Biomedical subjects

G D Zhou

Publications and source records attributed to G D Zhou.

At least 19 recordsLinked to original sources

PubMed2005

Recognizing names in biomedical texts using mutual information independence model and SVM plus sigmoid.

In this paper, we present a biomedical name recognition system, called PowerBioNE. In order to deal with the special phenomena in the biomedical domain, various evidential features are proposed and integrated through a mutual information independence model (MIIM). In addition, a support vector machine (SVM) plus sigmoid is proposed to resolve the data sparseness problem in the MIIM. In this way, the data sparseness problem in MIIM-based biomedical name recognition can be resolved effectively and a biomedical name recognition system with better performance and better portability can be achieved. Finally, we present two post-processing modules to deal with the nested entity name and abbreviation phenomena in the biomedical domain to further improve the performance. Evaluation shows that our system achieves F-measures of 69.1 and 71.2 on the 23 classes of GENIA V1.1 and V3.0, respectively. In particular, our system achieves an F-measure of 77.8 on the "protein" class of GENIA V3.0. It also shows that our system outperforms the best-reported system on GENIA V1.1 and V3.0.

Abstracting and Indexing↗

PubMed2002

Phytotoxicity of dredged sediment from urban canal as land application.

Phytotoxicity of dredged sediment from Hangzhou section of the Grand Canal as land application was evaluated by pakchoi (Brassica chinensis L.) germination tests and pot experiments. Germination rates of pakchoi in the dredged sediment and in sediment-applied soils were both significantly higher than that in the soil controls, while the germination rate between the sediment-applied soils was no significant difference. In pot experiments, plant height and biomass were increased by the dredged sediment application rate in the rate of lower than 540 t ha(-1), but decreased when the application rate was over this rate. Concentrations of Zn and Cu in pakchoi were linearly increased with the increasing of the application rate of the dredged sediment. Both plant height and biomass of pakchoi in sediment-treated red soil were higher than that in sediment-treated paddy soil, regardless the application rate. The results suggest that plant biomass of pakchoi may be used as an indicator of the phytotoxicity of the dredged sediment. It also showed that red soil is more suitable to accept the dredged sediment than paddy soil, and 270 t ha(-1) is a safe application rate both in red soil and paddy soil.

Biomass↗

PubMed2001

Effects of dietary transition metals on oxidative DNA lesions in neonatal rats.

Bulky endogenous oxidative lesions (type II I-compounds) reflect DNA damage associated with oxidative stress. As shown by 32P-postlabeling, their levels are enhanced by pro-oxidant genotoxins and also shortly after normal birth in several rat tissues as a function of time and the maternal diet. In order to elucidate which dietary components contribute to postnatal DNA damage, we have focused, herein, on the possible role of transition metals (iron, copper, and nickel). Pregnant Fischer 344 (F344) rats were fed AIN-93G purified diet containing different amounts of iron, copper, and nickel, or Purina-5001 natural-ingredient diet (which contains relatively high concentrations of these metals). Type II I-compounds were estimated by nuclease P1-enhanced 32P-postlabeling in liver and lung DNA of fetuses and at 24h and day 9 post-partum. Increased postnatal oxidative damage was detected in liver but not lung DNA of neonates exposed to higher amounts of dietary transition metals. There were significant positive linear correlations between maternal transition metal intake and neonatal, but not fetal and maternal type II I-compound levels. The results show that transition metals in the maternal diet affect perinatal oxidative DNA damage, presumably via a Fenton-type reaction. They also provide evidence for optimal levels in the maternal diet of transition metals, which on one hand, are essential for life, but on the other, can cause potentially deleterious DNA alterations in the offspring.

Animals↗

PubMed2001

A 32P-postlabeling assay for the oxidative DNA lesion 8,5'-cyclo-2'-deoxyadenosine in mammalian tissues: evidence that four type II I-compounds are dinucleotides containing the lesion in the 3' nucleotide.

8,5'-Cyclopurine-2'-deoxynucleotides, which are strong blocks to mammalian DNA and RNA polymerases, represent a novel class of oxidative DNA lesion in that they are specifically repaired by nucleotide excision repair but not by base excision repair or direct enzymatic reversion. Previous studies using thin layer chromatography of (32)P-postlabeled DNA digests have detected several bulky oxidative lesions of unknown structure, called I-compounds, in DNA from normal mammalian organs. We investigated whether any of these type II I-compounds contained 8,5'-cyclo-2'-deoxyadenosine (cA). Two previously detected type II I-compounds were found to be dinucleotides of the sequence pAp-cAp and pCp-cAp. Furthermore, a modification of the technique resulted in detection of two additional I-compounds, pTp-cAp and pGp-cAp. Each I-compound isolated from neonatal rat liver DNA matched authentic (32)P-labeled cA-containing chromatographic standards under nine different chromatographic conditions. Their levels increased significantly after normal birth. The (32)P-postlabeling technique used here is capable of detecting 1-5 lesions/diploid mammalian cell. Thus, it should now be possible to detect changes of cA levels resulting from low level ionizing radiation and other conditions associated with oxidative stress, and to assess cA levels in tissues from patients with the genetic disease xeroderma pigmentosum who are unable to carry out nucleotide excision repair.

Animals↗

PubMed2001

[Pathological and virological studies of the liver tissues from the patients with sporadic hepatitis E].

OBJECTIVE: To study the pathological feature, viral distribution and replication in the liver tissue of sporadic hepatitis E(HE), and to explore the mechanism of the liver injury induced by hepatitis E virus(HEV). METHODS: The total bioptic liver tissues (n=54) were obtained from the patients with sporadic hepatitis E, including the clinical acute stage (n=20), the convalescent stage (n=16), and the chronic hepatitis B (CHB) overlapped with HEV infection recently (n=18). The pathological changes in the liver tissues were observed under the light and the electron microscope. HEV RNA was detected by in situ hybridization, and Kupffer cells were marked with immunohistochemistry. RESULTS: The HE liver tissues showed the pathological features in the clinical acute stage, presenting frequently with feathery degeneration of hepatocytes (100%), cholangiolar cholestasis (75.0%), and double nuclei and multinuclei hepatocytes (65.0%). The apoptotic body of hepatocyte was larger and irregular, and the proliferation of Kupffer cells was prominent. HEV RNA was distributed in hepatocyte cytoplasm near the nuclei. The positive rate of HEV RNA in acute stage was evidently higher than that in convalescent stage (100% vs 12.5%,P < 0.001), and the HEV RNA positive hepatocytes and the viral copies in acute stage were also more than in convalescent stage, in which the liver tissues were becoming normal. The liver tissue changes of the CBH overlapped with HEV infection were more severe compared with the single CHB. CONCLUSIONS: Sporadic HE had histopathological characteristics. HEV infection and replication in hepatocytes occurred mainly during clinical acute stage and regressed in convalescent stage, which suggested sporadic acute HE may have a good result. The immune-mediated liver injury by lymphocytes might be a main pathogenesis of HE,but the liver injury induced directly by HEV might not be excluded.

Adolescent↗

PubMed1999

Endogenous formation and significance of 1,N2-propanodeoxyguanosine adducts.

The detection of 1,N2-propanodeoxyguanosine adducts in the DNA of rodent and human tissues as endogenous lesions has raised important questions regarding the source of their formation and their roles in carcinogenesis. Both in vitro and in vivo studies have generated substantial evidence which supports the involvement of short- and long-chain enals derived from oxidized polyunsaturated fatty acids (PUFAs) in their formation. These studies show that: (1) the cyclic propano adducts are common products from reactions of enals with DNA bases; (2) they are formed specifically from linoleic acid (LA; omega-6) and docosahexaenoic acid (omega-3) under in vitro stimulated lipid peroxidation conditions; (3) the levels of propano adducts are dramatically increased in rat liver DNA upon depletion of glutathione; (4) the adduct levels are increased in the liver DNA of the CCl4-treated rats and the mutant strain of Long Evans rats which are genetically predisposed to increased lipid peroxidation; and (5) adduct levels are significantly higher in older rats than in newborn rats. These studies collectively demonstrate that tissue lipid peroxidation is a main endogenous pathway leading to propano adduction in DNA. The possible contribution from environmental sources, however, cannot be completely excluded. The mutagenicity of enals and the mutations observed in site-specific mutagenesis studies using a model 1,N2-propanodeoxyguanosine adduct suggest that these adducts are potential promutagenic lesions. The increased levels of the propano adducts in the tissue of carcinogen-treated animals also provide suggestive evidence for their roles in carcinogenesis. The involvement of these adducts in tumor promotion is speculated on the basis that oxidative condition in tissues is believed to be associated with this process.

Animals↗

PubMed1999

Bulky endogenous DNA modifications (I-compounds) -possible structural origins and functional implications.

I-compounds are bulky covalent DNA modifications which increase with age in tissues of unexposed laboratory animals and are derived from endogenous DNA-reactive intermediates of nutrient and oxygen metabolism. They have been classified into 2 major groups, i.e., type I and type II. Profiles and levels of type I I-compounds show considerable variation depending on species, strain, tissue, and gender, but are also affected by diet and chemical and hormonal exposures, indicating their formation to be determined by genetic and environmental factors. For example, sex hormones, dietary oat lipids, and isoprenoids affect their profiles and/or levels in tissue DNA. A gradual depletion of many type I I-compounds occurs during carcinogenesis, as many carcinogens/tumor promoters significantly reduce their levels, and neoplasms display very low levels, apparently independent of growth rate, indicating a loss of the ability to form these modified nucleotides. Conversely, dietary restriction, the most effective method to retard carcinogenesis and aging, significantly elevates type I I-compound levels, as compared to age-matched ad libitum-fed animals. Levels of many liver and kidney I-compounds exhibit genotype- and diet-dependent positive linear correlations with median life span. Formation of high levels of oat-related type I I-compounds has been associated with reduced formation of carcinogen-induced preneoplastic hepatic foci. These results suggest that such DNA modifications may not represent DNA lesions but may rather be functionally important. This view is supported by circadian rhythms displayed by some I-compounds. Thus, certain type I I-compounds may play a protective role against carcinogenesis and age-associated degenerative processes. Type II I-compounds, on the other hand, represent DNA damage and include several bulky lesions, which are enhanced by pro-oxidant carcinogens such as ferric nitrilotri- acetate (Fe-NTA) in target organ (kidney) DNA of rodents and are identical to products generated by oxidizing DNA or oligonucleotides under Fenton reaction conditions in vitro. Some of these products appear to be base-base or base-sugar intrastrand crosslinks. Notably, Fe-NTA reduces the levels of type I I-compounds in renal DNA. Type II I-compound levels are increased in tissue DNA of normal newborn rats. The formation of oxidative DNA lesions in neonates is most likely caused by oxidative stress associated with the sudden increase of partial oxygen pressure in arterial blood and tissues at birth. In view of the rapid cell replication at this developmental stage, endogenous oxidative DNA lesions sustained early in life may contribute to the development of cancer and degenerative diseases later in life.

Animals↗

PubMed1999

Genotoxicity of complex PAH mixtures recovered from contaminated lake sediments as assessed by three different methods.

Although human exposure generally occurs to mixtures of chemicals, limited toxicological information is available to characterize the potential interactions of the components of environmental mixtures. This study was conducted to compare the genotoxicity of chemically characterized polycyclic aromatic hydrocarbon (PAH) mixtures using in vitro and in vivo techniques. A total of three extracts (E1-E3) were selected from sediment samples collected from a lake adjacent to an abandoned coal gasification site. Sediments were collected on a grid moving downstream and away from the most likely source of PAH contamination, with E1 collected closest to the shore, E2 at an intermediate distance, and E3 furthest from the shore. The sediment samples were extracted in methylene chloride and methanol, dried, and redissolved in an appropriate solvent for evaluation in a battery of genotoxicity assays. Samples were evaluated for their ability to produce point mutations in bacteria and DNA adducts in vitro without metabolic activation or in vivo. Samples were also analyzed using GC/MS. Sample E1 had both the highest concentration of benzo(a)pyrene (BP) (46.5 ppm) and carcinogenic PAHs and, using 32P-postlabeling, induced the highest adduct levels overall in vitro and in vivo. Sample E2, which had a BP concentration of 14 ppm, induced the greatest number of revertants in the bacterial mutagenicity assay. Sample E3, which had the lowest level of carcinogenic PAHs and BP, induced the lowest adduct levels. However, E3 was capable of inducing a positive genotoxic response in bacteria (with S9), although the slope of the response at lower doses was less than that of E2. The in vivo data showed that the major adduct formed by E1 and E2 was a BP adduct. This information could not have been obtained with the Salmonella or in vitro postlabeling tests. Among internal organs, the extracts of all three samples induced the greatest adduct levels in the lung, similarly to previous complex PAH mixtures studied. These data demonstrate the limitations of predicting genotoxic or carcinogenic potential based on chemical analysis or a single biological test. The results suggest that mixture interactions, cytotoxicity and metabolism are likely to have an influence on the potential of a complex mixture of chemicals to produce a carcinogenic effect. In addition, the concentration of genotoxic PAHs and both in vitro and in vivo DNA adduct formations were decreased with increasing distance from the shoreline.

Animals↗

PubMed1999

Acute elevation by short-term dietary restriction or food deprivation of type I I-compound levels in rat liver DNA.

Type I I-compounds are bulky endogenous DNA modifications detectable by 32P postlabeling that exhibit age, species, tissue, genotype, gender, and diet dependence. Their formation appears unrelated to oxidative stress. In fact, several lines of indirect evidence suggest that many type I I-compounds may represent normal functional DNA modifications. For example, long-term dietary restriction (DR), which retards the development of age-related diseases including cancer and extends median and maximum life spans, unexpectedly elicits significant increases rather than decreases in the levels of many I-compounds in different rodent tissues. Positive linear correlations have been observed between such levels and median life spans of the animals. In the present work we have investigated 1) whether elevation of I-compound levels does not depend on chronic DR, i.e., occurs after a short period of DR or fasting, and 2) whether I-compound levels return to control values after the animals are returned to unrestricted feeding after food deprivation. Female Fischer 344 rats (approx 140 g each) were randomized into three groups. Group I was fed a natural ingredient (Purina 5001) diet ad libitum (AL) throughout the study, Group 2 was switched to 60% of the AL amount (40% DR) at 0 hour, and Group 3 was given no food for up to 72 hours and then returned to AL feeding until the end of the experiment. Liver DNA of individual rats (n = 4) was isolated for I-compound analysis at 24, 72, and 240 hours. Restricted and food-deprived rats showed elevated levels of hepatic I-compounds, with fasting eliciting the highest levels. These effects were seen as early as the 24-hour time point. Refeeding after 72 hours of food deprivation restored the levels to control values, measured at 240 hours. Our observations are discussed in relation to carcinogenesis and tumor promotion. The almost instantaneous changes of endogenous DNA modifications showed their exquisite sensitivity to nutritional factors and provided strong new evidence for precise regulation of their formation and removal.

Animals↗

PubMed1998

High levels of endogenous DNA adducts (I-compounds) in pig liver. Modulation by high cholesterol/high fat diet.

I (indigenous)-compounds are bulky endogenous DNA adducts which are detected by 32P-postlabeling in unexposed animals. I-compound levels in rodents depend on age, species, strain, gender, tissue, diet, and chemical exposure. There are two classes of I-compounds, type I and type II. While many type I I-compounds may not reflect DNA damage, type II I-compounds have been identified as oxidative DNA lesions some of which can be produced in vitro under Fenton reaction conditions. In rats, caloric restriction (CR) increases the levels of many type I I-compounds compared with ad libitum fed animals, while high fat diet has the opposite effect. Here, we have tested whether hepatic DNA of a non-rodent mammal, the pig, contains I-compounds and whether feeding a high cholesterol/high fat (HC/HF) diet modulates their levels, assuming this would affect the formation of lipid-related precursors and cause oxidative stress. Male Yorkshire pigs aged 2 months old, were fed either control or HC/HF diet (control diet supplemented with 2% cholesterol and 19% lard) for 2 months. Pig liver DNA contained at least 19 type I and five type II I-compounds. Among the former, only five matched corresponding spots in rat liver DNA, while all the latter DNA lesions were detected in both species. The levels of both types of DNA modifications were six to eight-fold higher in pig DNA. HC/HF diet reduced levels of many type I I-compounds up to several fold but had little effect on the oxidative lesions. Several type I I-compounds showed negative linear correlations with serum cholesterol levels, while this association was positive for total type II I-compounds. The substantially elevated steady-state levels of bulky endogenous DNA adducts in the species with the longer life expectancy were surprising. Thus, for the first time, an intimate link between nutritional status and endogenous DNA modifications has been established in a non-rodent system. We propose that in order to explain our observations, differences in diet composition, antioxidant defenses, and DNA repair, as well as cytochrome P450 modulation of precursor levels and hormonal effects need to be considered.

Animals↗

PubMed1998

Inhibition of CYP1A1-dependent activity by the polynuclear aromatic hydrocarbon (PAH) fluoranthene.

Polynuclear aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants, and recently bioassay-based induction studies have been used to determine exposures to complex mixtures of PAHs. Induction of CYP1A1-dependent activity in H4IIE rat hepatoma cells has been used extensively as a bioassay for halogenated aromatic hydrocarbons and more recently for PAHs. Fluoranthene (FL) is a prevalent PAH contaminant in diverse environmental samples, and FL did not induce CYP1A1-dependent ethoxyresorufin O-deethylase (EROD) activity significantly in H4IIE cells. However, in cells cotreated with 2 x 10(-5) M FL plus the potent inducers 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or benzo[k]fluoranthene (BkF) (2 x 10(-8) M), there was a significant decrease in EROD activities. Furthermore, treatment of TCDD-induced rat microsomes with FL caused an 80% decrease in EROD activity. Studies showed that FL did not affect induction of CYP1A1 protein or mRNA levels in H4IIE cells, and analysis of enzyme inhibition data using microsomal CYP1A1 indicated that FL noncompetitively inhibited CYP1A1-dependent activity. 32P-Postlabeling revealed no significant FL-DNA adduct formation in H4IIE cells treated with FL. However, in cells cotreated with FL plus BkF or benzo[a]pyrene (BaP), certain PAH-DNA adducts were induced 2-fold. This study demonstrated that FL is an inhibitor of CYP1A1-dependent enzyme activity in rat hepatoma H4IIE cells and that the genotoxic potency of some carcinogenic PAHs may be modulated by FL in mixtures containing relatively high levels of this compound.

Animals↗

PubMed1998

Partial characterization of two major liver I-compounds as unstable adducts which are readily hydrolyzed to unmodified guanine nucleotides.

I-compounds are endogenous bulky DNA modifications which are detected by nuclease P1-enhanced 32P-post-labeling in tissue DNA of animals not knowingly exposed to carcinogens. Their profiles and levels depend inter alia on animal age, species, strain, tissue, gender, diet and exposure to chemicals such as cytochrome P450 inducers and carcinogens. Due to lack of sufficient material obtainable from in vivo sources, chemical structures of I-compounds and their parent normal bases have not yet been identified. In this report we provide 32P-post-labeling and chromatographic evidence that two prominent I-compounds, herein called C1 and C2, which occur at relatively high levels in pig liver DNA are guanine derivatives. This result was obtained by showing that both compounds, isolated from 32P-post-labeling thin-layer maps, were chemically unstable, i.e. they could be readily hydrolyzed to 32P-post-labeled deoxyguanosine 3',5'-bisphosphate by heating in water. C1 appeared particularly labile, undergoing hydrolysis during thin-layer chromatography at pH 3.3 without heating. Several other I-compounds and adducts, as well as the four normal DNA nucleotides, were, however, highly resistant to hydrolysis under the conditions used here. The possible significance of these findings will be briefly discussed.

Animals↗

PubMed1997

Organ-specific oxidative DNA damage associated with normal birth in rats.

Mammalian DNA contains bulky endogenous DNA modifications (I-compounds), which increase with age in unexposed animals, as shown by 32P-postlabeling. We have examined the perinatal formation of a subclass (type II) of I-compounds in rat liver, kidney, skin and lung. These I-compounds represent bulky oxidative DNA lesions, defined herein as intrastrand base-base and base-sugar cross-links, adducts of lipid peroxidation products and DNA-protein cross-links. We observed a rapid increase in the levels of five bulky oxidative DNA lesions during the first hours after normal birth of rats, with total levels increasing 4.2-, 3.0- and 1.3-fold, respectively, in liver, kidney and skin. This effect was not noted in lung. The results were consistent with oxidative stress induced by the known sudden increase in partial oxygen pressure at birth in blood and tissues, implying inadequate antioxidant defenses in the affected neonatal organs. Hepatic oxidative damage appeared intensified by increased concentrations of pro-oxidants and reduced concentrations of antioxidants in the maternal diet. The postnatal DNA lesions are postulated to be premutagenic, as indicated by their bulky nature and persistence. Pathophysiological effects of oxidative DNA damage would be exacerbated by rapid cell proliferation in neonatal tissues and consequent fixation as mutations. In addition to inherited mutations, DNA lesions acquired as a consequence of normal birth may play a hitherto unrecognized role in spontaneous carcinogenesis and age-related degenerative diseases.

Animals↗

PubMed1997

Enhanced levels in neonatal rat liver of 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-hydroxydeoxyguanosine), a major mutagenic oxidative DNA lesion.

The purpose of this study was to determine whether the level of 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-hydroxy-2'-deoxyguanosine) (8-oxo-dG), a major mutagenic DNA oxidation product, is enhanced in newborn rat liver DNA as a consequence of oxidative stress incurred during the early postnatal period. 32P-postlabeling showed this adduct to increase approximately 2-fold from the 20th day of gestation (2 days before birth) to a peak level at 50-53 h after birth. Postnatal levels exceeded fetal levels at all time points investigated, i.e. 0.5-1, 8, 24, 50-53, 100, 216 and 432 h after birth. Increased formation of this mutagenic DNA lesion during the critical postnatal phase when there is rapid cell proliferation in all tissues is proposed to contribute to carcinogenesis in susceptible tissues later in life.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1997

Comparative 32P-postlabeling analysis of exogenous and endogenous DNA adducts in mouse skin exposed to a wood-preserving waste extract, a complex mixture of polycyclic and polychlorinated chemicals.

Wood preserving waste (WPW) sites contain numerous toxic compounds, including phenols, polycyclic aromatic hydrocarbons (PAHs), polychlorinated dibenzodioxins, and dibenzofurans. Previous in vitro and in vivo 32P-postlabeling studies showed the induction of multiple carcinogen-DNA adducts by WPW extracts. We now have tested the hypothesis in a mouse skin bioassay that a WPW extract not only causes the formation of exogenous, xenobiotic-derived DNA adducts, but also alters the levels of endogenous DNA modifications. Skin DNA of female ICR mice treated topically with an organic WPW extract was found by 32P-postlabeling to contain significantly increased levels of bulky oxidative DNA lesions (type II I-compounds), in addition to exogenous PAH-derived adducts. The mechanism of this increase is postulated to proceed through electrophilic quinoid compounds, which presumably were formed from phenols by chemical reactions of waste material or biologically by oxidative metabolism. On the other hand, the levels of another class of endogenous DNA adducts (type I I-compounds) were reduced significantly in exposed skin DNA. This effect was explained by the presence of cytochrome P450 inducers in the extract. All three types of DNA alterations observed may play a significant role in carcinogenesis. Our results imply that in addition to exogenous carcinogen-DNA adducts, alterations of endogenous DNA modifications may need to be considered in evaluating carcinogenic risk from toxic chemical wastes and the effects of remediation measures.

Acetone↗

PubMed1996

DNA damage induced in mouse tissues by organic wood preserving waste extracts as assayed by 32P-postlabeling.

Numerous wood preserving waste (WPW) sites in the United States pose genotoxic hazards. WPWs consist of complex mixtures containing toxic, including genotoxic, compounds which are derived from the preservatives coal tar creosote and pentachlorophenol (PCP) and other polychlorinated aromatics. The genotoxicity of WPW extracts, which has not been tested in mammals, cannot be evaluated on the basis of data for individual components because of possible compound interactions. Therefore, whole extracts need to be assayed. 32P-postlabeling represents a powerful tool to determine DNA adduct formation by complex genotoxic mixtures, such as cigarette smoke, diesel exhaust, and coke oven and foundry emissions in experimental animals and humans. In the present study, a mouse bioassay was used in combination with 32P-postlabeling to determine DNA adduct formation induced by hexane/acetone extracts of two samples from a WPW site. Female ICR mice were treated dermally with extract corresponding to 3 mg residue or vehicle control once per day for 2 days and killed 24 h later. Skin, lung, liver, kidney, and heart DNA preparations were assayed by nuclease P1-enhanced postlabeling. Adduct profiles were tissue-specific and displayed a multitude of non-polar DNA adducts with levels amounting to one adduct in 1.6 x 10(6) DNA nucleotides in skin (both extracts) and one adduct in 3.2 x 10(7) or 1.2 x 10(7) DNA nucleotides in liver (extract 1 or extract 2). Based on their chromatographic properties, these adducts appeared largely derived from polycyclic aromatic hydrocarbons (PAHs) present in the extracts. One of the major adducts was identified as the 32P-labeled derivative of the reaction product of 7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7, 8,9,10-tetrahydrobenzo[a]pyrene (BPDE I) with N2 of deoxyguanosine. Total non-polar DNA adduct levels were highest in skin and lung, amounting to 17.4 and 24.0% of the skin values for extracts 1 and 2, respectively, in lung while the corresponding levels in liver were 5.0 and 12.6%. These results were in accord with the carcinogenic potencies of PAHs in these organs. Extract 2 induced higher adduct levels in internal organs, although its PAH concentrations were lower than those of extract 1, i.e. lung, liver, kidney, and heart had 1.4, 2.5, 1.9, and 1.7 times higher total adduct levels and 1.6, 3.3, 1.6, and 1.9 times higher benzo[a]pyrene adduct levels. With the exception of total adducts in lung, the differences between the two extracts were all significant, suggestive of compound interactions. The benzo[a]pyrene adduct levels in the five tissues correlated linearly with total adduct levels and thus represented a surrogate for the latter. Overall, the results suggest that DNA adducts in mouse tissues, as analyzed by 32P-postlabeling, are suitable biomarkers and dosimeters of the genotoxicity of WPW extracts.

Animals↗

PubMed1996

Organ-specific oxidative DNA damage associated with normal birth in rats.

Animals↗

PubMed1995

Intensification and depletion of specific bulky renal DNA adducts (I-compounds) following exposure of male F344 rats to the renal carcinogen ferric nitrilotriacetate (Fe-NTA).

The effects of the renal carcinogen ferric nitrilotriacetate (Fe-NTA) on kidney DNA of male F344 rats were studied to determine whether bulky DNA oxidation products (putative intrastrand crosslinks) could be detected by 32P-postlabeling in the target organ of carcinogenesis. Rats (10-11 weeks old) were given a single dose of Fe-NTA (15 mg Fe/kg body weight) i.p. at 3:00 pm. After 5 h, renal DNA from Fe-NTA-treated and vehicle control animals was assayed by 32P-postlabeling. Thin-layer chromatography and quantitative analysis of two labeled nucleotide fractions of increasing polarity, L and C, showed that three spots (L1, L2, and C3) were intensified 3.5- to 4.2-fold in treated animals. L1 consisted of subfractions L1a, L1b, and L1c, which could be resolved chromatographically. L1c, L2, and C3 were identical to DNA oxidation products generated by the Fenton reaction in vitro, while L1a and L1b apparently did not arise by this mechanism. DNA damage and toxicity appeared reduced in younger animals and animals treated in the morning, presumably due to differences in antioxidant defenses. Liver and lung (non-target organs) DNA did not exhibit enhanced L1, L2, and C3 spots. In addition to augmenting renal I-compounds, Fe-NTA reduced the levels of three major polar kidney I-compounds (C4, C5, and C6) to 22-53% of control. This reduction did not appear to arise by direct oxidative DNA damage, resembling the previously documented loss of liver I-compounds induced by numerous hepatocarcinogens. Two of these I-compounds (C4 and C5) have been reported to exhibit positive linear correlations with median lifespan of male F344 rats. The pleiotropic response of kidney I-compound levels to Fe-NTA was consistent with different roles of different types (I and II) of I-compounds in Fe-NTA-mediated renal carcinogenesis. The results strongly support a causal relationship between oxidative DNA lesions and Fe-NTA-mediated carcinogenesis.

Age Factors↗