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Plenary Session: Toxicogenomics
Abstracts / Toxicology Letters 172S (2007) S1–S240
nucleotide excision repair in pulmonary epithelial target cells. So far however, direct evidence for a role of neutrophils in pulmonary genotoxicity has largely been derived from in vitro studies using co-cultures of activated neutrophils and a variety of target cells. Evidence from in vivo studies is primarily circumstantial and additional (experimental animal) studies are still needed to substantiate causality. This will provide a better insight into the role of neutrophils in pulmonary cancer development, and may, hence, lead to novel approaches for cancer prevention strategies. doi:10.1016/j.toxlet.2007.05.102 68 Astroglial cells and neuronal injury in Parkinson’s disease Ron Tjalkens Colorado State University, Fort Collins, CO, United States Astrocytes are the principal non-neuronal cell type of the central nervous system and maintain neuronal homeostasis through provision of metabolic intermediates for ATP synthesis, modulation of neurotransmitter uptake, and protection against oxidative and excitotoxic stress. However, increased production of inflammatory cytokines and nitric oxide (NO) by activated astrocytes cells damages adjacent neurons and contributes to the progression of injury in neurodegenerative disorders such as Parkinson’s disease. Production of inflammatory mediators in glial cells is positively regulated by the transcription factor, nuclear factor kappa B (NF-B), and is antagonized by nuclear receptors, such as the peroxisome proliferator-activated receptor gamma (PPAR␥) and retinoid X receptor (RXR). It has recently been demonstrated that pharmacologic agonists of PPAR␥ are neuroprotective in models of Parkinson’s disease, but a molecular understanding of the mechanism by which these compounds exert their neuroprotective effects is lacking. PPAR␥ gamma has been shown to interact with the p65 subunit of NF-B and the nuclear corepressor complex (NCoR) in immune cells but similar interactions in neural cells have not been described. Understanding the mechanism by which nuclear receptors modulate the expression of inflammatory genes within glia may aid the development of new therapeutic modalities designed to exploit these regulatory properties (supported by NIH-ES012941 and by the American Parkinson Disease Association). doi:10.1016/j.toxlet.2007.05.103
S29
Plenary Session 69 Toxicogenomics: An overview of ongoing projects by the HESI Committee on genomics in risk assessment Jonathan Lyon GlaxoSmithKline, Welwyn, Hertfordshire, United Kingdom Genomic technology can provide additional insight into mechanisms of toxicity, which will over time become increasingly accepted as part of the overall data package used in risk assessment. The HESI Genomics Committee aims to advance the application of genomics in risk assessment by addressing scientific and technical issues relating to use of genomics as a means of understanding toxic response and mechanism. The multi-sector Committee also provides a scientific forum for government, industry and academia to discuss interpretation and application of genomic data. In 2004, the Committee initiated four Working Groups to conduct projects due for completion in 2007: The State of the Science Working Group recently completed a comprehensive cross-sector survey to capture the current status, future direction and key challenges facing toxicogenomics. The Genetic Toxicity Group have investigated the utility of gene-profile based characterization of compounds which are positive in in vitro mammalian assays. The Baseline Database Group have established a pilot database of control animal microarray data, to facilitate data mining and as a reference source for background gene expression levels and variation. As a publicly accessible resource this database will also aid validation of expression-based toxicity markers and control genes. Finally, the Mechanisms Group is completing a toxicogenomic study with multiple timepoints, doses and controls as a case study for open discussion regarding technical and interpretive practices. This study, of doxorubicin cardiotoxicity, will generate significant new molecular information about this clinically relevant toxicity and, due to the comprehensive study design, will also provide insight into how time and dose alter gene expression and the relationship to the onset of toxicity (threshold). doi:10.1016/j.toxlet.2007.05.104
nucleotide excision repair in pulmonary epithelial target cells. So far however, direct evidence for a role of neutrophils in pulmonary genotoxicity has largely been derived from in vitro studies using co-cultures of activated neutrophils and a variety of target cells. Evidence from in vivo studies is primarily circumstantial and additional (experimental animal) studies are still needed to substantiate causality. This will provide a better insight into the role of neutrophils in pulmonary cancer development, and may, hence, lead to novel approaches for cancer prevention strategies. doi:10.1016/j.toxlet.2007.05.102 68 Astroglial cells and neuronal injury in Parkinson’s disease Ron Tjalkens Colorado State University, Fort Collins, CO, United States Astrocytes are the principal non-neuronal cell type of the central nervous system and maintain neuronal homeostasis through provision of metabolic intermediates for ATP synthesis, modulation of neurotransmitter uptake, and protection against oxidative and excitotoxic stress. However, increased production of inflammatory cytokines and nitric oxide (NO) by activated astrocytes cells damages adjacent neurons and contributes to the progression of injury in neurodegenerative disorders such as Parkinson’s disease. Production of inflammatory mediators in glial cells is positively regulated by the transcription factor, nuclear factor kappa B (NF-B), and is antagonized by nuclear receptors, such as the peroxisome proliferator-activated receptor gamma (PPAR␥) and retinoid X receptor (RXR). It has recently been demonstrated that pharmacologic agonists of PPAR␥ are neuroprotective in models of Parkinson’s disease, but a molecular understanding of the mechanism by which these compounds exert their neuroprotective effects is lacking. PPAR␥ gamma has been shown to interact with the p65 subunit of NF-B and the nuclear corepressor complex (NCoR) in immune cells but similar interactions in neural cells have not been described. Understanding the mechanism by which nuclear receptors modulate the expression of inflammatory genes within glia may aid the development of new therapeutic modalities designed to exploit these regulatory properties (supported by NIH-ES012941 and by the American Parkinson Disease Association). doi:10.1016/j.toxlet.2007.05.103
S29
Plenary Session 69 Toxicogenomics: An overview of ongoing projects by the HESI Committee on genomics in risk assessment Jonathan Lyon GlaxoSmithKline, Welwyn, Hertfordshire, United Kingdom Genomic technology can provide additional insight into mechanisms of toxicity, which will over time become increasingly accepted as part of the overall data package used in risk assessment. The HESI Genomics Committee aims to advance the application of genomics in risk assessment by addressing scientific and technical issues relating to use of genomics as a means of understanding toxic response and mechanism. The multi-sector Committee also provides a scientific forum for government, industry and academia to discuss interpretation and application of genomic data. In 2004, the Committee initiated four Working Groups to conduct projects due for completion in 2007: The State of the Science Working Group recently completed a comprehensive cross-sector survey to capture the current status, future direction and key challenges facing toxicogenomics. The Genetic Toxicity Group have investigated the utility of gene-profile based characterization of compounds which are positive in in vitro mammalian assays. The Baseline Database Group have established a pilot database of control animal microarray data, to facilitate data mining and as a reference source for background gene expression levels and variation. As a publicly accessible resource this database will also aid validation of expression-based toxicity markers and control genes. Finally, the Mechanisms Group is completing a toxicogenomic study with multiple timepoints, doses and controls as a case study for open discussion regarding technical and interpretive practices. This study, of doxorubicin cardiotoxicity, will generate significant new molecular information about this clinically relevant toxicity and, due to the comprehensive study design, will also provide insight into how time and dose alter gene expression and the relationship to the onset of toxicity (threshold). doi:10.1016/j.toxlet.2007.05.104