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Biomarkers of exposure, of cytogenetic effect and of genetic susceptibility in workers exposed to styrene
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Abstracts / Toxicology Letters 205S (2011) S60–S179
P1025 Inducible nitric oxide synthase gene polymorphism in acute pancreatitis G. Ozhan ∗ , F.M. Sari, B. Alpertunga Department of Pharmaceutical Toxicology, Istanbul University, Faculty of Pharmacy, Istanbul, Turkey Purpose: Acute pancreatitis (AP) is an initially localized inflammation of the pancreatic gland. The incidence of AP has been increasing over the last few decades. The precise mechanisms by which etiological factors induce AP are not yet known, but when initiated, common inflammatory pathways seem to be involved, with cytokines being their components of major importance. The inducible nitric oxide synthase gene (iNOS) is an enzyme involved in the pathway of reactive oxygen and induced in response to infection, cytokines. iNOS is capable of generating large quantities of nitric oxide (NO) produced by macrophages during inflammation. The objective of this study was to investigate the association between iNOS genotypes and AP. Methods: We studied the case–control association of single nucleotide polymorphisms (SNPs) in iNOS gene in patients with AP in Turkish population. The SNPs were Ser608Leu which results in an amino acid substitution, 1173C/T and 954G/C both in the gene promoter region that is linked to increased enzyme expression, resulting in higher NO production. Statistical analysis was conducted by using the computer software Statistical Package for Social Sciences-SPSS. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by conditional logistic regression analyses. Besides, haplotype frequencies were estimated from genotype data by PHASE software. The distribution of haplotypes in the cases and controls was compared by 2 test. Results: We believe that the results obtained from this study will be beneficial to the development of efficacious preventive strategies and therapies for inflammation-associated cancers. doi:10.1016/j.toxlet.2011.05.259
P1026 Biomarkers of exposure, of cytogenetic effect and of genetic susceptibility in workers exposed to styrene M.J. Prieto-Castelló 1,∗ , D. Marhuenda Amorós 2 , A. Corno Caparrós 3 , J.M. García-Sagredo 4 , A. Cardona Llorens 2 1
Pathology and Surgery, Miguel Hernández University, San Juan de Alicante, Spain, 2 Pathology and Surgery, Faculty Of Medicine, Miguel Hernandez University, San Juan de Alicante, Spain, 3 Faculty Of Pharmacy, Engineering Department, Miguel Hernandez University, San Juan de Alicante, Spain, 4 Medical Genetics Service, Ramon y Cajal Universitary Hospital, Madrid, Spain Styrene is widely used in the production of synthetic rubber, resins, polyesters, plastics and reinforced marble products. Styrene metabolism involves cytochrome P450 enzymes (CYP)-mediated that by oxidation convert styrene to its genotoxic metabolite styrene-7,8-oxide (SO). SO is mainly hydrolysed to styrene glycol by the microsomal epoxide hydrolase (mEH), and subsequently oxidized by alcohol and aldehyde dehydrogenases to the main urinary metabolites, mandelic acid (MA) and phenylglyoxylic acid (PGA). SO is detoxified to a minor extent, by conjugation mediated by glutathione S-transferases (GSTs).The aim of this study was to evaluate if individual polymorphisms in xenobiotic metabolizing enzymes could modify individual susceptibility to the possible genotoxic
effect of the styrene exposure. Forty-three male workers exposed to styrene from marble industry were studied. Urinary concentrations of MA and PGA were determined, genetic damage was studied by means of micronucleus (MN) test and the possible influence of genetic polymorphisms of EPHX1 (codons 113 and 139), GSTM1 (gene deletion) and CYP2E1 (Pst1 polymorphism) was investigated. Tobacco smoking was associated with increased MN frequencies and MN levels were also associated with number of cigarettes per day (p < 0.05). When EPHX1 genotypes were classified in low, medium, and high with respect to the expected mEH activity, an increase in MN frequency was observed with decreasing mEH activity in smoker workers. Although differences were not statistically significant these findings are consistent with the detoxifying activity of this enzyme. Our results suggest that EPHX1 polymorphisms and smoking habit may influence induction of cytogenetic damage by SO in styrene exposed workers. doi:10.1016/j.toxlet.2011.05.260
P1027 CYP1A2 and circadian genes expression in nurses under different work shifts E. Reszka 1,∗ , B. Peplonska 2 , E. Wieczorek 1 , W. Sobala 2 , A. Bukowska 2 , J. Gromadzinska 1 , J. Lie 3 , W. Wasowicz 1 1
Department of Toxicology and Carcinogenesis, Nofer Institute of Occupational Medicine, Lodz, Poland, 2 Department of Environmental Epidemiology, Institute of Occupational Medicine, Lodz, Poland, 3 National Institute of Occupational Health, Oslo, Norway Epidemiological studies have found that long-term nightworking women have a higher risk of breast cancer risk than women who do not work at night. According to circadian rhythm disruption hypothesis the underlying mechanism involves suppression of melatonin production caused by exposure to light at night. Circadian genes are responsible for adaptation of circadian rhythm and may influence cancer-related pathways. CYP1A2 is involved in melatonin metabolism. The cross-sectional study of 360 nurses currently working on rotating night-shifts and 365 nurses who work only during the day was carried out in Lodz, Poland. The Regional Ethics Committee approved the study protocol, and a written consent was obtained from each participant of the study. Information on occupational history and breast cancer risk factors was collected during in-person interviews. hCYP1A2, hBmal1, hClock, hCry1, hCry2, hPer1, hPer2, hPer3 genes expression in circulating blood leukocytes were analysed among 184 matched samples, using Real-Time PCR assays. All the subjects expressed detectable mRNA transcripts level in blood leukocytes with large inter-individual variation. Upregulation of all investigated genes was observed in nurses working night shifts compared to nurses working day shifts, however significant changes in genes expression were observed for hCYP1A2, hPer1 and hPer3. The highest transcript level of these three genes was observed among nurses with the highest intensity of night shift work. Shift work may reveal a potential impact of artificial light at night on hCYP1A2, hPer1 and hPer3 transcripts level in circulating leukocytes. This project is supported by a grant from the Polish-Norwegian Research Fund (PNRF 243-AI-1/07). doi:10.1016/j.toxlet.2011.05.261
Abstracts / Toxicology Letters 205S (2011) S60–S179
P1025 Inducible nitric oxide synthase gene polymorphism in acute pancreatitis G. Ozhan ∗ , F.M. Sari, B. Alpertunga Department of Pharmaceutical Toxicology, Istanbul University, Faculty of Pharmacy, Istanbul, Turkey Purpose: Acute pancreatitis (AP) is an initially localized inflammation of the pancreatic gland. The incidence of AP has been increasing over the last few decades. The precise mechanisms by which etiological factors induce AP are not yet known, but when initiated, common inflammatory pathways seem to be involved, with cytokines being their components of major importance. The inducible nitric oxide synthase gene (iNOS) is an enzyme involved in the pathway of reactive oxygen and induced in response to infection, cytokines. iNOS is capable of generating large quantities of nitric oxide (NO) produced by macrophages during inflammation. The objective of this study was to investigate the association between iNOS genotypes and AP. Methods: We studied the case–control association of single nucleotide polymorphisms (SNPs) in iNOS gene in patients with AP in Turkish population. The SNPs were Ser608Leu which results in an amino acid substitution, 1173C/T and 954G/C both in the gene promoter region that is linked to increased enzyme expression, resulting in higher NO production. Statistical analysis was conducted by using the computer software Statistical Package for Social Sciences-SPSS. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by conditional logistic regression analyses. Besides, haplotype frequencies were estimated from genotype data by PHASE software. The distribution of haplotypes in the cases and controls was compared by 2 test. Results: We believe that the results obtained from this study will be beneficial to the development of efficacious preventive strategies and therapies for inflammation-associated cancers. doi:10.1016/j.toxlet.2011.05.259
P1026 Biomarkers of exposure, of cytogenetic effect and of genetic susceptibility in workers exposed to styrene M.J. Prieto-Castelló 1,∗ , D. Marhuenda Amorós 2 , A. Corno Caparrós 3 , J.M. García-Sagredo 4 , A. Cardona Llorens 2 1
Pathology and Surgery, Miguel Hernández University, San Juan de Alicante, Spain, 2 Pathology and Surgery, Faculty Of Medicine, Miguel Hernandez University, San Juan de Alicante, Spain, 3 Faculty Of Pharmacy, Engineering Department, Miguel Hernandez University, San Juan de Alicante, Spain, 4 Medical Genetics Service, Ramon y Cajal Universitary Hospital, Madrid, Spain Styrene is widely used in the production of synthetic rubber, resins, polyesters, plastics and reinforced marble products. Styrene metabolism involves cytochrome P450 enzymes (CYP)-mediated that by oxidation convert styrene to its genotoxic metabolite styrene-7,8-oxide (SO). SO is mainly hydrolysed to styrene glycol by the microsomal epoxide hydrolase (mEH), and subsequently oxidized by alcohol and aldehyde dehydrogenases to the main urinary metabolites, mandelic acid (MA) and phenylglyoxylic acid (PGA). SO is detoxified to a minor extent, by conjugation mediated by glutathione S-transferases (GSTs).The aim of this study was to evaluate if individual polymorphisms in xenobiotic metabolizing enzymes could modify individual susceptibility to the possible genotoxic
effect of the styrene exposure. Forty-three male workers exposed to styrene from marble industry were studied. Urinary concentrations of MA and PGA were determined, genetic damage was studied by means of micronucleus (MN) test and the possible influence of genetic polymorphisms of EPHX1 (codons 113 and 139), GSTM1 (gene deletion) and CYP2E1 (Pst1 polymorphism) was investigated. Tobacco smoking was associated with increased MN frequencies and MN levels were also associated with number of cigarettes per day (p < 0.05). When EPHX1 genotypes were classified in low, medium, and high with respect to the expected mEH activity, an increase in MN frequency was observed with decreasing mEH activity in smoker workers. Although differences were not statistically significant these findings are consistent with the detoxifying activity of this enzyme. Our results suggest that EPHX1 polymorphisms and smoking habit may influence induction of cytogenetic damage by SO in styrene exposed workers. doi:10.1016/j.toxlet.2011.05.260
P1027 CYP1A2 and circadian genes expression in nurses under different work shifts E. Reszka 1,∗ , B. Peplonska 2 , E. Wieczorek 1 , W. Sobala 2 , A. Bukowska 2 , J. Gromadzinska 1 , J. Lie 3 , W. Wasowicz 1 1
Department of Toxicology and Carcinogenesis, Nofer Institute of Occupational Medicine, Lodz, Poland, 2 Department of Environmental Epidemiology, Institute of Occupational Medicine, Lodz, Poland, 3 National Institute of Occupational Health, Oslo, Norway Epidemiological studies have found that long-term nightworking women have a higher risk of breast cancer risk than women who do not work at night. According to circadian rhythm disruption hypothesis the underlying mechanism involves suppression of melatonin production caused by exposure to light at night. Circadian genes are responsible for adaptation of circadian rhythm and may influence cancer-related pathways. CYP1A2 is involved in melatonin metabolism. The cross-sectional study of 360 nurses currently working on rotating night-shifts and 365 nurses who work only during the day was carried out in Lodz, Poland. The Regional Ethics Committee approved the study protocol, and a written consent was obtained from each participant of the study. Information on occupational history and breast cancer risk factors was collected during in-person interviews. hCYP1A2, hBmal1, hClock, hCry1, hCry2, hPer1, hPer2, hPer3 genes expression in circulating blood leukocytes were analysed among 184 matched samples, using Real-Time PCR assays. All the subjects expressed detectable mRNA transcripts level in blood leukocytes with large inter-individual variation. Upregulation of all investigated genes was observed in nurses working night shifts compared to nurses working day shifts, however significant changes in genes expression were observed for hCYP1A2, hPer1 and hPer3. The highest transcript level of these three genes was observed among nurses with the highest intensity of night shift work. Shift work may reveal a potential impact of artificial light at night on hCYP1A2, hPer1 and hPer3 transcripts level in circulating leukocytes. This project is supported by a grant from the Polish-Norwegian Research Fund (PNRF 243-AI-1/07). doi:10.1016/j.toxlet.2011.05.261