title: Deoxynivalenol induced mouse skin tumor initiation: Elucidation of molecular mechanisms in human HaCaT keratinocytes.
abstract: Among food contaminants, mycotoxins are toxic to both human and animal health. Our prior studies suggest that Deoxynivalenol (DON), a mycotoxin, behaves as a tumor promoter by inducing edema, hyperplasia, ODC activity and activation of MAPK's in mouse skin. In this study, topical application of DON, 336 and 672 nmol significantly enhanced ROS levels, DNA damage and apoptosis with concomitant downregulation of Ki-67, cyclin D, cyclin E, cyclin A and cyclin-dependent kinases (CDK4 and CDK2) thereby resulting in tumor initiation in mouse skin. Further, the elucidation of molecular mechanisms of tumor initiation by DON (0.42-3.37 nmol/ml) in HaCaT keratinocytes, revealed (i) enhanced ROS generation with cell cycle phase arrest in G0/G1 phase, (ii) increase in levels of 8-OxoG (6-24 hr) and γH2AX protein, (iii) significant enhancement in oxidative stress marker enzymes LPO, GSH, GR with concomitant decrease in antioxidant enzymes catalase, GPx, GST, SOD and mitochondrial membrane potential after DON (1.68 nmol) treatment, (iv) suppression of Nrf2 translocation to nucleus, enhanced phosphorylation with subsequent activation ERK1/2, p38 and JNK MAPK's following DON (1.68 nmol) treatment, (v) overexpression of c-jun, c-fos proteins, upregulation of Bax along with downregulation of Bcl-2 proteins, (vi) increase in cytochrome-c, caspase-9, caspase-3 and poly ADP ribose polymerase levels leads to apoptosis. Pretreatment of superoxide dismutase, mannitol and ethanol to HaCaT cells resulted in significant reduction in ROS levels and apoptosis indicating the role of superoxide and hydroxyl radicals in DON induced apoptosis as an early event and skin tumor initiation as a late event.
authors.affiliation: Food Drug and Chemical Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India.|Department of Biochemistry, Banaras Hindu University (BHU), Varanasi, Uttar Pradesh, India.
authors.forename: Sakshi
authors.initials: S
authors.lastname: Mishra
authors.affiliation: Food Drug and Chemical Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India.
authors.forename: Prachi
authors.initials: P
authors.lastname: Tewari
authors.affiliation: Pathology Laboratory, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, Uttar Pradesh, 226001, India.
authors.forename: Bhushan P
authors.initials: BP
authors.lastname: Chaudhari
authors.affiliation: Food Drug and Chemical Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India.
authors.forename: Premendra D
authors.initials: PD
authors.lastname: Dwivedi
authors.affiliation: Department of Biochemistry, Banaras Hindu University (BHU), Varanasi, Uttar Pradesh, India.
authors.forename: Haushila P
authors.initials: HP
authors.lastname: Pandey
authors.affiliation: Food Drug and Chemical Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India.
authors.forename: Mukul
authors.initials: M
authors.lastname: Das
mesh_terms: D000818:Animals; D017209:Apoptosis; D002273:Carcinogens / Q000633:toxicity*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D004249:DNA Damage; D005506:Food Contamination; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D017382:Reactive Oxygen Species / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000378:metabolism; D014255:Trichothecenes / Q000633:toxicity*
chemical_list: D002273:Carcinogens; D018797:Cell Cycle Proteins; D017382:Reactive Oxygen Species; D014255:Trichothecenes; C007262:deoxynivalenol
keywords: DNA damage; HaCaT cells; deoxynivalenol; mycotoxins; oxidative stress; tumor initiation