title: Chemically-induced unscheduled DNA synthesis in cultures of adult human epidermal keratinocytes.
abstract: Skin is a major target organ for many experimental carcinogens that exist in our environment and the majority of previous carcinogenicity studies have utilised animal derived models. In view of the fact, that many of these environmental chemicals exhibit species- and tissue-specific metabolism, a human skin tissue derived model would be a distinct advantage. Squamous epithelial carcinoma is a predominant form of skin cancer in man and, in theory, human epidermal keratinocytes present an appropriate target cell to employ as an in vitro system to study epidermal carcinogenesis. This report demonstrates the valuable potential of human keratinocyte cultures as a suitable model for mechanistic studies on factors which may influence DNA damage and, hence, the subsequent development of cancer in human epidermis. Keratinocytes were serially cultivated from adult human skin samples and maintained in culture for at least 3 passages. Tertiary cultures, isolated from 3 separate individuals, were exposed to the direct-acting experimental carcinogen, methyl methanesulphonate (CAS No. 66-27-3), and benzo[a]pyrene (CAS No. 50-32-8), which requires metabolic activation. DNA repair was assessed by a quantitative autoradiographic technique. Methyl methanesulphonate and benzo[a]pyrene both elicited a dose-related increase in unscheduled DNA synthesis in cultures prepared from each individual. Inter-individual variation in the response was observed for each chemical, but this was greater in the case of benzo[a]pyrene, which indicates inter-individual variation in both xenobiotic metabolism activity and DNA repair capacity.
authors.affiliation: Robens Institute of Health and Safety, University of Surrey, Guildford UK.
authors.forename: J N
authors.initials: JN
authors.lastname: Lawrence
authors.forename: D J
authors.initials: DJ
authors.lastname: Benford
mesh_terms: D000328:Adult; D001564:Benzo(a)pyrene; D015197:Carcinogenicity Tests / Q000379:methods; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced*; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis* / Q000187:drug effects; D004249:DNA Damage; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects*; D008741:Methyl Methanesulfonate; D009152:Mutagenicity Tests / Q000379:methods*; D009499:Neutral Red / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced*
chemical_list: D009499:Neutral Red; D001564:Benzo(a)pyrene; D004247:DNA; D008741:Methyl Methanesulfonate