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Late effects of early exposures to endocrine disrupting chemicals in rats
S01 / Toxicology Letters 280S (2017) S8–S10
S01-03 Late effects of early exposures to endocrine disrupting chemicals in rats Julie Boberg, Ulla Hass Division of Diet, Disease Prevention and Toxicology, Technical University of Denmark, Lyngby, Denmark Endocrine disrupting compounds may interfere with tissues at critical developmental stages and give rise to cancer later in life. This talk will focus on early-life exposure to endocrine disrupting chemicals which is associated with increased risk for carcinogenesis in mammary and prostate glands in experimental models. On the other hand, some naturally occurring endocrine disruptors (phyto-estrogens) have been proposed as protective against mammary cancer. Our recent rat studies showed an increased prevalence of intraductal hyperplasia of mammary glands after perinatal exposure to estrogenic chemicals, and this was associated with early changes in pre-pubertal mammary development. In the prostate, we observed a shift from the general age-related atrophy towards hyperplasia in aging rats that had been exposed perinatally to a mixture of human relevant anti-androgenic chemicals. This causes concern that human perinatal exposure to environmental chemicals may increase the risk of prostate or mammary cancer later in life. Possible modes of action and the human relevance of these findings will be discussed. http://dx.doi.org/10.1016/j.toxlet.2017.07.219 S01-04 Integrating genetics, epigenomics and transcriptomics to elucidate mechanisms of xenobiotic-induced non-genotoxic carcinogenesis Jonathan Moggs, Alberto Del Rio Espinola, Antonio Vitobello, Remi Terranova Preclinical Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland Although determining the human relevance of non-genotoxic carcinogenic compounds in animals remains a major challenge for toxicologists, elucidating mechanisms of xenobiotic-induced tumors in animals can provide industry, environmental and regulatory scientists with valuable tools for cancer hazard identification and risk assessment. The discovery that aberrant epigenetic events frequently accompany genetic mutations in human cancers has stimulated efforts to characterize xenobiotic-induced non-genotoxic carcinogenesis (NGC) at the molecular level in animal models. Integrated epigenomic and transcriptomic profiling of a well-characterized phenobarbital mouse model for drug-induced nuclear-receptor dependent liver tumor promotion has led to the identification of novel early biomarkers including dynamic changes in the DNA methylome (in particular 5-hydroxymethylcytosine) and increased expression of Dlk1-Dio3 imprinted gene cluster noncoding RNAs (including Meg3). The induction of Meg3 by phenobarbital occurs in defined perivenous populations of hepatocytes and may represent the early stages of hepatocyte de-differentiation and a return to pluripotency. Cross-species mapping of the phenobarbital-induced changes in liver chromatin architecture via DNase-seq, combined with genetic variant mapping, is providing novel insights into molecular basis for strain- and species-specific differences in
S9
the response of Meg3 to phenobarbital and its potential human relevance. http://dx.doi.org/10.1016/j.toxlet.2017.07.220 S01-05 Mesenchyme-derived growth factors/cytokines: Crucial for tumor promotion by non-genotoxic hepatocarcinogens Bettina Grasl-Kraupp, Marzieh Nejabat, Teresa Riegler, Wolfgang Huber, Rolf Schulte-Hermann Institute of Cancer Research, Medical University Vienna, Vienna, Austria Many environmental pollutants or frequently prescribed drugs are non-genotoxic carcinogens (NGC) in rodent liver. Their mode of action and the health risks for humans are unclear. We investigated the impact of two model NGC, the anti-epileptic drug phenobarbital (PB) and the progestin and contraceptive cyproterone acetate (CPA), on the intrahepatic epithelial-mesenchymal dialogue and growth of first stages of carcinogenesis, using rat liver as model. Transcriptomics and bio-informatic analyses revealed that PB and CPA induced extensive changes in the transcriptome patterns of mesenchymal liver cells (MC) affecting many cytokines and growth factors. MC from PB-treated animals produced and secreted enhanced levels of TNF␣, which induced in hepatocytes (HC) nuclear translocation and activation of NFB and protection from pro-apoptotic stimuli. PB-treated MC released also heparinbinding epidermal growth factor-like growth factor (HBEGF) and growth and differentiation factor 15 (GDF15) for DNA synthesis induction and suppression of apoptosis. MC, isolated from CPA-treated animals, showed enhanced expression and secretion of hepatocyte growth factor (HGF), which raised dramatically DNA replication not only of hepatocytes but also first stages of hepatocarcinogenesis. In conclusion, NGC may not affect exclusively the hepatic parenchyma, as generally assumed. The profound effects on the hepatic mesenchyme and the subsequent release of proinflammatory cytokines, growth and survival factors appear to be crucial for tumor promotion by NGC. These findings require verification with other NGC as well as with other organs and species. New insight generated along these lines will improve concepts of risk assessment of NGC. http://dx.doi.org/10.1016/j.toxlet.2017.07.221 S01-06 Environmental immune disruptors, inflammation and carcinogenesis: A state of the science and new horizons William H. Bisson 1,2 1 Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, United States 2 Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States
Over the past two decades, inflammation has emerged as an important contributor to carcinogenesis. A number of cellular mechanisms involved in inflammation-induced tumor initiation, promotion and progression have been reported. These include genomic instability events not directly involving DNA mutations like chromatin remodelling, epigenetic changes and altered
S01-03 Late effects of early exposures to endocrine disrupting chemicals in rats Julie Boberg, Ulla Hass Division of Diet, Disease Prevention and Toxicology, Technical University of Denmark, Lyngby, Denmark Endocrine disrupting compounds may interfere with tissues at critical developmental stages and give rise to cancer later in life. This talk will focus on early-life exposure to endocrine disrupting chemicals which is associated with increased risk for carcinogenesis in mammary and prostate glands in experimental models. On the other hand, some naturally occurring endocrine disruptors (phyto-estrogens) have been proposed as protective against mammary cancer. Our recent rat studies showed an increased prevalence of intraductal hyperplasia of mammary glands after perinatal exposure to estrogenic chemicals, and this was associated with early changes in pre-pubertal mammary development. In the prostate, we observed a shift from the general age-related atrophy towards hyperplasia in aging rats that had been exposed perinatally to a mixture of human relevant anti-androgenic chemicals. This causes concern that human perinatal exposure to environmental chemicals may increase the risk of prostate or mammary cancer later in life. Possible modes of action and the human relevance of these findings will be discussed. http://dx.doi.org/10.1016/j.toxlet.2017.07.219 S01-04 Integrating genetics, epigenomics and transcriptomics to elucidate mechanisms of xenobiotic-induced non-genotoxic carcinogenesis Jonathan Moggs, Alberto Del Rio Espinola, Antonio Vitobello, Remi Terranova Preclinical Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland Although determining the human relevance of non-genotoxic carcinogenic compounds in animals remains a major challenge for toxicologists, elucidating mechanisms of xenobiotic-induced tumors in animals can provide industry, environmental and regulatory scientists with valuable tools for cancer hazard identification and risk assessment. The discovery that aberrant epigenetic events frequently accompany genetic mutations in human cancers has stimulated efforts to characterize xenobiotic-induced non-genotoxic carcinogenesis (NGC) at the molecular level in animal models. Integrated epigenomic and transcriptomic profiling of a well-characterized phenobarbital mouse model for drug-induced nuclear-receptor dependent liver tumor promotion has led to the identification of novel early biomarkers including dynamic changes in the DNA methylome (in particular 5-hydroxymethylcytosine) and increased expression of Dlk1-Dio3 imprinted gene cluster noncoding RNAs (including Meg3). The induction of Meg3 by phenobarbital occurs in defined perivenous populations of hepatocytes and may represent the early stages of hepatocyte de-differentiation and a return to pluripotency. Cross-species mapping of the phenobarbital-induced changes in liver chromatin architecture via DNase-seq, combined with genetic variant mapping, is providing novel insights into molecular basis for strain- and species-specific differences in
S9
the response of Meg3 to phenobarbital and its potential human relevance. http://dx.doi.org/10.1016/j.toxlet.2017.07.220 S01-05 Mesenchyme-derived growth factors/cytokines: Crucial for tumor promotion by non-genotoxic hepatocarcinogens Bettina Grasl-Kraupp, Marzieh Nejabat, Teresa Riegler, Wolfgang Huber, Rolf Schulte-Hermann Institute of Cancer Research, Medical University Vienna, Vienna, Austria Many environmental pollutants or frequently prescribed drugs are non-genotoxic carcinogens (NGC) in rodent liver. Their mode of action and the health risks for humans are unclear. We investigated the impact of two model NGC, the anti-epileptic drug phenobarbital (PB) and the progestin and contraceptive cyproterone acetate (CPA), on the intrahepatic epithelial-mesenchymal dialogue and growth of first stages of carcinogenesis, using rat liver as model. Transcriptomics and bio-informatic analyses revealed that PB and CPA induced extensive changes in the transcriptome patterns of mesenchymal liver cells (MC) affecting many cytokines and growth factors. MC from PB-treated animals produced and secreted enhanced levels of TNF␣, which induced in hepatocytes (HC) nuclear translocation and activation of NFB and protection from pro-apoptotic stimuli. PB-treated MC released also heparinbinding epidermal growth factor-like growth factor (HBEGF) and growth and differentiation factor 15 (GDF15) for DNA synthesis induction and suppression of apoptosis. MC, isolated from CPA-treated animals, showed enhanced expression and secretion of hepatocyte growth factor (HGF), which raised dramatically DNA replication not only of hepatocytes but also first stages of hepatocarcinogenesis. In conclusion, NGC may not affect exclusively the hepatic parenchyma, as generally assumed. The profound effects on the hepatic mesenchyme and the subsequent release of proinflammatory cytokines, growth and survival factors appear to be crucial for tumor promotion by NGC. These findings require verification with other NGC as well as with other organs and species. New insight generated along these lines will improve concepts of risk assessment of NGC. http://dx.doi.org/10.1016/j.toxlet.2017.07.221 S01-06 Environmental immune disruptors, inflammation and carcinogenesis: A state of the science and new horizons William H. Bisson 1,2 1 Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, United States 2 Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States
Over the past two decades, inflammation has emerged as an important contributor to carcinogenesis. A number of cellular mechanisms involved in inflammation-induced tumor initiation, promotion and progression have been reported. These include genomic instability events not directly involving DNA mutations like chromatin remodelling, epigenetic changes and altered