title: Stress gene activity in HepG2 cells after sulfur mustard exposure.
abstract: Monitoring temporal stress gene (SG) levels is one method of characterizing cellular responses to toxic-level chemical exposures. The goal of this study was to determine human cellular SG profiles following sulfur mustard (SM) exposure. This would establish a baseline for development of a rapid screening method for potential therapeutic compounds that could modulate SM toxicity. We used a panel of cells consisting of 14 HepG2-derived cell lines each stably transformed with a stress gene promoter (SGP) or stress gene response element (SGRE) controlling the transcription of the reporter gene chloramphenicol acetyltransferase (CAT). The SGP and SGRE reporter constructs represent SGs associated with DNA damage, protein damage, oxidative stress, inflammation, second messenger systems and xenobiotic metabolism enzymes. All SGP and SGRE activities were changed from control following SM exposure over dose and the 24-h time-course study. Metallothionein 2A promoter (MT2A) was induced throughout the study time at high SM concentration. DNA-damage markers were induced after 12 h. Protein damage, inflammation and second messenger systems increased after 16 h post-SM exposure. These results show that over time and increasing SM exposure concentrations the HepG2 cells produced differential activation of SGPs and SGREs associated with DNA and protein damage, second messenger system activation and inflammation/oxidative stress. This suggests that the HepG2 cell reporter construct system would be a useful tool for studying the effects of known therapeutic drug families that may lower these cell-damage markers during SM exposure.
authors.affiliation: Applied Pharmacology Branch, Pharmacology Division, United States Army Medical Research Institute of Chemical Defense, APG, MD 21010-5400, USA. john.schlager@amedd.army.mil
authors.forename: J J
authors.initials: JJ
authors.lastname: Schlager
authors.forename: B W
authors.initials: BW
authors.lastname: Hart
mesh_terms: D002273:Carcinogens / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008113:Liver Neoplasms / Q000473:pathology; D009151:Mustard Gas / Q000633:toxicity*; D010084:Oxidation-Reduction; D011401:Promoter Regions, Genetic / Q000187:drug effects; D013312:Stress, Physiological / Q000235:genetics*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D002273:Carcinogens; D015500:Chloramphenicol O-Acetyltransferase; D009151:Mustard Gas