• Lack of promoting effects of phenobarbital at low dose on diethylnitrosamine-induced hepatocarcinogenesis in TGF-alpha transgenic mice.

      Puatanachokchai, Rawiwan; Kakuni, Masakazu; Wanibuchi, Hideki; Kinoshita, Anna; Kang, Jin Seok; Salim, Elsayed I.; Morimura, Keiichirou; Tamano, Seiko; Merlino, Glenn T.; Fukushima, Shoji (2009-03-16)
      Phenobarbital (PB), a rodent non-genotoxic carcinogen, showed hormesis, biphasic effects on rat liver carcinogenesis. To test the hypothesis that the hormesis earlier observed for PB induced hepatocarcinogenesis might also exist in the TGF-alpha transgenic mice model, one which is highly susceptible to carcinogenesis, the carcinogenic or promotion effects of a wide range of phenobarbital (PB) concentrations were investigated. Two weeks after a single i.p. dose of 5 mg /kg bw of diethylnitrosamine (DEN) to 15 day old mice, animals were treated with diet containing PB at doses of 0, 2, 15 or 500 ppm. The incidence and multiplicity of tumors, including hepatocellular adenomas and carcinomas, were significantly increased by the high dose of PB, but no significant difference among the groups receiving 2 and 15 ppm for liver tumors when compared to DEN alone group. The proliferating cell nuclear antigen indices for liver tumors and surrounding hepatocytes in high dose PB treated mice were significantly increased, but no change was noted at the lower doses. The total cytochrome P450 content in the liver was also elevated by 500 ppm of PB, while hepatic 8-OHdG levels demonstrated no significant change. In conclusion, PB at high dose enhances DEN-induced hepatocarcinogenesis in TGF-alpha transgenic mice, but low doses lack any significant effects. One possible mechanism of phenobarbital carcinogenicity might be influenced by cytochrome P450 system exhibiting a strong promoting activity for liver of mice.

      Huang, Wenlin; Caudill, Samuel P.; Grainger, James; Needham, Larry L.; Patterson, Donald G. (2006-05-05)
      Urine samples collected in 1999 and 2000 as part of the National Health and Nutrition Examination Survey (NHANES) were analyzed for 14 monohydroxy polycyclic aromatic hydrocarbons (PAH, metabolites of 7 PAH compounds) and for the first time reference range values were calculated for these metabolites in the U.S. population. The purpose of this paper is to explore differences in these PAH metabolites between children (6-11 years old), adolescents, and adults. More than 99% of the urine samples contained a detectable amount of 1-hydroxypyrene (1-OHpyrene), a metabolite of pyrene. We found that children in the youngest age group (6-11 years) had a geometric mean level (creatinine corrected data) 30% higher than children and adults in the other age groups, but no statistical differences existed between the two genders and among different racial groups. Smokers and persons exposed to environmental tobacco smoke (ETS) in 12-19-year-old group and the 20-year-and-older group had higher levels of urinary 1-OHpyrene by a factor of 2-3 than non-smokers in the corresponding age group. Measurements of 3-hydroxyphenanthrene also suggested increased levels in children and in smokers. These results may indicate that young children are at a greater risk for PAH exposure, or that they absorb, distribute, metabolize, or eliminate PAH differently than adults.
    • Lifelong persistence of AML associated MLL partial tandem duplications (MLL-PTD) in healthy adults.

      Basecke, Jorg; Podleschny, Martina; Clemens, Robert; Schnittger, Susanne; Viereck, Volker; Trumper, Lorenz; Griesinger, Frank (2006-09)
      AML-associated MLL-PTD contribute to leukemogenesis by a gain of function and confer an unfavorable prognosis. Like other leukemia associated aberrations they are also present in healthy adults. To delineate the leukemogenic mechanism we tracked down MLL-PTD in normal hematopoiesis and investigated cord blood samples. MLL-PTD were observed in 56/60 (93%) of all cord bloods. In contrast to AML, the transcript frequency in cord blood was four log scales lower as determined by real-time PCR. The CD34+ progenitor cell, CD33+ myeloid, CD19+ B-lymphoid and CD3+ T-lymphoid subfractions were positive. The ubiquitous presence of MLL-PTD in cord blood implicates a lifelong exposure, not an accumulation during lifetime. Since also present in the stem cell subfraction, these factors seem not to be major determinants in MLL-PTD leukemogenesis.
    • Lung cancer risk among former uranium miners of the WISMUT Company in Germany.

      Brüske-Hohlfeld, Irene; Rosario, Angelika Schaffrath; Wölke, Gabriele; Heinrich, Joachim; Kreuzer, Michaela; Kreienbrock, Lothar; Wichmann, H-Erich (2006-03)
      After 1946, the WISMUT Company developed the third-largest uranium-mining province in the world in the German Democratic Republic. METHODS: A case-control study among former WISMUT miners was conducted to investigate the lung cancer risk in relation to attained age, time since exposure, exposure duration, and exposure rate. It consisted of 505 patients with lung cancer and 1,073 controls matched to cases according to the year of birth. The cumulative exposure to radon and radon decay products was calculated as the sum of yearly exposures and expressed in Working Level Months (WLM). Cases had a mean cumulative exposure of 552 WLM compared to 420 WLM in controls. RESULTS: There was a statistically significant increase in lung cancer risk for cumulative exposures above 800 WLM. Under the assumption of a linear risk model, there was a significant increase in the relative risk of 0.10 per 100 WLM after adjusting for smoking and asbestos exposure. For current smokers the increase in relative risk was lower (0.05 per 100 WLM), whereas it was higher (0.20 per 100 WLM) among nonsmokers and longtime ex-smokers. After correcting in a sensitivity analysis for the fact that the controls of this study had a higher average exposure than the population of WISMUT workers they were recruited from, the adjusted ERR increased to 0.24 per 100 WLM. Lung cancer risk declined with time since exposure, except for exposures received 45 or more years ago. No inverse dose rate effect was observed.

      González, Carlos A.; Jakszyn, Paula; Pera, Guillem; Agudo, Antonio; Bingham, Sheila; Palli, Domenico; Ferrari, Pietro; Boeing, Heiner; del Giudice, Giuseppe; Plebani, Mario; et al. (2006-03-01)
    • Metabolic profile in workers occupationally exposed to arsenic: role of GST polymorphisms.

      Marcos, Ricardo; Martínez, Valeria; Hernández, Alba; Creus, Amadeu; Sekaran, Chandra; Tokunaga, Hiroshi; Quinteros, Domingo (2006-03)
      Arsenic is a well-known human carcinogen with a ubiquitous distribution in the natural environment. Chronic exposure to inorganic arsenic involves a biotransformation process that leds to the main excretion of organic methylated metabolites, such as monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), as well as the parental inorganic species. Interindividual variation in arsenic metabolism has been extensively reported, and polymorphisms in genes involved in such process could be related to changes in the arsenic excretion profile and the response to chronic exposures. Our analysis of the metabolic profiles in three groups of workers exposed to different arsenic exposure levels showed high amounts of inorganic arsenic and MMA in the most-exposed workers versus the least-exposed workers, in whom high amounts of DMA were observed. With respect to the role of different genetic polymorphisms in the glutathione S-transferase (GST) genes in the modulation of the urinary profiles, for the overall population only a tendency was just observed between GSTM1 null and MMA excretion as well as between GSTP1 val/val and DMA excretion.
    • Modifying effect of dietary sesaminol glucosides on the formation of azoxymethane-induced premalignant lesions of rat colon.

      Sheng, HongQiang; Hirose, Yoshinobu; Hata, Kazuya; Zheng, Qiao; Kuno, Toshiya; Asano, Nami; Yamada, Yasuhiro; Hara, Akira; Osawa, Toshihiko; Mori, Hideki (2007-02-08)
      Sesame, which has been reported to have preventive effects against various disordered conditions, contains small quantities of lignans and several precursors to them such as sesaminol glucosides (SG). The lignans have the potent antioxidative activity and are suggested to have chemopreventive property. In the present study, we evaluated the modulating effect of SG on the development of colon precancerous lesions, aberrant crypt foci (ACF) and beta-catenin-accumulated crypts (BCAC), in the azoxymethane (AOM)-induced short-term model using male F344 rats. Dietary SG (500 ppm) significantly decreased the incidence of AOM-induced ACF when compared to the control (P<0.01). The incidences of AOM-induced BCAC in the SG-treated groups (250 or 500 ppm) were also significantly lower than that of the control group (P<0.01). Interestingly, administration of 500 ppm SG clearly decreased serum triglyceride level and mRNA expression of intestinal fatty acid-binding protein in the colonic mucosa, as compared to the control. These findings indicate that dietary SG inhibits AOM-induced carcinogenesis and suggest SG as a possible chemopreventive agent.
    • Molecular biomarkers of oxidative stress associated with bromate carcinogenicity.

      Delker, Don; Hatch, Gary; Allen, James; Crissman, Bobby; George, Michael; Geter, David; Kilburn, Steve; Moore, Tanya; Nelson, Gail; Roop, Barbara; et al. (2006-04-17)
      Potassium bromate (KBrO3) is a chemical oxidizing agent found in drinking water as a disinfection byproduct of surface water ozonation. Chronic exposures to KBrO3 cause renal cell tumors in rats, hamsters and mice and thyroid and testicular mesothelial tumors in rats. Experimental evidence indicates that bromate mediates toxicological effects via the induction of oxidative stress. To investigate the contribution of oxidative stress in KBrO3-induced cancer, male F344 rats were administered KBrO3 in their drinking water at multiple concentrations for 2-100 weeks. Gene expression analyses were performed on kidney, thyroid and mesothelial cell RNA. Families of mRNA transcripts differentially expressed with respect to bromate treatment included multiple cancer, cell death, ion transport and oxidative stress genes. Multiple glutathione metabolism genes were up-regulated in kidney following carcinogenic (400 mg/L) but not non-carcinogenic (20 mg/L) bromate exposures. 8-Oxodeoxyguanosine glycosylase (Ogg1) mRNA was up-regulated in response to bromate treatment in kidney but not thyroid. A dramatic decrease in global gene expression changes was observed following 1mg/L compared to 20 mg/L bromate exposures. In a separate study oxygen-18 (18O) labeled KBrO3 was administered to male rats by oral gavage and tissues were analyzed for 18O deposition. Tissue enrichment of 18O was observed at 5 and 24 h post-KBr18O3 exposure with the highest enrichment occurring in the liver followed by the kidney, thyroid and testes. The kidney dose response observed was biphasic showing similar statistical increases in 18O deposition between 0.25 and 50 mg/L (equivalent dose) KBr18O3 followed by a much greater increase above 50 mg/L. These results suggest that carcinogenic doses of potassium bromate require attainment of a threshold at which oxidation of tissues occurs and that gene expression profiles may be predictive of these physiological changes in renal homeostasis.
    • Multiplex ligation-dependent probe amplification: a diagnostic tool for simultaneous identification of different genetic markers in glial tumors.

      Jeuken, Judith; Cornelissen, Sandra; Boots-Sprenger, Sandra; Gijsen, Sabine; Wesseling, Pieter (2006-09)
      Genetic aberrations in tumors are predictive for chemosensitivity and survival. A test is needed that allows simultaneous detection of multiple changes and that is widely applicable in a routine diagnostic setting. Multiplex ligation-dependent probe amplification (MLPA) allows detection of DNA copy number changes of up to 45 loci in one relatively simple, semiquantitative polymerase chain reaction-based assay. To assess the applicability of MLPA, we performed MLPA analysis to detect relevant genetic markers in a spectrum of 88 gliomas. The vast majority of these tumors (n = 79) were previously characterized by comparative genomic hybridization. With MLPA kit P088 (78 cases), complete and partial loss of 1p and 19q were reliably identified, even in samples containing only 50% tumor DNA. Distinct 1p deletions exist with different clinically prognostic consequences, and in contrast to the commonly used diagnostic strategies (loss of heterozygosity or fluorescent in situ hybridization 1p36), P088 allows detection of such distinct 1p losses. Combining P088 with P105 will further increase the accurate prediction of clinical behavior because this kit identified markers (EGFR, PTEN, and CDKN2A) of high-grade malignancy in 41 cases analyzed. We conclude that MLPA is a reliable diagnostic tool for simultaneous identification of different region-specific genetic aberrations of tumors.
    • Mutagenesis and carcinogenesis caused by the oxidation of nucleic acids.

      Genomes and their precursor nucleotides are highly exposed to reactive oxygen species, which are generated both as byproducts of oxygen respiration or molecular executors in the host defense, and by environmental exposure to ionizing radiation and chemicals. To counteract such oxidative damage in nucleic acids, mammalian cells are equipped with three distinct enzymes. MTH1 protein hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-2'-deoxyguanosine triphosphate and 2-hydroxy-2'-deoxyadenosine triphosphate (2-OH-dATP), to the corresponding monophosphates. We observed increased susceptibility to spontaneous carcinogenesis in MTH1-null mice, which exhibit an increased occurrence of A:T-->C:G and G:C-->T:A transversion mutations. 8-Oxoguanine (8-oxoG) DNA glycosylase, encoded by the OGG1 gene, and adenine DNA glycosylase, encoded by the MUTYH gene, are responsible for the suppression of G:C to T:A transversions caused by the accumulation of 8-oxoG in the genome. Deficiency of these enzymes leads to increased tumorigenesis in the lung and intestinal tract in mice, respectively. MUTYH deficiency may also increase G:C to T:A transversions through the misincorporation of 2-OH-dATP, especially in the intestinal tract, since MUTYH can excise 2-hydroxyadenine opposite guanine in genomic DNA and the repair activity is selectively impaired by a mutation found in patients with autosomal recessive colorectal adenomatous polyposis.


    • Occupational upper airway disease.

      Walusiak-Skorupa, Jolanta (2006-02)

    • Oxidative DNA damage in cucumber cotyledons irradiated with ultraviolet light.


    • Pendimethalin exposure and cancer incidence among pesticide applicators.



