Infrared spectral models demonstrate that exposure to environmental chemicals leads to new forms of DNA

Abstract

Environmental chemicals are known to induce a high degree of hydroxyl radical-mediated damage in DNA. Accordingly, we tested the hypothesis that this exposure leads to new forms of DNA using principal components analysis of Fourier transform infrared spectra. The hepatic DNA of English sole (controls) from an essentially clean environment was compared with that of sole inhabiting a chemically contaminated environment. All livers studied were cancer-free; however, a high incidence of liver cancer has been found in the exposed population. The exposed sole were sampled twice, 2 years apart, while the sediments in which they live were under remediation. After obtaining infrared spectra, the first three principal components (PC1, PC2, and PC3) were calculated and found to represent 97% of the total spectral variance. When the principal component scores were plotted in 3-dimensional space, clusters of points were obtained that represented the DNA from the control and exposed groups. Each of the points was derived from Ϸ10 6 wavenumber-absorbance correlations. The spatial location of a point was a highly discriminating measure of DNA structure. The clusters of points were completely separated, demonstrating that the three groups could be 100% correctly classified. The points from the control group were tightly clustered whereas those from the exposed groups were highly diverse. The findings demonstrate that exposure to environmental chemicals results in new, structurally diverse forms of DNA that likely play an important role in carcinogenesis.English sole exposed to environmental chemicals in their natural habitat (Duwamish River, Seattle, WA) have been shown to have a remarkably high degree of base damage resulting from the attack of the hydroxyl radical (⅐OH) on DNA (1). The base damage included substantial increases in mutagenic hydroxy derivatives [8-hydroxyadenine (8-OHAde) and 8-hydroxyguanine (8-OH-Gua)] (2, 3) and ringopened products [e.g., 2,6-diamino-4-hydroxy-5-formamidopyrimidine] compared with controls. In another study of English sole from the Duwamish River (4), positive correlations were found between 8-OH-Ade and 8-OH-Gua and incidences of a variety of nonneoplastic hepatic lesions. These included basophilic foci (a putatively preneoplastic lesion) and megalocytic hepatosis (a putatively degenerative or cytotoxic lesion) (5, 6). The ⅐OH was likely a common etiological factor in the formation of the base modifications and the hepatic lesions, which is consistent with its proposed role in tumor formation (7)(8)(9)(10)(11). The sole population from the Duwamish River was shown to have a high incidence of liver cancer; however, this condition rarely occurs in fish from uncontaminated environments (5, 6).The ⅐OH is believed to arise from H 2 O 2 via the Fe 2ϩ -mediated Fenton reaction (12). H 2 O 2 , which readily crosses the nuclear membrane, is likely produced via redox cycling of sediment contaminants, such as polynuclear aromatic hydrocarbons and chlorinated pesticides, to which the fish are ex...

Single 8-oxo-guanine and 8-oxo-adenine lesions induce marked changes in the backbone structure of a 25-base DNA strand

“…In an attempt to answer this question, we used Fourier transform-infrared (FT-IR) spectroscopy with multivariate statistics to delineate structural differences between thin films of a 25-base DNA strand and comparable strands containing centrally located single G o and A o groups. FT-IR͞statistical analysis was previously used to study subtle changes in base and phospho-deoxyribose structures of DNA in relation to tumor progression (13)(14)(15)(16)(17)(18)(19). In the present study, a number of spectral differences attributable to base interactions and backbone conformations were identified between the 25-base parent strand and derivatives containing G o and A o substituents.…”

“…In this regard, FT-IR spectroscopy with multivariate statistics is known to be sensitive to subtle changes in the base and backbone structures of DNA in cancer-prone tissues and neoplasms [e.g., prostate (15) and breast (14,18,19)]. The FT-IR͞statistical approach is thus an attractive means for acquiring information on conformational and other changes in a variety of synthetic and natural DNA structures (17).…”

Development of a cancer DNA phenotype prior to tumor formation

“…Results and Discussion MCA-Induced DNA Damage Before Tumor Formation. We have demonstrated that the FTIR statistical models of DNA used in this study are capable of identifying a variety of subtle changes in base functional group and backbone structures as well as alterations in conformational properties (20) associated with carcinogenesis (19,21,(23)(24)(25). Specifically, this technology has been used most recently to discriminate between DNA structures of normal prostate tissues, primary tumors, metastasizing primary tumors, and distant metastases of the prostate (18).…”

Cancer-related changes in prostate DNA as men age and early identification of metastasis in primary prostate tumors

“…We have also reported (14), using statistical models of Fourier transform-IR (FT-IR) spectra, virtually perfect discrimination between the DNA of histologically normal prostates, benign prostatic hyperplasia, and prostatic adenocarcinoma. Significant spectral (structural) differences identified in the bases and backbones of each of the DNA groups contributed to this discrimination.…”