March, 2017 Look Inside ToxSci

March, 2017 Look Inside ToxSci TOXICOLOGICAL SCIENCES, 156(1), 2017, 1 doi: 10.1093/toxsci/kfx037 Look Inside ToxSci From the Editor’s Desk Nanomaterials seem to be everywhere. They are widely used in industrial applications and are making their way into a host of con- sumer products from cosmetics and sunscreens to textiles. It is essential that we carefully evaluate the safety of these products and there are several articles in this issue that do exactly that. While it was unintentional, nanomaterials are also all over this month’s cover- all of the artwork is from those nano-related articles. These visually exciting images seem appropriate for the issue that coin- cides with our upcoming Annual Meeting in Baltimore, Maryland. On that note, our Annual Meeting served as the impetus for my ac- companying editorial “Science, Societies, and Society.” I hope to see many of our readers in Baltimore and encourage you to Look Inside ToxSci for the best original research in the field of toxicology.—Gary W. Miller to more rapidly identify drugs that produce organ specific toxicity. Editor’s Highlights View Abstract—Robert L. Tanguay Flies, genes, and narcotics: The solvent toluene is a central nervous system depressant that can induce narcosis. Toluene is Neurotoxicity of anticancer drugs: Severe side effects of commonly used in industry and for many years was found in prod- anticancer drugs often limit their dose levels and/or duration of ucts such as typing correction fluid (since removed because of the treatment in cancer patients. One of the target organs for these abuse liability). In order to identify genes involved in mediating the side effects is often the nervous system; in particular narcotic effects of toluene Bushnell and coworkers employed the chemotherapy-induced peripheral neuropathy (CIPN) is a very Drosophila Genetic Reference Panel, a collection of 200 lines of common adverse effect of old and new anticancer compounds, Drosophila melanogaster. Millions of gene variants for the narcotic ac- which can persist even after termination of treatment and se- tions of toluene were examined. The group found 88 variants associ- verely limit quality of life. There is limited knowledge on the ated with 66 genes. Of those genes 52 had human homologues. mechanism(s) underlying CIPN, and no remedies are available. While the group suspected to identify genes involved in neurotrans- The study by Guo and colleagues in this issue presents an in vitro mitter regulation, most of the identified genes had not previously model, based on rat dorsal root ganglion cells, which allows identi- been associated with toluene-associated narcosis or the classical fication of compounds that may cause CIPN by direct neuronal neurotransmitter pathways. Identified genes included those in- toxicity, and may be useful to study precise molecular mecha- volved in embryological morphogenesis, development, and signal- nisms and possible therapeutic interventions. The system utilizes ing providing new clues to mediators of toluene actions. This study an automated microscopy system and specific labeling for differ- is an excellent example of the use of powerful genetic tools to iden- ent cells and cellular structures, which allows the identification of tify mediatorsofchemicalresponses. View Abstract—Gary W. Miller morphologic alterations. The results obtained with compounds tested in this “pilot exercise” indicate the promise, as well as the limitations, of this in vitro approach. View Abstract—Lucio G. Costa Zebrafish reporters and liver injury: Drug induced liver injury (DILI) is a major reason for drug development failures. Successful drug development is significantly hampered by the Epigenetics and liver carcinognes: Evaluating the carcino- lack of in vivo systems thatrapidly andcosteffectivelydetectDILI. genic risks of non-genotoxic agents remains a challenge, in part Although, zebrafish are increasingly used for drug development due to multiple modes of action that result in tumorigenesis. and for preclinical toxicological assessments, to date this model Focusing on epigenomic alterations, Pogribny and colleagues inves- has not been adapted to specifically detect liver injury. In the tigate the non-genotoxic liver carcinogen methapyrilene alongside study by Poon and associates. (p. 133) the authors used a non-genotoxic non-carcinogenic usnic acid in the liver and kidney systematic approach to develop a series of zebrafish eGFP- tissue of Fischer 344 rats. Following methapyrilene exposure, they transgenic lines as tools to detect liver toxicity. By coupling com- identify target organ specific effects on histone acetylation in liver, parative toxicogenomics following exposures to drugs that are which were not identified following usnic acid exposure. known to cause DILI in humans, the authors identified a novel set Importantly, the organ specific epigenetic deacetylation of histone of common up-regulated by genes. The promoters from a subset H3 lysine 9 following methapyrileneexposurewas foundtocorre- of these genes were used to developed a set of stable transgenic lated with reduced expression of cancer-related genes including lines to determine if they would be responsive to DILI drugs. Using homeobox and PPAR alpha. Careful analysis of target specific alter- non-invasive imaging, these reporter lines produced time and ations on the epigenome are crucialtohelpidentifyearly mecha- concentration dependent induction in endodermal organs follow- nistic markersoftumor promotion and will providenew ing exposure to a set of reference and test drugs. These transgenic opportunities for assessing the carcinogenic potential of toxicants lines and this systematic approach may provide a powerful means and novel drug compounds. View Abstract—Dana Dolinoy Published by Oxford University Press on behalf of the Society of Toxicology 2017. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Toxicological Sciences Oxford University Press

March, 2017 Look Inside ToxSci

Toxicological Sciences , Volume 156 (1) – Mar 1, 2017
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Published by Oxford University Press on behalf of the Society of Toxicology 2017.
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1096-6080
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1096-0929
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10.1093/toxsci/kfx037
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Abstract

TOXICOLOGICAL SCIENCES, 156(1), 2017, 1 doi: 10.1093/toxsci/kfx037 Look Inside ToxSci From the Editor’s Desk Nanomaterials seem to be everywhere. They are widely used in industrial applications and are making their way into a host of con- sumer products from cosmetics and sunscreens to textiles. It is essential that we carefully evaluate the safety of these products and there are several articles in this issue that do exactly that. While it was unintentional, nanomaterials are also all over this month’s cover- all of the artwork is from those nano-related articles. These visually exciting images seem appropriate for the issue that coin- cides with our upcoming Annual Meeting in Baltimore, Maryland. On that note, our Annual Meeting served as the impetus for my ac- companying editorial “Science, Societies, and Society.” I hope to see many of our readers in Baltimore and encourage you to Look Inside ToxSci for the best original research in the field of toxicology.—Gary W. Miller to more rapidly identify drugs that produce organ specific toxicity. Editor’s Highlights View Abstract—Robert L. Tanguay Flies, genes, and narcotics: The solvent toluene is a central nervous system depressant that can induce narcosis. Toluene is Neurotoxicity of anticancer drugs: Severe side effects of commonly used in industry and for many years was found in prod- anticancer drugs often limit their dose levels and/or duration of ucts such as typing correction fluid (since removed because of the treatment in cancer patients. One of the target organs for these abuse liability). In order to identify genes involved in mediating the side effects is often the nervous system; in particular narcotic effects of toluene Bushnell and coworkers employed the chemotherapy-induced peripheral neuropathy (CIPN) is a very Drosophila Genetic Reference Panel, a collection of 200 lines of common adverse effect of old and new anticancer compounds, Drosophila melanogaster. Millions of gene variants for the narcotic ac- which can persist even after termination of treatment and se- tions of toluene were examined. The group found 88 variants associ- verely limit quality of life. There is limited knowledge on the ated with 66 genes. Of those genes 52 had human homologues. mechanism(s) underlying CIPN, and no remedies are available. While the group suspected to identify genes involved in neurotrans- The study by Guo and colleagues in this issue presents an in vitro mitter regulation, most of the identified genes had not previously model, based on rat dorsal root ganglion cells, which allows identi- been associated with toluene-associated narcosis or the classical fication of compounds that may cause CIPN by direct neuronal neurotransmitter pathways. Identified genes included those in- toxicity, and may be useful to study precise molecular mecha- volved in embryological morphogenesis, development, and signal- nisms and possible therapeutic interventions. The system utilizes ing providing new clues to mediators of toluene actions. This study an automated microscopy system and specific labeling for differ- is an excellent example of the use of powerful genetic tools to iden- ent cells and cellular structures, which allows the identification of tify mediatorsofchemicalresponses. View Abstract—Gary W. Miller morphologic alterations. The results obtained with compounds tested in this “pilot exercise” indicate the promise, as well as the limitations, of this in vitro approach. View Abstract—Lucio G. Costa Zebrafish reporters and liver injury: Drug induced liver injury (DILI) is a major reason for drug development failures. Successful drug development is significantly hampered by the Epigenetics and liver carcinognes: Evaluating the carcino- lack of in vivo systems thatrapidly andcosteffectivelydetectDILI. genic risks of non-genotoxic agents remains a challenge, in part Although, zebrafish are increasingly used for drug development due to multiple modes of action that result in tumorigenesis. and for preclinical toxicological assessments, to date this model Focusing on epigenomic alterations, Pogribny and colleagues inves- has not been adapted to specifically detect liver injury. In the tigate the non-genotoxic liver carcinogen methapyrilene alongside study by Poon and associates. (p. 133) the authors used a non-genotoxic non-carcinogenic usnic acid in the liver and kidney systematic approach to develop a series of zebrafish eGFP- tissue of Fischer 344 rats. Following methapyrilene exposure, they transgenic lines as tools to detect liver toxicity. By coupling com- identify target organ specific effects on histone acetylation in liver, parative toxicogenomics following exposures to drugs that are which were not identified following usnic acid exposure. known to cause DILI in humans, the authors identified a novel set Importantly, the organ specific epigenetic deacetylation of histone of common up-regulated by genes. The promoters from a subset H3 lysine 9 following methapyrileneexposurewas foundtocorre- of these genes were used to developed a set of stable transgenic lated with reduced expression of cancer-related genes including lines to determine if they would be responsive to DILI drugs. Using homeobox and PPAR alpha. Careful analysis of target specific alter- non-invasive imaging, these reporter lines produced time and ations on the epigenome are crucialtohelpidentifyearly mecha- concentration dependent induction in endodermal organs follow- nistic markersoftumor promotion and will providenew ing exposure to a set of reference and test drugs. These transgenic opportunities for assessing the carcinogenic potential of toxicants lines and this systematic approach may provide a powerful means and novel drug compounds. View Abstract—Dana Dolinoy Published by Oxford University Press on behalf of the Society of Toxicology 2017.

Journal

Toxicological SciencesOxford University Press

Published: Mar 1, 2017

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