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Breast cancer in Danish women: A prospective case–control study on breast cancer risk upon exposure to perfluorinated compounds
S70
Abstracts / Toxicology Letters 221S (2013) S59–S256
P03-02 Breast cancer in Danish women: A prospective case–control study on breast cancer risk upon exposure to perfluorinated compounds Eva Cecilie Bonefeld-Jorgensen ∗ , Manhai Long, Stine F. Overvad, Jørn Olsen Department for Public Health, Aarhus University, Denmark Breast cancer (BC) is the most common cancer for women in the western world. Exposure to persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) might contribute to the risk of BC. Animal studies indicate that perfluorinated compounds (PFCs) impact on mammary tissues causing increases in mammary fibroadenomas. Recently, we demonstrated a significant association between serum PFC and BC risk in Greenlandic Inuit. The aim of the present prospective study was to evaluate associations between serum levels of PFCs in young Danish women and the risk of BC later in life. The study includes samples from 250 BC cases and 233 controls prospectively sampled during 1996–2002. The serum levels of 16 PFCs (perfluorocarboxylated acids (PFCAs), perfluorosulfonated acids (PFSAs) and perflurooctane-sulfonamide (PFOSA)) were determined by liquid chromatography-tandem mass spectrometry with electrospray ionization in negative mode. Questionnaires data for sampling age, body mass index before pregnancy, parity, oral contraceptives use, menarche age, smoking, beer and wine drinking, maternal education and physical activity. Data quartiles showed that the BC cases had significantly higher serum level of perfluorooctanoic acid (PFOA) and PFOSA than that of controls after adjustment for age, BMI, parity, OC use, menarche age, smoking, beer and wine drinking, maternal education and physical activity. An increased tendency of odds ratio in quartiles of PFOA, sum PFSA and sum PFCA upon adjustment for confounders was observed. In summary, the serum level of PFCs is a risk factor for development of BC in Danish women supported by our previous study in Greenlandic Inuit. http://dx.doi.org/10.1016/j.toxlet.2013.05.049
P03-03 Carcinogenicity testing of eliglustat in the mouse and rat Rafif Dagher 1,∗ , Judith Marquis 1 , Malene Watzinger 2 , Roy Forster 2 1
Genzyme Corporation, Waltham, USA, 2 CiToxLAB, Evreux, France
Eliglustat is in development for oral treatment of the inherited metabolic disorder Gaucher disease type 1 (GD1). This lysosomal storage disease results from a deficiency of the catabolic enzyme acid-()-glucosidase leading to accumulation of glycolipid. The principal substrate of acid-()-glucosidase is glucosylceramide (GL-1); eliglustat acts to reduce production of GL-1 by inhibition of glucosylceramide synthase. Since treatment of GD1 patients will require chronic treatment with eliglustat, carcinogenicity studies are required. We have evaluated potential carcinogenicity in chronic (2-year) bioassays in the Swiss CD-1 mouse (by dietary administration) and Sprague-Dawley rat (by oral gavage). In the mouse study, treatment with eliglustat did not influence overall survival rates of treated mice at dose-levels up to 75 mg/kg/day. Reduced bodyweight gain at the high dose level indicated that the MTD had been achieved. At histopathology, no treatment related
increases in tumour incidence were observed in any groups of eliglustat treated mice. Similarly, in the rat study there was no effect of eliglustat on the overall survival rates up to the high dose level (75 (males) or 50 mg/kg/day (females)). Reduced bodyweight gain at the high dose level indicated that the MTD had been achieved. At histopathology, no treatment related increases in tumour incidence were observed in any groups of eliglustat treated rats. The only neoplastic lesions that were noted were among those that occur spontaneously in these animal models. It was concluded that eliglustat is not carcinogenic after oral administration to mice or rats. http://dx.doi.org/10.1016/j.toxlet.2013.05.050
P03-04 Cigarette sidestream smoke is a source of environmental estrogen Lih-Ann Li ∗ , Lun-Cheng Kuo, Chun-Ju Lin, Pei-Rung Wu Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan, ROC Serum estrogen level and tumor aromatase expression exhibit an inverse association with poor prognosis of lung adenocarcinoma, suggesting that estrogen plays a role in promoting this cancer. Exposure to exogenous estrogen is expected to increase the risk of lung adenocarcinoma. Secondhand cigarette smoke, a major environmental risk factor for never smokers, contains vast amounts of aromatic compounds in the particulate phase. In this study, we examine whether the extract of cigarette sidestream smoke particulates (CSSP) has estrogenic and/or antiestrogenic effects in lung adenocarcinoma cells. Our results demonstrate that the CSSP extract contains a dose-dependent estrogenic effect and activates ER␣ cumulatively with 17-estradiol (E2) in lung adenocarcinoma cells. ICI 182,780 antagonizes CSSP-induced ER␣ transcriptional activity as well as that induced by E2. However, the CSSP extract regulates the nuclear entry, serine phosphorylation, and protein degradation of ER␣ in a similar but different manner from E2. As compared with E2 and ICI 182,780, ER␣ is rather stable under the CSSP treatment, suggesting that CSSP has a long-lasting estrogenic effect. http://dx.doi.org/10.1016/j.toxlet.2013.05.051
P03-05 Combined effect of the SOD mimic MnTnHex-2-PyP5+ and doxorubicin on the migration and invasiveness of breast cancer cells A.S. Fernandes 1,2,∗ , A. Flórido 1,2 , M. Cipriano 2 , I. Batinic-Haberle 3 , J. Miranda 2 , N. Saraiva 1 , P.S. Guerreiro 2 , M. Castro 2 , N.G. Oliveira 2 1
CBIOS, University Lusófona, Campo Grande 376, 1749-024 Lisboa, Portugal, 2 Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Fac. Farmácia da University Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal, 3 Department of Radiation Oncology, Duke University Medical School, Durham, NC, USA Breast cancer metastases are a major cause of cancer mortality. Reactive oxygen species (ROS) have been greatly implicated in cancer at different levels, including in cell migration and invasion, which are key determinants for the metastatic process. MnTnHex2-PyP5+ is a porphyrin-based potent superoxide dismutase mimic
Abstracts / Toxicology Letters 221S (2013) S59–S256
P03-02 Breast cancer in Danish women: A prospective case–control study on breast cancer risk upon exposure to perfluorinated compounds Eva Cecilie Bonefeld-Jorgensen ∗ , Manhai Long, Stine F. Overvad, Jørn Olsen Department for Public Health, Aarhus University, Denmark Breast cancer (BC) is the most common cancer for women in the western world. Exposure to persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) might contribute to the risk of BC. Animal studies indicate that perfluorinated compounds (PFCs) impact on mammary tissues causing increases in mammary fibroadenomas. Recently, we demonstrated a significant association between serum PFC and BC risk in Greenlandic Inuit. The aim of the present prospective study was to evaluate associations between serum levels of PFCs in young Danish women and the risk of BC later in life. The study includes samples from 250 BC cases and 233 controls prospectively sampled during 1996–2002. The serum levels of 16 PFCs (perfluorocarboxylated acids (PFCAs), perfluorosulfonated acids (PFSAs) and perflurooctane-sulfonamide (PFOSA)) were determined by liquid chromatography-tandem mass spectrometry with electrospray ionization in negative mode. Questionnaires data for sampling age, body mass index before pregnancy, parity, oral contraceptives use, menarche age, smoking, beer and wine drinking, maternal education and physical activity. Data quartiles showed that the BC cases had significantly higher serum level of perfluorooctanoic acid (PFOA) and PFOSA than that of controls after adjustment for age, BMI, parity, OC use, menarche age, smoking, beer and wine drinking, maternal education and physical activity. An increased tendency of odds ratio in quartiles of PFOA, sum PFSA and sum PFCA upon adjustment for confounders was observed. In summary, the serum level of PFCs is a risk factor for development of BC in Danish women supported by our previous study in Greenlandic Inuit. http://dx.doi.org/10.1016/j.toxlet.2013.05.049
P03-03 Carcinogenicity testing of eliglustat in the mouse and rat Rafif Dagher 1,∗ , Judith Marquis 1 , Malene Watzinger 2 , Roy Forster 2 1
Genzyme Corporation, Waltham, USA, 2 CiToxLAB, Evreux, France
Eliglustat is in development for oral treatment of the inherited metabolic disorder Gaucher disease type 1 (GD1). This lysosomal storage disease results from a deficiency of the catabolic enzyme acid-()-glucosidase leading to accumulation of glycolipid. The principal substrate of acid-()-glucosidase is glucosylceramide (GL-1); eliglustat acts to reduce production of GL-1 by inhibition of glucosylceramide synthase. Since treatment of GD1 patients will require chronic treatment with eliglustat, carcinogenicity studies are required. We have evaluated potential carcinogenicity in chronic (2-year) bioassays in the Swiss CD-1 mouse (by dietary administration) and Sprague-Dawley rat (by oral gavage). In the mouse study, treatment with eliglustat did not influence overall survival rates of treated mice at dose-levels up to 75 mg/kg/day. Reduced bodyweight gain at the high dose level indicated that the MTD had been achieved. At histopathology, no treatment related
increases in tumour incidence were observed in any groups of eliglustat treated mice. Similarly, in the rat study there was no effect of eliglustat on the overall survival rates up to the high dose level (75 (males) or 50 mg/kg/day (females)). Reduced bodyweight gain at the high dose level indicated that the MTD had been achieved. At histopathology, no treatment related increases in tumour incidence were observed in any groups of eliglustat treated rats. The only neoplastic lesions that were noted were among those that occur spontaneously in these animal models. It was concluded that eliglustat is not carcinogenic after oral administration to mice or rats. http://dx.doi.org/10.1016/j.toxlet.2013.05.050
P03-04 Cigarette sidestream smoke is a source of environmental estrogen Lih-Ann Li ∗ , Lun-Cheng Kuo, Chun-Ju Lin, Pei-Rung Wu Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan, ROC Serum estrogen level and tumor aromatase expression exhibit an inverse association with poor prognosis of lung adenocarcinoma, suggesting that estrogen plays a role in promoting this cancer. Exposure to exogenous estrogen is expected to increase the risk of lung adenocarcinoma. Secondhand cigarette smoke, a major environmental risk factor for never smokers, contains vast amounts of aromatic compounds in the particulate phase. In this study, we examine whether the extract of cigarette sidestream smoke particulates (CSSP) has estrogenic and/or antiestrogenic effects in lung adenocarcinoma cells. Our results demonstrate that the CSSP extract contains a dose-dependent estrogenic effect and activates ER␣ cumulatively with 17-estradiol (E2) in lung adenocarcinoma cells. ICI 182,780 antagonizes CSSP-induced ER␣ transcriptional activity as well as that induced by E2. However, the CSSP extract regulates the nuclear entry, serine phosphorylation, and protein degradation of ER␣ in a similar but different manner from E2. As compared with E2 and ICI 182,780, ER␣ is rather stable under the CSSP treatment, suggesting that CSSP has a long-lasting estrogenic effect. http://dx.doi.org/10.1016/j.toxlet.2013.05.051
P03-05 Combined effect of the SOD mimic MnTnHex-2-PyP5+ and doxorubicin on the migration and invasiveness of breast cancer cells A.S. Fernandes 1,2,∗ , A. Flórido 1,2 , M. Cipriano 2 , I. Batinic-Haberle 3 , J. Miranda 2 , N. Saraiva 1 , P.S. Guerreiro 2 , M. Castro 2 , N.G. Oliveira 2 1
CBIOS, University Lusófona, Campo Grande 376, 1749-024 Lisboa, Portugal, 2 Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Fac. Farmácia da University Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal, 3 Department of Radiation Oncology, Duke University Medical School, Durham, NC, USA Breast cancer metastases are a major cause of cancer mortality. Reactive oxygen species (ROS) have been greatly implicated in cancer at different levels, including in cell migration and invasion, which are key determinants for the metastatic process. MnTnHex2-PyP5+ is a porphyrin-based potent superoxide dismutase mimic