4-hydroxy-2-nonenal and Skin-Neoplasms

Topics: Aldehydes; Animals; Carcinogenesis; DNA Damage; Female; Humans; Melanoma; Metformin; Mice; Oxidative Stress; Radiation Injuries, Experimental; Radiodermatitis; Skin; Skin Neoplasms; Tumor Suppressor Protein p53; Tyrosine; Ultraviolet Rays

Ultraviolet (UV) radiation results in a significant loss in years of healthy life, approximately 1.5 million disability-adjusted life years (DALYs), and is associated with greater than 60,000 deaths annually worldwide that are attributed to melanoma and other skin cancers. Currently, there are no standardized biomarkers or assay panels to assess oxidative stress skin injury patterns in human skin exposed to ionizing radiation. Using biopsy specimens from chronic solar UV-exposed and UV-protected skin, we demonstrate that UV radiation-induced oxidative skin injury can be evaluated by an immunohistochemical panel that stains 8-hydroxydeoxyguanosine (8-OH-dG) to assess DNA adducts, 4-hydroxy-2-nonenal (HNE) to assess lipid peroxidation, and advanced glycation end products (AGEs) to assess protein damage. We believe this panel contains the necessary cellular biomarkers to evaluate topical agents, such as sunscreens and anti-oxidants that are designed to prevent oxidative skin damage and may reduce UV-associated skin aging, carcinogenesis, and inflammatory skin diseases. We envision that this panel will become an important tool for researchers developing topical agents to protect against UV radiation and other oxidants and ultimately lead to reductions in lost years of healthy life, DALYs, and annual deaths associated with UV radiation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Deoxyguanosine; DNA Adducts; Glycation End Products, Advanced; Humans; Immunohistochemistry; Lipid Peroxidation; Melanoma; Oxidative Stress; Skin; Skin Neoplasms; Ultraviolet Rays

The incidence of nonmelanoma skin cancer (NMSC) is equivalent to that of all other cancers combined. Previously, we mapped the 12-O-tetradecanoylphorbol-13-acetate (TPA) skin tumor promotion susceptibility locus, Psl1, to distal chromosome 9 in crosses of sensitive DBA/2 mice with relatively resistant C57BL/6 mice. Here, we used the mouse two-stage skin carcinogenesis model to identify the gene(s) responsible for the effects of Psl1.. Interval-specific congenic mouse strains (n ≥ 59 mice per strain) were used to more precisely map the Psl1 locus. Having identified glutathione S-transferase α4 (Gsta4) as a candidate tumor promotion susceptibility gene that mapped within the delimited region, we analyzed Gsta4-deficient mice (n = 62) for susceptibility to skin tumor promotion by TPA. We used quantitative polymerase chain reaction, western blotting, and immunohistochemistry to verify induction of Gsta4 in mouse epidermis following TPA treatment and biochemical assays to associate Gsta4 activity with tumor promotion susceptibility. In addition, single-nucleotide polymorphisms (SNPs) in GSTA4 were analyzed in a case-control study of 414 NMSC patients and 450 control subjects to examine their association with human NMSC. Statistical analyses of tumor studies in mice were one-sided, whereas all other statistical analyses were two-sided.. Analyses of congenic mice indicated that at least two loci, Psl1.1 and Psl1.2, map to distal chromosome 9 and confer susceptibility to skin tumor promotion by TPA. Gsta4 maps to Psl1.2 and was highly induced (mRNA and protein) in the epidermis of resistant C57BL/6 mice compared with that of sensitive DBA/2 mice following treatment with TPA. Gsta4 activity levels were also higher in the epidermis of C57BL/6 mice following treatment with TPA. Gsta4-deficient mice (C57BL/6.Gsta4(-/-) mice) were more sensitive to TPA skin tumor promotion (0.8 tumors per mouse vs 0.4 tumors per mouse in wild-type controls; difference = 0.4 tumors per mouse; 95% confidence interval = 0.1 to 0.7, P = .007). Furthermore, inheritance of polymorphisms in GSTA4 was associated with risk of human NMSC. Three SNPs were found to be independent predictors of NMSC risk. Two of these were associated with increased risk of NMSC (odds ratios [ORs] = 1.60 to 3.42), while the third was associated with decreased risk of NMSC (OR = 0.63). In addition, a fourth SNP was associated with decreased risk of basal cell carcinoma only (OR = 0.44).. Gsta4/GSTA4 is a novel susceptibility gene for NMSC that affects risk in both mice and humans.

Topics: Aldehydes; Animals; Carcinoma, Basal Cell; Case-Control Studies; Chromatography, Liquid; Cross-Linking Reagents; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Genotype; Glutathione Transferase; Humans; Immunohistochemistry; Mass Spectrometry; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Odds Ratio; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Risk Assessment; Risk Factors; RNA, Messenger; Skin Neoplasms; Time Factors

Trans-4-hydroxy-2-nonenal (HNE) is a product of lipid peroxidation. In the presence of t-butyl hydroperoxide the racemic HNE readily converts to its epoxide, 2,3-epoxy-4-hydroxynonanal (EH), as a pair of diastereomers. In this study, the potential roles of HNE and EH as tumor initiating agents were assessed. The mutagenicities of HNE and EH isomers in Salmonella strains TA100 and 104 were examined. In addition, the tumor initiating activities of HNE and EH were evaluated in bioassays involving either topical application in CD-1 mice or i.p. administration in newborn CD-1 mice. In the mutagenicity assays, EH isomers induced similar levels of revertants in both tester strains, although EG isomers were previously shown to react with bases in DNA with different specificity (Sodum, R.S. and Chung, F.-L., Cancer Res., 51, 137-143, 1991). The major isomer induced approximately 20,000 revertants/mumol in TA100 and 15,000 revertants/mumol in TA104, whereas, the minor isomer induced approximately 40,000 revertants/mumol in TA100 and 20,000 revertants/mumol in TA104. HNE was, however, not mutagenic under the assay conditions. In the tumor bioassays, EH was a weak tumorigen in CD-1 mice upon topical application followed by TPA promotion, yielding 0.55 tumors/mouse and 40% tumor incidence at a total dose of 128 mumol/mouse versus 0.02 tumors/mouse and 5% tumor incidence in the control group. Both HNE and EH induced liver tumors in male mice, but not in female mice. However, the incidences were not statistically significant. EH administered i.p. at a total dose of 200 nmol/mouse exacerbated the chronic spontaneous nephropathy in newborn CD-1 mice. Although the incidence of mild nephropathy was comparable in both EH-treated and control groups, the incidence of more severe lesions in mice treated with 200 nmol/mouse was 21%; while it was 0% in the control group. Furthermore, two mice at each dose level of EH showed a tubule profile with complex hyperplastic lining, suggestive of atypical hyperplasia. Again, HNE was not as active as EH in these bioassays. These results suggest a possible role of EH in tumorigenesis associated with lipid peroxidation.

Topics: Aldehydes; Animals; Animals, Newborn; Epoxy Compounds; Female; Kidney; Lipid Peroxidation; Liver Neoplasms, Experimental; Lung Neoplasms; Male; Mice; Mutagenicity Tests; Salmonella; Skin Neoplasms