Historical Perspective of Mitochondria in the Toxicological Sciences

Historical Perspective of Mitochondria in the Toxicological Sciences The subject of mitochondrial toxicology has witnessed growing interest and attention the past few decades. In 1983, the first year that the Toxicologist was indexed for keywords, only 5 abstracts were presented at the annual meeting that listed mitochondria as a key word. Five years later, the number was 8, as it was 10 years after that in 1998. Up to this point, the Society of Toxicology managed two primary journals; Fundamental and Applied Toxicology (FAAT), which it owned; and Toxicology and Applied Pharmacology (TAAP), which it managed editorially. January 1998 marked the publication of the first issue of Toxicological Sciences. Figure 1 illustrates the number of abstracts indexed to mitochondria that were published over the years in the Toxicologist (line graph) along with the number of manuscripts on the topic of mitochondrial toxicity that were published in the 3 journals; TAAP, FAAT, and Toxicol. Sci. Leading up to 1998 most of the articles published on mitochondrial toxicology appeared in TAAP with only 1–3 papers published in the Society-owned journal FAAT. However, that distribution shifted after the first few years where not only did the total number of publications on mitochondrial toxicology almost triple, but a greater proportion appeared in Toxicol. Sci. Figure 1. View largeDownload slide Plot of the number of abstracts indexed in the Toxicologist, and manuscripts searchable on the keyword mitochondria in the three journals associated with the Society of Toxicology since 1993. The vertical bar indicates the year that Toxicol. Sci. was first published. Figure 1. View largeDownload slide Plot of the number of abstracts indexed in the Toxicologist, and manuscripts searchable on the keyword mitochondria in the three journals associated with the Society of Toxicology since 1993. The vertical bar indicates the year that Toxicol. Sci. was first published. The first manuscript on mitochondrial toxicity published in Toxicol. Sci. appeared in the May issue (Custodio et al., 1998), which described the effect of acrylic acid on inducing the mitochondrial permeability transition in isolated hepatic mitochondria in vitro. Only 2 other papers on mitochondrial toxicology were published in Toxicol. Sci. that year, both looking at mitochondrial bioenergetics in isolated cells and both in the December issue (Ciaccio et al., 1998; Morshed et al., 1998). The following year the number of abstracts on mitochondrial toxicology published in The Toxicologist increased dramatically, which may have been an artifact of more robust indexing terminology. Regardless, it wasn’t until 2002 that the number of papers on mitochondrial toxicity published in Toxicol. Sci. reached double digits, which it has sustained for all but 2 years since, 2006 and 2009. Perhaps more impressive than the growth in number of publications has been the transformation in perspective of mitochondrial toxicity, from what was almost exclusively mitochondrial bioenergetics to the molecular regulation of cellular dynamics and metabolic homeostasis. In the 1980s and 90s most all of the attention was on the effect of exposures on mitochondrial adduct formation, free radical generation and glutathione status, the mitochondrial permeability transition, fatty acid oxidation and oxidative phosphorylation or respiration. Beginning in the late 1990s and peaking in the next decade, however, there was rapid growth in interest in the role of mitochondria in programmed cell death, apoptosis, the first report of which was published in Toxicol. Sci. in 1999 (Close et al., 1999) and since reviewed by several prominent scientists in the field (Jaeschke et al., 2002; Nicotera, 2003; Orrenius et al., 2011). Since its inception, Toxicol. Sci. has been a repository for publications of some of the most seminal research identifying mitochondria either as (1) primary targets or (2) critical transducers in the biological response to chemical exposures. Through this grew an increasing appreciation of the stringent integration of mitochondria as sensors of changing cellular environments and biological governors of adaptive adjustments in cell homeostasis that are manifested by way of mitochondrial fission, fusion, biogenesis and mitophagy. Toxicol. Sci. has also been a repository of publications on computational mitochondrial toxicology aimed at identifying potential high liability chemical compounds. The first attempt to define structure-activity relationships (SAR) for chemicals that affect mitochondrial metabolism, in context of the MTT assay, was published in 2002 in Toxicol. Sci. by the lab of John Frazier (Trohalaki et al., 2002); Additional publications in Toxicol. Sci. on mitochondrial SAR have since followed (Naven et al., 2013; Starkov and Wallace, 2002; Thompson et al., 2002). Likewise, some of the pioneering work with high throughput in vitro biological screens for mitochondrial toxicity has been published in Toxicol. Sci. (Wills et al., 2015; Xu et al., 2008), including its application to predict acute toxicity across phyla (Bhhatarai et al., 2015). In fact, selected screens have been incorporated into multiparametric models where mitochondrial toxicity was found to be a primary predictive determinant for both drug-induced liver (DILI) or cardiovascular injury (Laifenfeld et al., 2014; Pointon et al., 2013; Porceddu et al., 2012; Talbert et al., 2015; Tolosa et al., 2012; Xu et al., 2008), all published in Toxicol. Sci. From this brief review, it is apparent that Toxicological Sciences has been a primary source for publishing some of the most decisive discoveries relating to mitochondrial toxicity; In so doing the journal has successfully served as an effective medium for advancing understanding and perspective in this area. With the growing attention within SOT, there is every reason to believe that Toxicol. Sci. will continue long into the future to provide a pulse on the rapid advancement and evolving perspective of mitochondrial toxicology as a primary determinant of the cellular response to adverse chemical exposures. REFERENCES Bhhatarai B., Wilson D. M., Bartels M. J., Chaudhuri S., Price P. S., Carney E. W. ( 2015). Acute toxicity prediction in multiple species by leveraging mechanistic toxcast mitochondrial inhibition data and simulation of oral bioavailability. Toxicol. Sci.  147, 386– 396. Google Scholar CrossRef Search ADS PubMed  Ciaccio P. J., Gicquel E., O’Neill P. J., Scribner H. E., Vandenberghe Y. L. ( 1998). Investigation of the positive response of ethyl acrylate in the mouse lymphoma genotoxicity assay. Toxicol. Sci.  46, 324– 332. Google Scholar CrossRef Search ADS PubMed  Close A. H., Guo T. L., Shenker B. J. ( 1999). Activated human T lymphocytes exhibit reduced susceptibility to methylmercury chloride-induced apoptosis. Toxicol. Sci.  49, 68– 77. http://dx.doi.org/10.1093/toxsci/49.1.68 Google Scholar CrossRef Search ADS PubMed  Custodio J. B., Palmeira C. M., Moreno A. J., Wallace K. B. ( 1998). Acrylic acid induces the glutathione-independent mitochondrial permeability transition in vitro. Toxicol. Sci.  43, 19– 27. Google Scholar PubMed  Jaeschke H., Gores G. J., Cederbaum A. I., Hinson J. A., Pessayre D., Lemasters J. J. ( 2002). Mechanisms of hepatotoxicity. Toxicol. Sci.  65, 166– 176. Google Scholar CrossRef Search ADS PubMed  Laifenfeld D., Qiu L., Swiss R., Park J., Macoritto M., Will Y., Younis H. S., Lawton M. ( 2014). Utilization of causal reasoning of hepatic gene expression in rats to identify molecular pathways of idiosyncratic drug-induced liver injury. Toxicol. Sci.  137, 234– 248. http://dx.doi.org/10.1093/toxsci/kft232 Google Scholar CrossRef Search ADS PubMed  Morshed K. M., Jain S. K., McMartin K. E. ( 1998). Propylene glycol-mediated cell injury in a primary culture of human proximal tubule cells. Toxicol. Sci.  46, 410– 417. http://dx.doi.org/10.1093/toxsci/46.2.410 Google Scholar CrossRef Search ADS PubMed  Naven R. T., Swiss R., Klug-McLeod J., Will Y., Greene N. ( 2013). The development of structure-activity relationships for mitochondrial dysfunction: uncoupling of oxidative phosphorylation. Toxicol. Sci.  131, 271– 278. Google Scholar CrossRef Search ADS PubMed  Nicotera P. ( 2003). Molecular switches deciding the death of injured neurons. Toxicol Sci  74, 4– 9. http://dx.doi.org/10.1093/toxsci/kfg109 Google Scholar CrossRef Search ADS PubMed  Orrenius S., Nicotera P., Zhivotovsky B. ( 2011). Cell death mechanisms and their implications in toxicology. Toxicol. Sci.  119, 3– 19. http://dx.doi.org/10.1093/toxsci/kfq268 Google Scholar CrossRef Search ADS PubMed  Pointon A., Abi-Gerges N., Cross M. J., Sidaway J. E. ( 2013). Phenotypic profiling of structural cardiotoxins in vitro reveals dependency on multiple mechanisms of toxicity. Toxicol. Sci.  132, 317– 326. Google Scholar CrossRef Search ADS PubMed  Porceddu M., Buron N., Roussel C., Labbe G., Fromenty B., Borgne-Sanchez A. ( 2012). Prediction of liver injury induced by chemicals in human with a multiparametric assay on isolated mouse liver mitochondria. Toxicol. Sci.  129, 332– 345. Google Scholar CrossRef Search ADS PubMed  Starkov A. A., Wallace K. B. ( 2002). Structural determinants of fluorochemical-induced mitochondrial dysfunction. Toxicol. Sci.  66, 244– 252. http://dx.doi.org/10.1093/toxsci/66.2.244 Google Scholar CrossRef Search ADS PubMed  Talbert D. R., Doherty K. R., Trusk P. B., Moran D. M., Shell S. A., Bacus S. ( 2015). A multi-parameter in vitro screen in human stem cell-derived cardiomyocytes identifies ponatinib-induced structural and functional cardiac toxicity. Toxicol. Sci.  143, 147– 155. Google Scholar CrossRef Search ADS PubMed  Thompson R. W., Valentine H. L., Valentine W. M. ( 2002). In vivo and in vitro hepatotoxicity and glutathione interactions of N-methyldithiocarbamate and N, N-dimethyldithiocarbamate in the rat. Toxicol. Sci.  70, 269– 280. Google Scholar CrossRef Search ADS PubMed  Tolosa L., Pinto S., Donato M. T., Lahoz A., Castell J. V., O'Connor J. E., Gomez-Lechon M. J. ( 2012). Development of a multiparametric cell-based protocol to screen and classify the hepatotoxicity potential of drugs. Toxicol. Sci.  127, 187– 198. Google Scholar CrossRef Search ADS PubMed  Trohalaki S., Zellmer R. J., Pachter R., Hussain S. M., Frazier J. M. ( 2002). Risk assessment of high-energy chemicals by in vitro toxicity screening and quantitative structure-activity relationships. Toxicol. Sci.  68, 498– 507. Google Scholar CrossRef Search ADS PubMed  Wills L. P., Beeson G. C., Hoover D. B., Schnellmann R. G., Beeson C. C. ( 2015). Assessment of toxcast phase ii for mitochondrial liabilities using a high-throughput respirometric assay. Toxicol. Sci.  146, 226– 234. Google Scholar CrossRef Search ADS PubMed  Xu J. J., Henstock P. V., Dunn M. C., Smith A. R., Chabot J. R., de Graaf D. ( 2008). Cellular imaging predictions of clinical drug-induced liver injury. Toxicol. Sci.  105, 97– 105. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Toxicological Sciences Oxford University Press

Historical Perspective of Mitochondria in the Toxicological Sciences

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Oxford University Press
Copyright
© The Author(s) 2018. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com
ISSN
1096-6080
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D.O.I.
10.1093/toxsci/kfx250
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Abstract

The subject of mitochondrial toxicology has witnessed growing interest and attention the past few decades. In 1983, the first year that the Toxicologist was indexed for keywords, only 5 abstracts were presented at the annual meeting that listed mitochondria as a key word. Five years later, the number was 8, as it was 10 years after that in 1998. Up to this point, the Society of Toxicology managed two primary journals; Fundamental and Applied Toxicology (FAAT), which it owned; and Toxicology and Applied Pharmacology (TAAP), which it managed editorially. January 1998 marked the publication of the first issue of Toxicological Sciences. Figure 1 illustrates the number of abstracts indexed to mitochondria that were published over the years in the Toxicologist (line graph) along with the number of manuscripts on the topic of mitochondrial toxicity that were published in the 3 journals; TAAP, FAAT, and Toxicol. Sci. Leading up to 1998 most of the articles published on mitochondrial toxicology appeared in TAAP with only 1–3 papers published in the Society-owned journal FAAT. However, that distribution shifted after the first few years where not only did the total number of publications on mitochondrial toxicology almost triple, but a greater proportion appeared in Toxicol. Sci. Figure 1. View largeDownload slide Plot of the number of abstracts indexed in the Toxicologist, and manuscripts searchable on the keyword mitochondria in the three journals associated with the Society of Toxicology since 1993. The vertical bar indicates the year that Toxicol. Sci. was first published. Figure 1. View largeDownload slide Plot of the number of abstracts indexed in the Toxicologist, and manuscripts searchable on the keyword mitochondria in the three journals associated with the Society of Toxicology since 1993. The vertical bar indicates the year that Toxicol. Sci. was first published. The first manuscript on mitochondrial toxicity published in Toxicol. Sci. appeared in the May issue (Custodio et al., 1998), which described the effect of acrylic acid on inducing the mitochondrial permeability transition in isolated hepatic mitochondria in vitro. Only 2 other papers on mitochondrial toxicology were published in Toxicol. Sci. that year, both looking at mitochondrial bioenergetics in isolated cells and both in the December issue (Ciaccio et al., 1998; Morshed et al., 1998). The following year the number of abstracts on mitochondrial toxicology published in The Toxicologist increased dramatically, which may have been an artifact of more robust indexing terminology. Regardless, it wasn’t until 2002 that the number of papers on mitochondrial toxicity published in Toxicol. Sci. reached double digits, which it has sustained for all but 2 years since, 2006 and 2009. Perhaps more impressive than the growth in number of publications has been the transformation in perspective of mitochondrial toxicity, from what was almost exclusively mitochondrial bioenergetics to the molecular regulation of cellular dynamics and metabolic homeostasis. In the 1980s and 90s most all of the attention was on the effect of exposures on mitochondrial adduct formation, free radical generation and glutathione status, the mitochondrial permeability transition, fatty acid oxidation and oxidative phosphorylation or respiration. Beginning in the late 1990s and peaking in the next decade, however, there was rapid growth in interest in the role of mitochondria in programmed cell death, apoptosis, the first report of which was published in Toxicol. Sci. in 1999 (Close et al., 1999) and since reviewed by several prominent scientists in the field (Jaeschke et al., 2002; Nicotera, 2003; Orrenius et al., 2011). Since its inception, Toxicol. Sci. has been a repository for publications of some of the most seminal research identifying mitochondria either as (1) primary targets or (2) critical transducers in the biological response to chemical exposures. Through this grew an increasing appreciation of the stringent integration of mitochondria as sensors of changing cellular environments and biological governors of adaptive adjustments in cell homeostasis that are manifested by way of mitochondrial fission, fusion, biogenesis and mitophagy. Toxicol. Sci. has also been a repository of publications on computational mitochondrial toxicology aimed at identifying potential high liability chemical compounds. The first attempt to define structure-activity relationships (SAR) for chemicals that affect mitochondrial metabolism, in context of the MTT assay, was published in 2002 in Toxicol. Sci. by the lab of John Frazier (Trohalaki et al., 2002); Additional publications in Toxicol. Sci. on mitochondrial SAR have since followed (Naven et al., 2013; Starkov and Wallace, 2002; Thompson et al., 2002). Likewise, some of the pioneering work with high throughput in vitro biological screens for mitochondrial toxicity has been published in Toxicol. Sci. (Wills et al., 2015; Xu et al., 2008), including its application to predict acute toxicity across phyla (Bhhatarai et al., 2015). In fact, selected screens have been incorporated into multiparametric models where mitochondrial toxicity was found to be a primary predictive determinant for both drug-induced liver (DILI) or cardiovascular injury (Laifenfeld et al., 2014; Pointon et al., 2013; Porceddu et al., 2012; Talbert et al., 2015; Tolosa et al., 2012; Xu et al., 2008), all published in Toxicol. Sci. From this brief review, it is apparent that Toxicological Sciences has been a primary source for publishing some of the most decisive discoveries relating to mitochondrial toxicity; In so doing the journal has successfully served as an effective medium for advancing understanding and perspective in this area. With the growing attention within SOT, there is every reason to believe that Toxicol. Sci. will continue long into the future to provide a pulse on the rapid advancement and evolving perspective of mitochondrial toxicology as a primary determinant of the cellular response to adverse chemical exposures. REFERENCES Bhhatarai B., Wilson D. M., Bartels M. J., Chaudhuri S., Price P. S., Carney E. W. ( 2015). Acute toxicity prediction in multiple species by leveraging mechanistic toxcast mitochondrial inhibition data and simulation of oral bioavailability. Toxicol. Sci.  147, 386– 396. Google Scholar CrossRef Search ADS PubMed  Ciaccio P. J., Gicquel E., O’Neill P. J., Scribner H. E., Vandenberghe Y. L. ( 1998). Investigation of the positive response of ethyl acrylate in the mouse lymphoma genotoxicity assay. Toxicol. Sci.  46, 324– 332. Google Scholar CrossRef Search ADS PubMed  Close A. H., Guo T. L., Shenker B. J. ( 1999). Activated human T lymphocytes exhibit reduced susceptibility to methylmercury chloride-induced apoptosis. Toxicol. Sci.  49, 68– 77. http://dx.doi.org/10.1093/toxsci/49.1.68 Google Scholar CrossRef Search ADS PubMed  Custodio J. B., Palmeira C. M., Moreno A. J., Wallace K. B. ( 1998). Acrylic acid induces the glutathione-independent mitochondrial permeability transition in vitro. Toxicol. Sci.  43, 19– 27. Google Scholar PubMed  Jaeschke H., Gores G. J., Cederbaum A. I., Hinson J. A., Pessayre D., Lemasters J. J. ( 2002). Mechanisms of hepatotoxicity. Toxicol. Sci.  65, 166– 176. Google Scholar CrossRef Search ADS PubMed  Laifenfeld D., Qiu L., Swiss R., Park J., Macoritto M., Will Y., Younis H. S., Lawton M. ( 2014). Utilization of causal reasoning of hepatic gene expression in rats to identify molecular pathways of idiosyncratic drug-induced liver injury. Toxicol. Sci.  137, 234– 248. http://dx.doi.org/10.1093/toxsci/kft232 Google Scholar CrossRef Search ADS PubMed  Morshed K. M., Jain S. K., McMartin K. E. ( 1998). Propylene glycol-mediated cell injury in a primary culture of human proximal tubule cells. Toxicol. Sci.  46, 410– 417. http://dx.doi.org/10.1093/toxsci/46.2.410 Google Scholar CrossRef Search ADS PubMed  Naven R. T., Swiss R., Klug-McLeod J., Will Y., Greene N. ( 2013). The development of structure-activity relationships for mitochondrial dysfunction: uncoupling of oxidative phosphorylation. Toxicol. Sci.  131, 271– 278. Google Scholar CrossRef Search ADS PubMed  Nicotera P. ( 2003). Molecular switches deciding the death of injured neurons. Toxicol Sci  74, 4– 9. http://dx.doi.org/10.1093/toxsci/kfg109 Google Scholar CrossRef Search ADS PubMed  Orrenius S., Nicotera P., Zhivotovsky B. ( 2011). Cell death mechanisms and their implications in toxicology. Toxicol. Sci.  119, 3– 19. http://dx.doi.org/10.1093/toxsci/kfq268 Google Scholar CrossRef Search ADS PubMed  Pointon A., Abi-Gerges N., Cross M. J., Sidaway J. E. ( 2013). Phenotypic profiling of structural cardiotoxins in vitro reveals dependency on multiple mechanisms of toxicity. Toxicol. Sci.  132, 317– 326. Google Scholar CrossRef Search ADS PubMed  Porceddu M., Buron N., Roussel C., Labbe G., Fromenty B., Borgne-Sanchez A. ( 2012). Prediction of liver injury induced by chemicals in human with a multiparametric assay on isolated mouse liver mitochondria. Toxicol. Sci.  129, 332– 345. Google Scholar CrossRef Search ADS PubMed  Starkov A. A., Wallace K. B. ( 2002). Structural determinants of fluorochemical-induced mitochondrial dysfunction. Toxicol. Sci.  66, 244– 252. http://dx.doi.org/10.1093/toxsci/66.2.244 Google Scholar CrossRef Search ADS PubMed  Talbert D. R., Doherty K. R., Trusk P. B., Moran D. M., Shell S. A., Bacus S. ( 2015). A multi-parameter in vitro screen in human stem cell-derived cardiomyocytes identifies ponatinib-induced structural and functional cardiac toxicity. Toxicol. Sci.  143, 147– 155. Google Scholar CrossRef Search ADS PubMed  Thompson R. W., Valentine H. L., Valentine W. M. ( 2002). In vivo and in vitro hepatotoxicity and glutathione interactions of N-methyldithiocarbamate and N, N-dimethyldithiocarbamate in the rat. Toxicol. Sci.  70, 269– 280. Google Scholar CrossRef Search ADS PubMed  Tolosa L., Pinto S., Donato M. T., Lahoz A., Castell J. V., O'Connor J. E., Gomez-Lechon M. J. ( 2012). Development of a multiparametric cell-based protocol to screen and classify the hepatotoxicity potential of drugs. Toxicol. Sci.  127, 187– 198. Google Scholar CrossRef Search ADS PubMed  Trohalaki S., Zellmer R. J., Pachter R., Hussain S. M., Frazier J. M. ( 2002). Risk assessment of high-energy chemicals by in vitro toxicity screening and quantitative structure-activity relationships. Toxicol. Sci.  68, 498– 507. Google Scholar CrossRef Search ADS PubMed  Wills L. P., Beeson G. C., Hoover D. B., Schnellmann R. G., Beeson C. C. ( 2015). Assessment of toxcast phase ii for mitochondrial liabilities using a high-throughput respirometric assay. Toxicol. Sci.  146, 226– 234. Google Scholar CrossRef Search ADS PubMed  Xu J. J., Henstock P. V., Dunn M. C., Smith A. R., Chabot J. R., de Graaf D. ( 2008). Cellular imaging predictions of clinical drug-induced liver injury. Toxicol. Sci.  105, 97– 105. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Journal

Toxicological SciencesOxford University Press

Published: Mar 1, 2018

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