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S J Gunselman

Publications and source records attributed to S J Gunselman.

10 recordsLinked to original sources

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

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 approximately 10(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.

Animals↗

Models of DNA structure achieve almost perfect discrimination between normal prostate, benign prostatic hyperplasia (BPH), and adenocarcinoma and have a high potential for predicting BPH and prostate cancer.

In our previous studies of DNA, wavenumber-absorbance relationships of infrared spectra analyzed by principal components analysis (PCA) were expressed as points in space. Each point represented a highly discriminating measure of structural modifications that altered vibrational and rotational motion, thus changing the spatial orientation of the points. PCA/Fourier transform-infrared technology has now provided a virtually perfect separation of clusters of points representing DNA from normal prostate tissue, BPH, and adenocarcinoma. The findings suggest that the progression of normal prostate tissue to BPH and to prostate cancer involves structural alterations in DNA that are distinctly different. The hydroxyl radical is likely a major contributor to these structural alterations, which is consistent with previous studies of breast cancer. Models based on logistic regression of infrared spectral data were used to calculate the probability of a tissue being BPH or adenocarcinoma. The models had a sensitivity and specificity of 100% for classifying normal vs. cancer and normal vs. BPH, and close to 100% for BPH vs. cancer. Thus, the PCA/Fourier transform-infrared technology was shown to be a powerful means for discriminating between normal prostate tissue, BPH and prostate cancer and has considerable promise for risk prediction and clinical application.

Adenocarcinoma↗

Mutagenic DNA base modifications are correlated with lesions in nonneoplastic hepatic tissue of the English sole carcinogenesis model.

Hydroxyl radical-induced mutagenic base modifications have been linked to neoplasia in a number of biological systems, including English sole from chemically contaminated urban environments. However, virtually no information exists on the relationship between the mutagenic base modifications and preneoplastic and other lesions found in tumor-free tissues prone to cancer. We studied six hepatic lesions in immature, neoplasm-free English sole exposed to an urban and reference environment and established correlations between the lesion incidence and concentrations of the mutagenic base modifications 8-hydroxyguanine and 8-hydroxyadenine. The lesions were putatively preneoplastic basophilic foci, hepatocellular karyomegaly, megalocytic hepatosis, hepatocellular vacuolar change, hyalin droplet formation, and apoptosis. With the exception of hepatocellular vacuolar change, significant positive correlations were found between the lesions and the mutagenic base modifications. The hydroxyl radical may be a common etiological factor in the formation of the base modifications and hepatic lesions.

Adenine↗

Tumor progression to the metastatic state involves structural modifications in DNA markedly different from those associated with primary tumor formation.

Wavenumber-absorbance relationships of infrared spectra of DNA analyzed by principal components analysis may be expressed as points in space. Each point represents a highly discriminating measure of DNA structure. Structural modifications of DNA, such as those induced by free radicals, alter vibrational and rotational motion and consequently change the spatial location of the points. Using this technology to analyze breast tumor DNA, we revealed a 94 degrees difference in direction between the progression of normal DNA-->primary tumor DNA and the progression of primary tumor DNA-->metastatic tumor DNA (P < 0.001). This sharp directional change was accompanied by a substantial increase in the structural diversity of the metastatic tumor DNA (P = 0.003), which, on the basis of the volume of the core cluster of points, could comprise as many as 11 x 10(9) different phenotypes. This suggests that the heterogeneity and varied physiological properties known to characterize malignant tumor cell populations may at least partially arise from these diverse phenotypes. The evidence suggests that the progression to the metastatic state involves structural modifications in DNA that are markedly different from the modifications associated with the formation of the primary tumor. Overall, the findings of this and earlier studies imply that the observed DNA alter-ations are a pivotal factor in the etiology of breast cancer and a formidable barrier to overcome in intervention to control the disease. In terms of cancer etiology and prediction, the technology described has potentially wide application to studies in which the structural status of DNA is an important consideration.

Breast↗

Progression of human breast cancers to the metastatic state is linked to hydroxyl radical-induced DNA damage.

Hydroxyl radical damage in metastatic tumor DNA was elucidated in women with breast cancer, and a comparison was made with nonmetastatic tumor DNA. The damage was identified by using statistical models of modified base and Fourier transform-infrared spectral data. The modified base models revealed a greater than 2-fold increase in hydroxyl radical damage in the metastatic tumor DNA compared with the nonmetastatic tumor DNA. The metastatic tumor DNA also exhibited substantially greater base diversity than the nonmetastatic DNA, and a progression of radical-induced base damage was found to be associated with the growth of metastatic tumors. A three-dimensional plot of principal components from factor analysis, derived from infrared spectral data, also showed that the metastatic tumor DNA was substantially more diverse than the tightly grouped nonmetastatic tumor DNA. These cohesive, independently derived findings suggest that the hydroxyl radical generates DNA phenotypes with various metastatic potentials that likely contribute to the diverse physiological properties and heterogeneity characteristic of metastatic cell populations.

Breast Neoplasms↗

The etiology and prediction of breast cancer. Fourier transform-infrared spectroscopy reveals progressive alterations in breast DNA leading to a cancer-like phenotype in a high proportion of normal women.

BACKGROUND: The authors previously have shown by gas chromatography-mass spectrometry that the hydroxyl radical (.OH) induces alterations in the DNA base structure of the female breast, which are premalignant markers of breast cancer. Fourier transform-infrared (FT-IR)-spectroscopy also has a high potential for revealing a broad array of structural changes in DNA that may provide important new insight into breast cancer etiology and prediction. METHODS: DNA from normal reduction mammoplasty tissue, invasive ductal carcinoma, and nearby microscopically normal tissue was analyzed by FT-IR spectroscopy. Statistical models based on DNA spectral properties were developed and compared with a statistical model previously used with base modifications. RESULTS: Substantial differences were found in the spectral properties of DNA from women with normal and cancerous breast tissue, indicating an ability to discriminate cancerous tissue from noncancerous tissue with a sensitivity and specificity of 83%. Most importantly, the normal population was divided into subgroups in which a nonrandom progression was identified and a cancer-like DNA phenotype that was highly correlated (r > or = 0.90) with that of the patients with cancer was exhibited in 59% of the women. The spectral data, which also were highly correlated with the base-model data, were used to establish a model for predicting the probability of breast cancer. Consistent with the high cancer reoccurrence rate in the ipsilateral breast, 8 of 10 of the microscopically normal tissue specimens remaining after tumor excision were classified as cancerous using this model. CONCLUSIONS: Progressive structural changes in the DNA of the normal female breast, leading to a premalignant cancer-like phenotype in a high proportion of women, are the basis for a new paradigm for understanding the etiology of breast cancer and predicting its occurrence at early stages of oncogenesis. The results also suggest therapeutic strategies for potentially reversing the extent of DNA damage, which may be useful in disease prevention and treatment.

Breast↗

Fourier-transform infrared spectroscopy and gas chromatography-mass spectrometry reveal a remarkable degree of structural damage in the DNA of wild fish exposed to toxic chemicals.

The use of gas chromatography-mass spectrometry with selected ion monitoring (GC-MS/SIM) and Fourier-transform infrared (FT-IR) spectroscopy revealed a remarkable degree of damage in the hepatic DNA of fish exposed to toxic environmental chemicals, compared with controls. The exposed fish, which were neoplasm-free, were part of a population with a high incidence of liver cancer. GC-MS/SIM showed markedly high concentrations of hydroxyl radical-induced ring-opening products (e.g., 2,6-diamino-4-hydroxy-5-formamidopyrimidine) and 8-hydroxy adducts of adenine and guanine (e.g., 8-hydroxyguanine) in the DNA. FT-IR spectroscopy revealed substantial changes in spectral areas, such as those assigned to NH vibrations of nucleotide bases and CO vibrations of deoxyribose. This diverse and extensive damage to DNA provides a perspective of premalignant changes resulting from xenobiotic exposure and a promising basis for predicting cancer risk in animals and humans.

Animals↗

The etiology of breast cancer. Characteristic alteration in hydroxyl radical-induced DNA base lesions during oncogenesis with potential for evaluating incidence risk.

BACKGROUND: Substantial hydroxyl radical (.OH)-induced base lesions, recently found in the DNA of invasive ductal carcinoma of the female breast, are likely to be intimately related to oncogenesis. However, virtually no information was available regarding relationships between the different base lesions in the normal and cancerous breast. Such information is essential in understanding initial stages in the development of breast cancer and the potential of the base lesions as early predictors of cancer risk. METHODS: The .OH-induced DNA base lesions in normal reduction mammoplasty tissue (RMT) were compared with those from invasive ductal carcinoma (IDC) and nearby microscopically normal tissue (MNT). Comparisons were then undertaken on relationships between the base lesion profiles in the normal and cancerous breast using 22 statistical models. RESULTS: DNA from the RMT was characterized by a high ratio of ring-opening products (e.g., 4,6-diamino-5-formamidopyrimidine) to hydroxy-adducts of adenine and guanine. A dramatic shift in this relationship in favor of carcinogenic hydroxy-adducts (e.g., 8-hydroxyguanine) was found in the cancerous breast. Statistical models with a high sensitivity (91%) and specificity (97%) provided a consistent means of classifying tissues (e.g., 96% correct). CONCLUSIONS: The dramatic shift in the DNA base lesion relationships in oncogenesis is attributed to alterations in the redox potential of the breast favoring oxidative conditions and cancer formation. These findings suggest that base lesion profiles are potential sentinels for cancer risk assessment. Further, intervention in controlling the tissue redox potential may provide benefit in delaying or preventing early oncogenic changes and the ultimate manifestation of cancer.

Breast↗