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Prenatal exposure to environmental tobacco smoke, genetic damage and DNA methylation
Abstracts / Toxicology Letters 238S (2015) S56–S383
ences with blank plasma samples were shown. In addition, using the fluorescence detector contributes, in itself, to increase the selectivity of the method. The method is precise, accurate, with average recovery percent between 86 and 92% (at three concentration levels) and has a LOD of 0.010 g/mL and a LOQ of 0.100 g/mL. The applicability of the method has been verified on the plasma samples from the patients with tramadol treatment in doses ranging from 100 mg to 400 mg/day, thus demonstrating the utility of the method for the quantification of therapeutic levels of tramadol. Conclusions: The developed method is rapid (with an analysis time of 5 min), involving simple experimental conditions, and an accurate and short extraction procedure. The proposed method can be used to assess tramadol levels in human plasma in both pharmacokinetic studies and in overdoses cases. http://dx.doi.org/10.1016/j.toxlet.2015.08.1080
P22-054 Prenatal exposure to environmental tobacco smoke, genetic damage and DNA methylation C. Costa 1,2,∗ , S. Silva 1,2 , J. Teixeira 1,2 1
Portuguese National Institute of Health, Environmental Health Department, Porto, Portugal 2 EPIUnit – Institute of Public Health, Porto, Portugal Pregnant women are a vulnerable population for tobaccocontrol efforts because cigarette smoking during pregnancy pose serious risks to foetal health. Besides smoking during pregnancy, environmental tobacco smoke (ETS) exposure should also be considered when discussing the effects of tobacco as it has been classified by EPA as a class A carcinogen. Several studies describe a variety of adverse effects on the health of non-smokers exposed to environmental tobacco smoke. While it seems likely that environmental factors are able to alter cellular gene expression, the mechanisms on its basis are not yet completely understood. Recently, it has been suggested that environmental factors can modify the epigenetic profile of the cell potentially mediating the harmful effects of tobacco smoking. Smoking has been associated with altered global methylation and differential methylation extent in several cancer-related genes. Thus, prenatal tobacco smoke exposure in early pregnancy may have important and lasting effects on DNA methylation and consequently influence gene expression and disease phenotypes across the life course. The present study aims to review available data on DNA damage and changes in patterns of DNA methylation in newborns resulting from in utero exposure to tobacco. Data here obtained identifies knowledge gaps in research related to risk of exposure and maternal consumption of tobacco for the health of the newborn. Understanding the harmful effects of tobacco on the health of a developing foetus is a compelling reason to promote cessation of tobacco use during pregnancy and optimize the current and future health not only of women but also their children. Acknowledgments: Carla Costa is supported by the grant SFRH/BPD/96196/2013, funded by FCT (QREN-POPH-Type 4.1 – Advanced training, subsidized by the European Social Fund and national funds of MEC). http://dx.doi.org/10.1016/j.toxlet.2015.08.1081
S379
P22-055 Correlation of rat intestinal permeability rate measures with human absorption and metabolism to improve BCS and BDDCS predictions M. Estudante 1,2 , C. Sampayo 1 , C. Carvalho 1,∗ , J. Morais 1 , L. Benet 2 1
FFUL, iMed.ULisboa, Lisbon, Portugal UCSF, Department of Bioengineering & Therapeutic Sciences, San Francisco, United States 2
Drug permeability rate (P) has been widely accepted as a screening tool for determining intestinal absorption. In 1995, the Biopharmaceutics Classification System (BCS) was proposed as predictive of drug absorption based on P and solubility. An important concern during drug development is the potential for drug–drug interactions (DDIs) as they can cause profound clinical effects, either by reducing or enhancing toxicity or efficacy. EU and USA DDI guidances reinforce the need for better transporter DDI predictive models. The Biopharmaceutics Drug Disposition Classification System (BDDCS), a modification of BCS that utilizes the extent of drug metabolism (M) together with intestinal P, predicts potential DDIs in several organs. Although correlations between BCS and BDDCS have been observed with drug P rates, discrepancies have been noted utilizing different P models [1]. Rat intestinal P techniques may offer advantages beyond established absorption tools (e.g. Caco-2 cell model) such as expression of relevant drug transporters and enzymes. Question: To investigate the utility of published rat intestinal P data to evaluate BCS and BDDCS predictions. Methods: Nineteen drugs were evaluated for the relationship of rat intestinal P to human extent of absorption (A) and metabolism (M). Metoprolol was used as the cut-off for high P. Results: Results indicate that rat intestine P data correlate with both BDDCS extent of M and BCS extent of A (p < 0.01). Conclusions: Preliminary data from the rat intestinal model appear to accurately predict BDDCS/BCS classifications.
Reference Larregieu, C.A., Benet, L.Z., 2014. Mol. Pharm. 11, 1335–1344.
http://dx.doi.org/10.1016/j.toxlet.2015.08.1082
P22-056 Soil contamination of PCDDs/PCDFs and dl-PCBs in the urban catchment in central Poland M. Zielinski 1 , M. Czerska 1 , M. Urbaniak 2 , J. Gromadzinska 1,∗ 1 Nofer Institute of Occupational Medicine, Toxicology and Carcinogenesis, Lodz, Poland 2 International Institute PAS European Regional Centre for Ecohydrology u/a UNESCO, Lodz, Poland
The latest studies demonstrated that most of pollutants, including Persistent Organic Pollutants (POPs) are related to the urban agglomerations. That is why these group of compounds including the polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and polychlorinated biphenyls (PCBs), have received the most attention according to their persistence in environment, bioaccumulation and hazard for biota. Their levels in soils increase with time as a result of cumulative atmospheric deposi-
ences with blank plasma samples were shown. In addition, using the fluorescence detector contributes, in itself, to increase the selectivity of the method. The method is precise, accurate, with average recovery percent between 86 and 92% (at three concentration levels) and has a LOD of 0.010 g/mL and a LOQ of 0.100 g/mL. The applicability of the method has been verified on the plasma samples from the patients with tramadol treatment in doses ranging from 100 mg to 400 mg/day, thus demonstrating the utility of the method for the quantification of therapeutic levels of tramadol. Conclusions: The developed method is rapid (with an analysis time of 5 min), involving simple experimental conditions, and an accurate and short extraction procedure. The proposed method can be used to assess tramadol levels in human plasma in both pharmacokinetic studies and in overdoses cases. http://dx.doi.org/10.1016/j.toxlet.2015.08.1080
P22-054 Prenatal exposure to environmental tobacco smoke, genetic damage and DNA methylation C. Costa 1,2,∗ , S. Silva 1,2 , J. Teixeira 1,2 1
Portuguese National Institute of Health, Environmental Health Department, Porto, Portugal 2 EPIUnit – Institute of Public Health, Porto, Portugal Pregnant women are a vulnerable population for tobaccocontrol efforts because cigarette smoking during pregnancy pose serious risks to foetal health. Besides smoking during pregnancy, environmental tobacco smoke (ETS) exposure should also be considered when discussing the effects of tobacco as it has been classified by EPA as a class A carcinogen. Several studies describe a variety of adverse effects on the health of non-smokers exposed to environmental tobacco smoke. While it seems likely that environmental factors are able to alter cellular gene expression, the mechanisms on its basis are not yet completely understood. Recently, it has been suggested that environmental factors can modify the epigenetic profile of the cell potentially mediating the harmful effects of tobacco smoking. Smoking has been associated with altered global methylation and differential methylation extent in several cancer-related genes. Thus, prenatal tobacco smoke exposure in early pregnancy may have important and lasting effects on DNA methylation and consequently influence gene expression and disease phenotypes across the life course. The present study aims to review available data on DNA damage and changes in patterns of DNA methylation in newborns resulting from in utero exposure to tobacco. Data here obtained identifies knowledge gaps in research related to risk of exposure and maternal consumption of tobacco for the health of the newborn. Understanding the harmful effects of tobacco on the health of a developing foetus is a compelling reason to promote cessation of tobacco use during pregnancy and optimize the current and future health not only of women but also their children. Acknowledgments: Carla Costa is supported by the grant SFRH/BPD/96196/2013, funded by FCT (QREN-POPH-Type 4.1 – Advanced training, subsidized by the European Social Fund and national funds of MEC). http://dx.doi.org/10.1016/j.toxlet.2015.08.1081
S379
P22-055 Correlation of rat intestinal permeability rate measures with human absorption and metabolism to improve BCS and BDDCS predictions M. Estudante 1,2 , C. Sampayo 1 , C. Carvalho 1,∗ , J. Morais 1 , L. Benet 2 1
FFUL, iMed.ULisboa, Lisbon, Portugal UCSF, Department of Bioengineering & Therapeutic Sciences, San Francisco, United States 2
Drug permeability rate (P) has been widely accepted as a screening tool for determining intestinal absorption. In 1995, the Biopharmaceutics Classification System (BCS) was proposed as predictive of drug absorption based on P and solubility. An important concern during drug development is the potential for drug–drug interactions (DDIs) as they can cause profound clinical effects, either by reducing or enhancing toxicity or efficacy. EU and USA DDI guidances reinforce the need for better transporter DDI predictive models. The Biopharmaceutics Drug Disposition Classification System (BDDCS), a modification of BCS that utilizes the extent of drug metabolism (M) together with intestinal P, predicts potential DDIs in several organs. Although correlations between BCS and BDDCS have been observed with drug P rates, discrepancies have been noted utilizing different P models [1]. Rat intestinal P techniques may offer advantages beyond established absorption tools (e.g. Caco-2 cell model) such as expression of relevant drug transporters and enzymes. Question: To investigate the utility of published rat intestinal P data to evaluate BCS and BDDCS predictions. Methods: Nineteen drugs were evaluated for the relationship of rat intestinal P to human extent of absorption (A) and metabolism (M). Metoprolol was used as the cut-off for high P. Results: Results indicate that rat intestine P data correlate with both BDDCS extent of M and BCS extent of A (p < 0.01). Conclusions: Preliminary data from the rat intestinal model appear to accurately predict BDDCS/BCS classifications.
Reference Larregieu, C.A., Benet, L.Z., 2014. Mol. Pharm. 11, 1335–1344.
http://dx.doi.org/10.1016/j.toxlet.2015.08.1082
P22-056 Soil contamination of PCDDs/PCDFs and dl-PCBs in the urban catchment in central Poland M. Zielinski 1 , M. Czerska 1 , M. Urbaniak 2 , J. Gromadzinska 1,∗ 1 Nofer Institute of Occupational Medicine, Toxicology and Carcinogenesis, Lodz, Poland 2 International Institute PAS European Regional Centre for Ecohydrology u/a UNESCO, Lodz, Poland
The latest studies demonstrated that most of pollutants, including Persistent Organic Pollutants (POPs) are related to the urban agglomerations. That is why these group of compounds including the polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and polychlorinated biphenyls (PCBs), have received the most attention according to their persistence in environment, bioaccumulation and hazard for biota. Their levels in soils increase with time as a result of cumulative atmospheric deposi-