Damage In Man Research Articles

Cytogenetic markers and their spatial distribution in a population living in proximity to areas sprayed with pesticides

Human populations are in contact with potentially toxic substances in varying amounts, if the exposure is work-related or direct, generally the amount of toxin is usually greater than if the exposure is environmental through the drifts that occur. It was proposed to determine the existence of genotoxic damage evaluated through Chromosomal Aberrations and Micronuclei assays and their spatial distribution pattern, as well as the possible relationship between that damage and the values found in biochemical biomarkers, in groups of individuals environmental exposure (respiratory exposure) to mixtures of pesticides, in the province of Córdoba-Argentina. Biochemical and hematological determinations were made in each samples. The results reveal that the monitoring of human populations through the analysis of cytogenetic markers enabled the detection of direct damage in man caused by polluting substances and the results were obtained rapidly. The disadvantage of this type of study is the inability to estimate the degree of exposure.

Uncertainty of Theme in the Postmodernist Fiction:

The current paper is titled Uncertainty of theme in the postmodernist fiction: The case of Pynchon's Entropy. It aims at clarifying how features of postmodernist text have an impact on theme production. Language is alienated as it does not refer to the conscious world. However, it refers to unconscious world which is characterized by cryptic and it does not make a sense of the world. The scope of the study throws light on the features of postmodernism to show how psychological factors are employed in the text and the functions of its stylistic features. It is hypothesized that damage in man's psyche has influenced postmodernist short story. The paper consists of four sections; the first section discusses the term Postmodernism as a concept. It explores how postmodernism views history and culture. The second section discusses the psychic elements employed in the short story to project man’s psyche under the pressure of conflicting great powers. The third sheds light on the stylistic features, writers have used at variance with the ones used in realist and modernist texts to gain particular needs. The conclusion recapitulates the finding of three sections. Finally, the paper provides recommendations for further researches.

Combining Extracellular miRNA Determination with Microfluidic 3D Cell Cultures for the Assessment of Nephrotoxicity: a Proof of Concept Study

Drug-induced kidney injury is often observed in the clinics and can lead to long-term organ failure. In this work, we evaluated a novel in vitro system that aims at detecting whether compounds can cause renal proximal tubule damage in man. For this, we implemented organotypic cultures of human conditionally immortalized proximal tubule epithelial cells overexpressing the organic anion transporter 1 (ciPTEC-OAT1) in a three-channel OrganoPlate under microfluidic conditions. Cells were exposed to four known nephrotoxicants (cisplatin, tenofovir, cyclosporine A, and tobramycin). The effect on cell viability and NAG release into the medium was determined. A novel panel of four miRNAs (mir-21, mir-29a, mir-34a, and mir-192) was selected as potential biomarkers of proximal tubule damage. After nephrotoxicant treatment, miRNA levels in culture medium were earlier indicators than cell viability (WST-8 assay) and outperformed NAG for proximal tubule damage. In particular, mir-29a, mir-34a, and mir-192 were highly reproducible between experiments and across compounds, whereas mir-21 showed more variability. Moreover, similar data were obtained in two different laboratories, underlining the reproducibility and technical transferability of the results, a key requirement for the implementation of novel biomarkers. In conclusion, the selected miRNAs behaved like sensitive biomarkers of damage to tubular epithelial cells caused by several nephrotoxicity mechanisms. This biomarker panel, in combination with the 3D cultures of ciPTEC-OAT1 in the OrganoPlate, represents a novel tool for in vitro nephrotoxicity detection. These results pave the way for the application of miRNAs in longitudinal, time-course in vitro toxicity studies.

From the Cover: MechanisticInsights in Cytotoxic and Cholestatic Potential of the Endothelial Receptor Antagonists Using HepaRG Cells.

Several endothelin receptor antagonists (ERAs) have been developed for the treatment of pulmonary arterial hypertension (PAH). Some of them have been related to clinical cases of hepatocellular injury (sitaxentan [SIT]) and/or cholestasis (bosentan [BOS]). We aimed to determine if ambrisentan (AMB) and macitentan (MAC), in addition to BOS and SIT, could potentially cause liver damage in man by use of human HepaRG cells. Our results showed that like BOS, MAC-induced cytotoxicity and cholestatic disorders characterized by bile canaliculi dilatation and impairment of myosin light chain kinase signaling. Macitentan also strongly inhibited taurocholic acid and carboxy-2',7'-dichlorofluorescein efflux while it had a much lower inhibitory effect on influx activity compared to BOS and SIT. Moreover, these three drugs caused decreased intracellular accumulation and parallel increased levels of total bile acids (BAs) in serum-free culture media. In addition, all drugs except AMB variably deregulated gene expression of BA transporters. In contrast, SIT was hepatotoxic without causing cholestatic damage, likely via the formation of reactive metabolites and AMB was not hepatotoxic. Together, our results show that some ERAs can be hepatotoxic and that the recently marketed MAC, structurally similar to BOS, can also cause cholestatic alterations in HepaRG cells. The absence of currently known or suspected cases of cholestasis in patients suffering from PAH treated with MAC is rationalized by the lower therapeutic doses and Cmax, and longer receptor residence time compared to BOS.

Protective role of Nigella sativa oil on renal damage induced by acetaminophen in male rats

Acetaminophen also called paracetamol is commonly used as analgesic and antipyretic agent which in high doses causes liver and kidney damage in man and animals. Nigella sativa oil have antioxidant properties. Thirty adult male rats were used and randomly divided into three equal groups. Group (A) untreated and served as control group; Group (B) rats were orally intubated (by gavages needle) acetaminophen suspension (150mg/kg B.W). Group (C) rats were given orally acetaminophen suspension (150mg/kg) plus 1ml/kg B.W of Nigella sativa oil for 42 days in both treated group. Fasting blood samples were collected at 21 and 42 days of experiment to study the following parameters: Serum creatinine concentration and blood urea nitrogen concentration. The results revealed a significant increase of acetaminophen group in serum creatinine and blood urea nitrogen concentrations as compression with GA. Animals treated with Nigella sativa oil plus acetaminophen (C) showed a significant decline in serum creatinine and blood urea nitrogen concentrations. In conclusion, the acetaminophen was effective in induction of oxidative stress and change in some biological markers related to kidney disease. Also it seems that Nigella sativa oil exerts protective actions against the damaging effect of acetaminophen

Topical application of superoxide dismutase mediated by HIV-TAT peptide attenuates UVB-induced damages in human skin

The purpose of this study was to evaluate whether topical application of superoxide dismutase with cell penetrating peptide (HIV-TAT) could protect against skin damage induced by UVB irradiation in humans. The permeability through stratum corneum of large proteins linked to TAT peptide was firstly confirmed by confocal microscopy and tape stripping. Ten healthy volunteers with either Fitzpatrick skin type II or III were recruited in this clinical study. TAT-SOD (300units/cm2) and vehicle cream were applied on two symmetric areas of both inner upper arms 1h prior to UVB irradiation. After one hour of pretreatment, subjects received 10 incremental doses of UVB on pretreated areas. 24h later, erythema, blood flow and apoptotic cells were measured. Pretreatment with TAT-SOD 1h prior to UVB radiation promoted a mean minimal erythema dose (MED) increase of 36.6±18.4% (p=0.013<0.05. n=10) compared to vehicle control. The median blood flow values of all subjects following 2 and 3-MED of UVB were 107.8±51.0units and 239.5±88.0units respectively, which account for 26% and 25% decrease with respect to vehicle groups. These data suggest that TAT-SOD significantly suppresses UVB induced erythema formation and blood flow rise. Furthermore, pretreatment with TAT-SOD 1h prior to 2-MED of UVB irradiation reduced the apoptotic sunburn cell formation by 47.6±8.6% (p<0.0001) in all subjects. Evaluating results generated from all measurements, we conclude that topical application of TAT-SOD significantly attenuates UVB-induced skin damage in man. These biological effects of TAT-SOD are probably mediated via its free radical scavenging properties, clearly differentiating it from other physical sunscreen agents.

Natural plant polyphenols for alleviating oxidative damage in man: Current status and future perspectives

The balance between oxidation and reduction is important for maintaining a healthy biological system. Oxidative stress results from an imbalance between excessive formation of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) and limited endogenous defense systems, and this imbalance can adversely alter lipids, proteins and DNA, causing a number of human diseases. Thus, exogenous antioxidants that can neutralize the effect of free radicals are needed to diminish the cumulative effects of oxidative damage over human life span. Current research reveals that phenolic compounds in plants possess high antioxidant activity and free radical scavenging capacity and can prevent the body from oxidative damage over human life span. This review focuses on the present understanding of free radicals and antioxidants and their importance in human health and disease. Information about the chemical features of free radicals as well as their deleterious effects on cell structures is reviewed. The chemical structure and anti-oxidative mechanisms of essential polyphenols and their potential health benefits are presented. In addition, the limitation of natural antioxidants and a perspective on likely future trends in this field are also discussed. Keywords: Free radicals, Oxidative stress, Natural antioxidants, Polyphenols, Health benefits, Reactive oxygen species, Reactive nitrogen species

Reductions in microfilaridermia by repeated ivermectin treatment are associated with lower Plasmodium-specific Th17 immune responses in Onchocerca volvulus-infected individuals.

Background37 million individuals are currently infected with Onchocerca volvulus (O. volvulus), a parasitic nematode that elicits various dermal manifestations and eye damage in man. Disease control is primarily based on distributing ivermectin in mass drug administration (MDA) programmes which aim at breaking transmission by eliminating microfilariae (MF), the worm's offspring. The majority of infected individuals present generalized onchocerciasis, which is characterized by hyporesponsive immune responses and high parasite burden including MF. Recently, in areas that have been part of MDA programmes, individuals have been identified that present nodules but are amicrofilaridermic (a-MF) and our previous study showed that this group has a distinct immune profile. Expanding on those findings we determined the immune responses of O. volvulus-infected individuals to a Plasmodium-derived antigen MSP-1 (merozoite surface protein-1), which is required by the parasite to enter erythrocytes.MethodsIsolated PBMCs from O. volvulus-infected individuals (164 MF+ and 46 a-MF) and non-infected volunteers from the same region (NEN), were stimulated with MSP-1 and the resulting supernatant screened for the presence of IL-5, IL-13, IFN-γ, TNF-α, IL-6, IL-17A and IL-10. These findings were then further analyzed following regression analysis using the covariates MF, ivermectin (IVM) and region. The latter referred to the Central or Ashanti regions of Ghana, which, at the time sampling, had received 8 or 1 round of MDA respectively.ResultsIL-5, IL-13 and IFN-γ responses to MSP-1 were not altered between NEN and O. volvulus-infected individuals nor were any associations revealed in the regression analysis. IL-10, IL-6 and TNF-α MSP-1 responses were, however, significantly elevated in cultures from infected individuals. Interestingly, when compared to a-MF individuals, MSP-induced IL-17A responses were significantly higher in MF+ patients. Following multivariable regression analysis these IL-10, IL-6, TNF-α and IL-17A responses were all dominantly associated with the regional covariate.ConclusionsConsequently, areas with a lowered infection pressure due to IVM MDA appear to influence bystander responses to Plasmodium-derived antigens in community members even if they have not regularly participated in the therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-015-0786-5) contains supplementary material, which is available to authorized users.

Using animal models for the study of uveitis

AbstractOur understanding of inflammatory responses and mechanisms of immune‐mediated tissue damage in man has been greatly facilitated by our animal models systems. The talk will discuss the utility of animal model in uveitis from two aspects. Firstly, permitting fundamental elucidation of immune pathogenic mechanisms that are at play in uveitis and secondly, delivering a platform for preclinical assessment of drug or biologic intervention. We have been fortunate to be able to further manipulate animal models to create spontaneous models of uveitis and also humanised models of uveitis to assess antigen repertoires and responsiveness. Further we now have persistent models of disease activity, which have illuminated mechanisms of tissue repair and also mechanisms of immune mediated angiogenesis. To this end. the models permit us to look at and translate through to man interventions that have benefitted uveitic patients, and such successes will be highlighted throughout the talk

Application of Dolichos biflorus in immunoassay detection of kidney collecting duct biomarkers

Currently there are no biomarkers for detecting collecting duct damage in man. Antibodies to several collecting duct-specific antigens exist but sandwich assays have been difficult to establish due to the need for two different antibodies to the same protein. We hypothesized that a collecting duct-specific lectin could be used in combination with a collecting duct-specific antibody to negate the need for two different antibodies. The collecting duct specificity of selected antibodies (NiCa II 13C2, Pap XI 3C7, HuPaP VII 2B11 and aquaporin 2), was verified by immunohistochemistry. Aquaporin 2 and Pap XI 3C7 were used successfully in setting up assays with the lectin Dolichos biflorus, using the Meso Scale Discovery (MSD) platform. Antigen expression was highest in the papillae of rat and human kidney (corresponding to the greatest density of collecting ducts) and was also present in normal urine. We propose that further qualification and validation would lead to an assay for detecting collecting duct damage in man.

Mannose-binding lectin null alleles are associated with preserved epithelial cell integrity following intestinal ischemia reperfusion in man

Mannose-binding lectin (MBL) deficiency is associated with reduced intestinal ischemia-reperfusion (IR) damage in rodents. We set out to investigate an association between frequently observed MBL deficiency and IR associated intestinal cell damage in man. Using a newly developed IR model of the human small intestine 29 patients were consecutively included. Part of the jejunum was subjected to 30 min of ischemia and reperfusion. The MBL genotype was assessed by means of quantitative-PCR analysis. Enterocyte loss was explored by measuring plasma intestinal-fatty acid binding protein (I-FABP) levels. Arterial and venous MBL plasma levels were measured to assess MBL consumption, MBL deposition was analyzed by immunofluorescence. Ethical approval and informed consent were obtained. The amount of epithelial cell damage varied significantly between the carriers of different mbl2 genotypes (ANOVA, p = 0.02). I-FABP release, representing disintegration of differentiated enterocytes, observed in homozygous wildtype individuals was twice ( p = 0.03) that measured in heterozygous and ten times ( p = 0.04) that observed in homozygous variant individuals. No MBL deposition was observed over the course of reperfusion. The data indicate that MBL influences intestinal epithelial cell integrity in an immediate and non-complement dependent manner during ischemia and reperfusion.

Urgent liver transplantation for Amanita phalloides poisoning

Amanita phalloides is a deadly wild mushroom causing severe damage in man ranging from diarrhea to organ dysfunction. If not treated, mortality is as high as 80%. Treatment includes supportive measures, inactivation of the toxin and if liver failure occurs liver transplantation. The indications for transplantation are debatable.

Consent and anonymization in research involving biobanks: differing terms and norms present serious barriers to an international framework.

Biological samples—such as tissues, blood and cells—are an increasingly important tool for research into human diseases and their genetic and physiological causes. To ease their storage and access, many of these samples are now stored in biobanks. The number of human biological samples in such collections amounted to several hundred million in 1999 in the USA alone—about one sample per US citizen (Eiseman, 2000; Azarow et al , 2003)—and is increasing rapidly. Three‐quarters of the clinical trials that drug companies submit to the US Food and Drug Administration (Rockville, MD, USA) for approval now include a provision for sampling and storing human tissue for future genetic analysis (Abbott, 2003). At the same time, there is a boom of population biobanks, as more and more countries establish new sample collections (Kaiser, 2002). Among the best known are: the Icelandic Health Sector Database; the Estonian Genome Project; the UK Biobank; the CARTaGENE Project in Quebec, Canada; the Banco Nacional de ADN in Spain; the International HapMap Project; and several US biobanks, such as the National Children's Study, the Marshfield Clinic's Personalized Medicine Research Project and the National Health and Nutrition Examinations Surveys. ![][1] This boom of biobanks has spawned a ‘boomlet’ of regulations and guidelines, which has created controversies, particularly about the importance and definition of informed consent. The consent of participants is usually required before biobank samples can be used in research, but the nature of this consent, and how it is obtained, vary widely. Many European guidelines take the view that general consent is acceptable to use samples for future, as yet unspecified, research projects; US and Canadian policy follows a more rigorous standard of consent. Until 2004, both Europe and the USA considered coded and linked anonymized samples—in which a code links the sample to its donor—as identifiable and therefore … [1]: /embed/graphic-1.gif

Genetic diversity and genetic burden in humans

We discuss categories of genetic diversity in humans. Neutral diversity, population differences in frequencies of genetic markers that we think are invisible to natural selection, provides a passive record of population history but is otherwise of little interest in human biology. Genetic variation related to disease can be separated into mutational noise and variation due to selection, either ongoing selection else effects of a past environment. We distinguish consequences of genetic diversity for fitness, relevant to evolution, and consequences for well-being, relevant to medicine and public health. We call genetic variation that causes impairment of health or well-being of individual humans “apparent genetic burden” and variation that has effects on fitness but not well-being “unapparent genetic burden”. We use “burden” to distinguish these notions from the classical concept of “genetic load” that refers to effects on population fitness, a concept formulated by Morton et al. [Morton, N.E., Crow, J.F., Muller, H.J., 1956. An estimate of the mutational damage in man from data on consanguineous marriages. Proc. Natl. Acad. Sci. U.S.A. 42, 855–863]. We distinguish adapted genes and adapted genotypes: an adapted gene is a gene that increases fitness of its bearer either in heterozygous or homozygous state or both, while an adapted genotype is a genotype that increases fitness of its bearer but is not transmitted intact to future generations. Balanced polymorphisms in which the heterozygote is superior in fitness may generate most adapted genotypes. In the face of major rapid environmental change adapted genotypes appear first but over time they are replaced by adapted genes. The presence of adapted genotypes is a good indication of recent environmental change: for example, there are apparently many polymorphisms in domestic animals of this nature, responses to domestication, and many fewer in wild animals (and in humans).

Supplementation with β-Hydroxy- β-Methylbutyrate (HMB) and α-Ketoisocaproic Acid (KIC) Reduces Signs and Symptoms of Exercise-Induced Muscle Damage in Man

This study examined the effects of beta-hydroxyl-beta-methylbutyrate (HMB) and alpha-ketoisocaproic acid (KIC) supplementation on signs and symptoms of exercise-induced muscle damage following a single bout of eccentrically biased resistance exercise. Six non-resistance trained male subjects performed an exercise protocol designed to induce muscle damage on two separate occasions, performed on the dominant or non-dominant arm in a counter-balanced crossover design. Subjects were assigned to an HMB/KIC (3 g HMB and 0.3 g alpha-ketoisocaproic acid, daily) or placebo treatment for 14 d prior to exercise in the counter-balanced crossover design. One repetition maximum (1RM), plasma creatine kinase activity (CK), delayed onset muscle soreness (DOMS), limb girth, and range of motion (ROM) were determined pre-exercise, at 1h, 24 h, 48 h, and 72 h post-exercise. DOMS and the percentage changes in 1RM, limb girth, and ROM all changed over the 72 h period (P < 0.05). HMB//IC supplementation attenuated the CK response, the percentage decrement in 1RM, and the percentage increase in limb girth (P < 0.05). In addition, DOMS was reduced at 24 h post-exercise (P < 0.05) in the HMB/KIC treatment. In conclusion, 14 d of HMB and KIC supplementation reduced signs and symptoms of exercise-induced muscle damage in non-resistance trained males following a single bout of eccentrically biased resistance exercise.

Decreasing the oxidant stress from paraquat in isolated perfused rat lung using captopril and niacin

The abilities of captopril and niacin to protect against the lung toxicity of paraquat (PQ) were studied. The anti-oxidative action of captopril, an angiotensin-converting enzyme inhibitor, appears to be attributable to the sulphahydryl group (SH) in the compound, which gives captopril the ability to scavenge reactive oxygen species. Niacin replenishes the NAD and ATP depletion caused by reactive oxygen species. PQ causes lung damage in man and in several species of laboratory animals. The damage is initially manifested by hemorrhage and edema, and later by consolidation of the lung and fibrosis development. In this study, the lungs of male Wistar rats (250-300 g in weight) were perfused by Krebs-Ringer buffer alone (control), niacin (150 microM), captopril (10 microM) and PQ (600 microM) in perfusion fluid, and the biochemical changes that occurred in isolated rat lung were examined within 1 h and compared to PQ alone. The results show that captopril significantly decreases the lung weight/body weight ratio when used as a pretreatment and a post-treatment to captopril (p<0.0001). The results also show that captopril (10 microM) and niacin (150 microM) significantly decreases PQ-induced lung toxicity. Lactate dehydrogenase (LDH) activity significantly decreased in treatment groups as compared to the PQ group (p<0.0001). This study suggests that paraquat causes increased lipid peroxidation and LDH activity and decreased glutathione (GSH) and total protein in isolated perfused rat lung. These effects are reduced under these experimental conditions by captopril and niacin.

Evaluation of a Multi-parameter Biomarker Set for Oxidative Damage in Man: Increased Urinary Excretion of Lipid, Protein and DNA Oxidation Products after One Hour of Exercise

The objective of the present study was to evaluate a comprehensive set of urinary biomarkers for oxidative damage to lipids, proteins and DNA, in man. Eighteen moderately trained males (mean age 24.6±0.7) exercised 60 min at 70% of maximal O2 uptake on a cycle ergometer. Urine fractions for 12 h were collected 1 day before, and for 3 consecutive days after exercise.As biomarkers of lipid peroxidation, 8 aldehydes (i.e. propanal, butanal, pentanal, hexanal, heptanal, octanal, nonanal and malondialdehyde—MDA)and acetone were analyzed in urines by gas chromatography with electron capture detection (GC-ECD). As a biomarker of protein oxidation, o,o′-dityrosine was analyzed in urine samples by a recently developed isotope dilution HPLC-atmospheric pressure chemical ionization (APCI)-tandem-mass spectrometry (HPLC-APCI-MS/MS) methodology. As a biomarker of oxidative DNA damage, urinary excretion of 8-hydroxy-2′-deoxyguanosine (8-OHdG) was measured by an ELISA method.On the day of exercise, significant increases were observed in urinary excretions of acetone ( p<0.025, n=18) and butanal ( p<0.01, n=18) in the 12 h daytime fractions compared to the daytime fraction before exercise. The urinary acetone excretion was also significantly ( p<0.05) increased on the 1st day after exercise. Octanal and nonanal were increased in the daytime urine fraction on the 2nd day after exercise. However, these increases were of borderline significance ( p=0.09 and p=0.07, respectively).Significantly elevated urinary o,o′-dityrosine amounts were observed in the daytime fraction on the day of exercise ( p<0.025) and on the 1st day after exercise ( p=0.07) compared to the before exercise daytime fraction.Excretion of urinary 8-OHdG was statistically significantly increased in the daytime fractions on the day of exercise ( p=0.07) and on the 1st day after exercise ( p<0.025) compared to before exercise daytime fraction.Increases in urinary excretions of acetone, propanal, pentanal, MDA and 8-OHdG significantly correlated with training status (hours of exercise/week) of the volunteers, while o,o′-dityrosine did not.To our knowledge, the present study is the first to evaluate a multi-parameter non-invasive biomarker set for damage to three main cellular targets of ROS. It shows that 1 h of exercise may already induce oxidative damage in moderately trained individuals and that the chosen urinary biomarkers are sensitive enough to monitor such damage.

Folate, DNA stability and colo-rectal neoplasia

Lower levels of dietary folate are associated with the development of epithelial cell tumours in man, particularly colo-rectal cancer. In the majority of epidemiological studies blood folate or reported folate intake have been shown to be inversely related to colo-rectal cancer risk. Folate, via its pivotal role in C1 metabolism, is crucial both for DNA synthesis and repair, and for DNA methylation. This function is compromised when vitamin B12 is low. Vitamin B12 deficiency has been shown to increase biomarkers of DNA damage in man but there is no evidence directly linking low vitamin B12 with cancer. Disturbingly, folate and vitamin B12 deficiencies are common in the general population, particularly in the underprivileged and the elderly. How folate and/or vitamin B12 deficiency influence carcinogenesis remains to be established, but it is currently believed that they may act to decrease DNA methylation, resulting in proto-oncogene activation, and/or to induce instability in the DNA molecule via a futile cycle of uracil misincorporation and removal. The relative importance of these two pathways may become clear by determining both DNA stability and cytosine methylation in individuals with different polymorphic variants of key folate-metabolising enzymes. 5,10-Methylenetetrahydrofolate reductase converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate and thereby controls whether folate is employed for DNA synthesis or DNA methylation. Colo-rectal cancer risk is decreased in subjects homozygous for a common variant (C677T) of the gene coding for this enzyme, suggesting that DNA synthesis and repair may be 'enhanced' in these individuals. Evidence from animal and human studies is presented here in support of folate acting to maintain genomic stability through both these mechanisms.

Inability of mature oocytes to create functional haploid genomes from somatic cell nuclei

Inability of mature oocytes to create functional haploid genomes from somatic cell nuclei

Association between 8-hydroxy-2′-deoxyguanosine levels in DNA of workers highly exposed to asbestos and their clinical data, occupational and non-occupational confounding factors, and cancer

In the preceding paper [B. Marczynski, P. Rozynek, T. Kraus, St. Schlösser, H.J. Raithel, X. Baur, Levels of 8-hydroxy-2′-deoxyguanosine in DNA of white blood cells from workers highly exposed to asbestos in Germany, Mutat. Res. (2000) submitted] we described significant increases ( p<0.001) in the levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG) adducts in the DNA of white blood cells (WBC) of workers highly exposed to asbestos fibers at the workplace relative to those found in the control group in all three study years (period between 1994 and 1997). The results show that the oxidative DNA damage in exposed individuals is between 1.7 times and twice that found in control samples for all 3 years of the study ( p<0.001). The aim of this study was to examine the association between the 8-OHdG levels in WBC DNA of workers highly exposed to asbestos fibers at the workplace and clinical data, occupational and non-occupational confounding factors, and cancer. There is no obvious correlation between the steady-state levels of 8-OHdG in the circulating WBC DNA of asbestos workers and possible confounding factors, such as the presence of benign asbestos-associated diseases, the duration of asbestos exposure, the latency period, the fixed cumulative fibrous dust dose (“fiber years”), age, smoking status, acute febrile infections, medicines, aspirin, calcium (Ca 2+), magnesium (Mg 2+), and the hormone and vitamin intake. This indicates that previous inhalation of asbestos fibers is the major factor responsible for the difference observed in oxidative DNA damage between asbestos workers and controls. For patients suffering from respiratory cancer, cancer of the gastrointestinal tract, mouth/pharynx/larynx, and urogenital tract the mean DNA-adduct level was significantly higher ( p<0.01) than that found in controls, but not significantly higher ( p>0.05) than that for asbestos-exposed patients without tumours. The formation of 8-OHdG adduct levels in WBC DNA of patients with hematopoietic cancer, chondrosarcomas and multiform glioblastomas was not significantly higher than that found in the control group ( p>0.05). Our results support the hypothesis that oxidative DNA damage in man caused by asbestos fibers plays a role in the formation of malignant tumours.