DOI":"10.1021\/tx200031q"},{"key":"e_1_2_9_103_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers16020331"},{"key":"e_1_2_9_104_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1319"},{"key":"e_1_2_9_105_1","doi-asserted-by":"publisher","DOI":"10.12998\/wjcc.v2.i12.835"},{"key":"e_1_2_9_106_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13148-017-0374-y"},{"key":"e_1_2_9_107_1","doi-asserted-by":"publisher","DOI":"10.3945\/an.111.000992"},{"key":"e_1_2_9_108_1","first-page":"30426","article-title":"Lactate Dehydrogenase a Potential Diagnostic Biomarker for Cancer: A Review of Literature","volume":"38","author":"Puranik N.","year":"2021","journal-title":"BJSTR"},{"key":"e_1_2_9_109_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2011-000653"},{"key":"e_1_2_9_110_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0100044"},{"key":"e_1_2_9_111_1","first-page":"5002","article-title":"Folate Deficiency Enhances the Development of Colonic Neoplasia in Dimethylhydrazine\u2010Treated Rats","volume":"52","author":"Cravo M. L.","year":"1992","journal-title":"Cancer Research"},{"key":"e_1_2_9_112_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgg036"},{"key":"e_1_2_9_113_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M410818200"},{"key":"e_1_2_9_114_1","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.EPI-10-1352"},{"key":"e_1_2_9_115_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13293-020-00291-x"},{"key":"e_1_2_9_116_1","doi-asserted-by":"publisher","DOI":"10.1002\/ski2.27"}],"container-title":["Journal of Biochemical and Molecular Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jbt.71117","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jbt.71117","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jbt.71117","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T18:59:42Z","timestamp":1792954782000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jbt.71117"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10]]},"references-count":115,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1002\/jbt.71117"],"URL":"https:\/\/doi.org\/10.1002\/jbt.71117","archive":["Portico"],"relation":{},"ISSN":["1095-6670","1099-0461"],"issn-type":[{"value":"1095-6670","type":"print"},{"value":"1099-0461","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10]]},"assertion":[{"value":"2026-02-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e71117"}}