Epigenome changes induced by environmental factors and cancer
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Abstracts / Toxicology Letters 221S (2013) S4–S30 S17 steps of toxicity evaluation, from authentication of composition to identification of active constituents. Currently in EU, genotoxicity tests for well-established and traditional herbal medicines are not mandatory; the only official precondition is negative Ames test for list entry status of tra- ditional use herbal medicines. Evaluation of genotoxicity takes place case-by-case; three cases will be presented: proven genotox- ins (alkylbenzenes, pyrrolizidine alkaloids, aristolochic acids, etc), potential genotoxicity of furocoumarins, and weak mutagenicity of hydroxyanthracene aglycones in Senna preparations. In these cases, risk evaluation of genotoxic constituents has benefited from hazard and risk assessment measures adopted for genotoxic impu- rities in conventional drugs. Recent introduction of the ICH M7 guideline on genotoxic impurities may lead to re-evaluation of procedures to assess genotoxicity of herbal medicines and their components. http://dx.doi.org/10.1016/j.toxlet.2013.06.057 Symposium 10: Genetic susceptibility: relevance to toxicology S10-1 Genetic susceptibility: relevance to toxicology Hans Ketelslegers ExxonMobil Petroleum and Chemical, Machelen, Belgium With the advent of inexpensive technologies for high- throughput genotyping to identify genetic variants, numerous gene-association studies have been published, many reporting findings of genetic susceptibility to several common diseases as well as non-disease endpoints. These findings are catalogued in several publicly available databases and have been used to sup- port efforts in developing new molecular epidemiological research, including study of occupational diseases, investigations of drug therapies, and application of (personalized) risk assessment. While recognized as major advances on one hand, many in the scientific community have cautioned that there is still uncertainty regarding some of the reported gene-association conclusions, par- ticularly those from earlier studies which have not been replicated. Nonetheless, this scientific discipline continues to grow in popular- ity in the mainstream media, academia, industry and government. There is potential for regulatory agencies to consider the use of genetic data in setting risk assessment and policy decisions. Fur- thermore, there may be an expectation or opportunity to have genetic testing available for employees to determine susceptibility. Therefore, guidance based on a systematic, science-based approach regarding appropriate design, interpretation and utilization of such information will be important. This introduction to the session will present the concepts of genetic susceptibility and gene–environment interactions using a case study related to environmental carcinogenesis, as an exam- ple. The potential implications of these concepts on data gathered in occupational settings will be discussed. http://dx.doi.org/10.1016/j.toxlet.2013.06.059 S10-2 Epigenome changes induced by environmental factors and cancer Zdenko Herceg International Agency for Research on Cancer (IARC), Lyon, France Remarkable progress in the field of epigenetics has turned aca- demic, medical and public attention to the potential applications of these new advances in medicine and various fields of biomedi- cal research. In addition to conceptual advances, the emergence of powerful technologies allowing the detection of epigenetic changes in high-throughput and genome-wide settings has dramatically accelerated cancer research and opened up new perspectives. The result is a broader appreciation of epigenetic phenomena in the etiology of common human diseases, most notably cancer. These advances also represent an exciting opportunity to incorporate epi- genetics and epigenomics into carcinogen identification and safety assessment. Although the application of epigenetic assays in car- cinogen evaluation is still in its infancy, important data are being generated and valuable scientific resources are being established that should catalyze future applications of epigenetic testing. The Human Epigenome Project and other major international epige- nomic sequencing initiatives will not only yield an unparalleled view of the “normal” epigenome in different tissues but also iden- tify epigenome variations against which carcinogen exposure can be assessed. I will discuss recent progress in our understanding of epigenetic mechanisms through which environmental stressors and endogenous factors may promote tumor development and pro- gression as well as its implications for biomarker discovery, risk assessment and cancer control. http://dx.doi.org/10.1016/j.toxlet.2013.06.060 S10-3 In vitro screening for population variability in chemical toxicity Ivan Rusyn University of North Carolina, Chapel Hill, NC, USA Our work aims to establish a population-wide human in vitro screening model for assessment of both the magnitude of and molecular causes for inter-individual genetic variability in chemical toxicity. The International Hap Map and the 1000 Genomes projects have established human lymphoblast cell lines from racially and geographically diverse populations. We used over 1000 of these cell lines, representing 9 populations from 5 continents, to screen hundreds of chemicals at 8 concentrations (0.3 nM–92 M) in a cell viability assay. Excellent between-plate and day-to-day repro- ducibility is achievable in these experiments which allows for uncoupling technical (e.g., experimental) and intrinsic (e.g., genetic) factors when estimating the extent of inter-individual variabil- ity. Across all compounds, clustering of cytotoxicity (e.g., EC10) profiles revealed similarity of responses in cell lines according to the genetic ancestry. For individual chemicals, population differ- ences were evident for about 40% of the compounds. Heritability analysis showed that cytotoxicity response of some chemicals was significantly heritable. Because cell lines used in this study have been densely genotyped or sequenced, analyses of genome-wide association, and association pathway analyses, were performed to identify significant associations between variants/genes/pathways and cytotoxicity. In addition, basal RNA sequencing transcriptional data is available for these cell lines and we performed correlation
Transcript of Epigenome changes induced by environmental factors and cancer
Abstracts / Toxicology Letters 221S (2013) S4–S30 S17
steps of toxicity evaluation, from authentication of composition toidentification of active constituents.
Currently in EU, genotoxicity tests for well-established andtraditional herbal medicines are not mandatory; the only officialprecondition is negative Ames test for list entry status of tra-ditional use herbal medicines. Evaluation of genotoxicity takesplace case-by-case; three cases will be presented: proven genotox-ins (alkylbenzenes, pyrrolizidine alkaloids, aristolochic acids, etc),potential genotoxicity of furocoumarins, and weak mutagenicityof hydroxyanthracene aglycones in Senna preparations. In thesecases, risk evaluation of genotoxic constituents has benefited fromhazard and risk assessment measures adopted for genotoxic impu-rities in conventional drugs. Recent introduction of the ICH M7guideline on genotoxic impurities may lead to re-evaluation ofprocedures to assess genotoxicity of herbal medicines and theircomponents.
http://dx.doi.org/10.1016/j.toxlet.2013.06.057
Symposium 10: Genetic susceptibility: relevance to toxicology
S10-1Genetic susceptibility: relevance to toxicology
Hans Ketelslegers
ExxonMobil Petroleum and Chemical, Machelen, Belgium
With the advent of inexpensive technologies for high-throughput genotyping to identify genetic variants, numerousgene-association studies have been published, many reportingfindings of genetic susceptibility to several common diseases aswell as non-disease endpoints. These findings are catalogued inseveral publicly available databases and have been used to sup-port efforts in developing new molecular epidemiological research,including study of occupational diseases, investigations of drugtherapies, and application of (personalized) risk assessment.
While recognized as major advances on one hand, many in thescientific community have cautioned that there is still uncertaintyregarding some of the reported gene-association conclusions, par-ticularly those from earlier studies which have not been replicated.Nonetheless, this scientific discipline continues to grow in popular-ity in the mainstream media, academia, industry and government.There is potential for regulatory agencies to consider the use ofgenetic data in setting risk assessment and policy decisions. Fur-thermore, there may be an expectation or opportunity to havegenetic testing available for employees to determine susceptibility.Therefore, guidance based on a systematic, science-based approachregarding appropriate design, interpretation and utilization of suchinformation will be important.
This introduction to the session will present the concepts ofgenetic susceptibility and gene–environment interactions using acase study related to environmental carcinogenesis, as an exam-ple. The potential implications of these concepts on data gatheredin occupational settings will be discussed.
http://dx.doi.org/10.1016/j.toxlet.2013.06.059
S10-2Epigenome changes induced by environmentalfactors and cancer
Zdenko Herceg
International Agency for Research on Cancer (IARC), Lyon, France
Remarkable progress in the field of epigenetics has turned aca-demic, medical and public attention to the potential applicationsof these new advances in medicine and various fields of biomedi-cal research. In addition to conceptual advances, the emergence ofpowerful technologies allowing the detection of epigenetic changesin high-throughput and genome-wide settings has dramaticallyaccelerated cancer research and opened up new perspectives. Theresult is a broader appreciation of epigenetic phenomena in theetiology of common human diseases, most notably cancer. Theseadvances also represent an exciting opportunity to incorporate epi-genetics and epigenomics into carcinogen identification and safetyassessment. Although the application of epigenetic assays in car-cinogen evaluation is still in its infancy, important data are beinggenerated and valuable scientific resources are being establishedthat should catalyze future applications of epigenetic testing. TheHuman Epigenome Project and other major international epige-nomic sequencing initiatives will not only yield an unparalleledview of the “normal” epigenome in different tissues but also iden-tify epigenome variations against which carcinogen exposure canbe assessed. I will discuss recent progress in our understandingof epigenetic mechanisms through which environmental stressorsand endogenous factors may promote tumor development and pro-gression as well as its implications for biomarker discovery, riskassessment and cancer control.
http://dx.doi.org/10.1016/j.toxlet.2013.06.060
S10-3In vitro screening for population variability inchemical toxicity
Ivan Rusyn
University of North Carolina, Chapel Hill, NC, USA
Our work aims to establish a population-wide human in vitroscreening model for assessment of both the magnitude of andmolecular causes for inter-individual genetic variability in chemicaltoxicity. The International Hap Map and the 1000 Genomes projectshave established human lymphoblast cell lines from racially andgeographically diverse populations. We used over 1000 of thesecell lines, representing 9 populations from 5 continents, to screenhundreds of chemicals at 8 concentrations (0.3 nM–92 �M) in acell viability assay. Excellent between-plate and day-to-day repro-ducibility is achievable in these experiments which allows foruncoupling technical (e.g., experimental) and intrinsic (e.g., genetic)factors when estimating the extent of inter-individual variabil-ity. Across all compounds, clustering of cytotoxicity (e.g., EC10)profiles revealed similarity of responses in cell lines according tothe genetic ancestry. For individual chemicals, population differ-ences were evident for about 40% of the compounds. Heritabilityanalysis showed that cytotoxicity response of some chemicals wassignificantly heritable. Because cell lines used in this study havebeen densely genotyped or sequenced, analyses of genome-wideassociation, and association pathway analyses, were performed toidentify significant associations between variants/genes/pathwaysand cytotoxicity. In addition, basal RNA sequencing transcriptionaldata is available for these cell lines and we performed correlation
