Transgenic Animal Models in Toxicology: Historical Perspectives and Future Outlook

Boverhof, Darrell R.; Chamberlain, M.; Elcombe, Clifford R.; Gonzalez, Frank J.; Heflich, Robert H.; Hernández, Lya G.; Jacobs, Abigail; Jacobson‐Kram, David; Luijten, Mirjam; Maggi, Adriana; Manjanatha, Mugimane G.; Benthem, Jan van; Gollapudi, B. Bhaskar

doi:10.1093/toxsci/kfr075

Cited by 90 publications

(66 citation statements)

References 181 publications

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“…The relatively small size, short generation time, and accelerated life span of rats and mice help to keep space and time required to perform a study manageable. In addition, most behavioral tests have been developed and validated in rats and mice; antibodies against thousands of proteins are commercially available for both species; and manipulation of mouse and rat DNA has proven to be feasible, allowing scientists to explore how specific genes function in health and disease (Boverhof et al, 2011; see also Lee et al, 2014, and references therein). However, the sensitivity of rats and mice to the acute toxicity of OP compounds is reportedly lower than that of humans.…”

Section: Animal Models Of Op Intoxicationmentioning

confidence: 99%

Animal Models That Best Reproduce the Clinical Manifestations of Human Intoxication with Organophosphorus Compounds

Pereira

Aracava

DeTolla

et al. 2014

J Pharmacol Exp Ther

100

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The translational capacity of data generated in preclinical toxicological studies is contingent upon several factors, including the appropriateness of the animal model. The primary objectives of this article are: 1) to analyze the natural history of acute and delayed signs and symptoms that develop following an acute exposure of humans to organophosphorus (OP) compounds, with an emphasis on nerve agents; 2) to identify animal models of the clinical manifestations of human exposure to OPs; and 3) to review the mechanisms that contribute to the immediate and delayed OP neurotoxicity. As discussed in this study, clinical manifestations of an acute exposure of humans to OP compounds can be faithfully reproduced in rodents and nonhuman primates. These manifestations include an acute cholinergic crisis in addition to signs of neurotoxicity that develop long after the OP exposure, particularly chronic neurologic deficits consisting of anxiety-related behavior and cognitive deficits, structural brain damage, and increased slow electroencephalographic frequencies. Because guinea pigs and nonhuman primates, like humans, have low levels of circulating carboxylesterases-the enzymes that metabolize and inactivate OP compounds-they stand out as appropriate animal models for studies of OP intoxication. These are critical points for the development of safe and effective therapeutic interventions against OP poisoning because approval of such therapies by the Food and Drug Administration is likely to rely on the Animal Efficacy Rule, which allows exclusive use of animal data as evidence of the effectiveness of a drug against pathologic conditions that cannot be ethically or feasibly tested in humans.

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Section: Animal Models Of Op Intoxicationmentioning

confidence: 99%

Animal Models That Best Reproduce the Clinical Manifestations of Human Intoxication with Organophosphorus Compounds

Pereira

Aracava

DeTolla

et al. 2014

J Pharmacol Exp Ther

100

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“…At present, the US FDA no longer recommends the Tg.AC model based on the problems observed with this model, and the number of Tg.AC studies has been decreasing. 2 In the present study, tumor development in the no-treatment group of rasH2 mice was limited, and no nodules were observed in mice treated with acetone. Similarly, in a 26-week short-term carcinogenecity study using rasH2 mice treated with ethanol, Vaseline, and acetone topically, skin nodules were not evident in any mice.…”

Section: Discussionmentioning

confidence: 41%

Tumor Promotion by 12-O-Tetradecanoylphorbol-13-Acetate in an Ultra-Short-Term Skin Carcinogenesis Bioassay Using rasH2 Mice

Kawabe¹,

Urano

Suguro³

et al. 2013

Vet Pathol

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Assessment of the skin tumor-promoting potential of 12-O-tetradecanoylphorbol-13-acetate (TPA) after initiation with 7,12-dimethylbenz [a]anthracene (DMBA) was conducted using rasH2 transgenic (Tg) mice and their nontransgenic (non-Tg) littermates. Mice were treated with DMBA (50 mg/100 mL acetone) on clipped back skin at the commencement of the study, and 1 week thereafter, TPA was applied at 8 mg/200 mL or 4 mg/200 mL acetone, once or twice weekly, for 7 weeks. Skin nodules were observed in the rasH2 Tg mice from week 4, and the incidence reached 100% at weeks 5 and 6. The number of skin nodules (multiplicity) in the 8-mg twice-weekly, 8-mg once-weekly, 4-mg twice-weekly, and 4-mg once-weekly groups was 62.4, 46.2, 62.6, and 36.9, respectively. The non-Tg mice also developed skin nodules, but the sensitivity to induction in the rasH2 Tg mice was higher. No nodules were observed in the acetone groups, but single nodules were apparent in the no-treatment rasH2 Tg and non-Tg groups. In conclusion, skin promotion effects could be detected within only 8 weeks in the rasH2 mice, and the concentration of 4 mg TPA once weekly was sufficient as a positive control. This short-term skin carcinogenesis bioassay using rasH2 mice could represent a useful tool for the assessment of drug and chemical safety with cutaneous treatment.Keywords rasH2 mouse, DMBA, TPA, ultra-short-term skin carcinogenesis bioassayThe standard regulatory requirements for new chemicals include lifetime carcinogenicity testing in 2 rodent species, typically rats and mice, of each sex. This is very timeconsuming and expensive in terms of financial and human resources. 15,19 The International Conference on Harmonization (ICH) therefore recommended reducing long-term protocols and using any one species with addition of an alternative bioassay. 6 We have focused on the medium-term carcinogenicity study as one alternative to the long-term carcinogenicity bioassay. This is based on the 2-stage concept of carcinogenesis, and bioassays for skin, liver, urinary bladder, and so on have been established. [3][4][5]7,21 We have conducted several investigations of pharmaceutical products or cosmetic components in a 2-stage skin carcinogenesis model with 7,12-dimethylbenz[a]anthracene (DMBA) as the initiator using CD-1 (ICR) mice, and this assay has recently been scheduled for approval by the Japanese pharmaceutical regulatory authorities. 4,5,21 The CB6F1-Tg rasH2 transgenic (rasH2) mouse carries the prototype human c-Ha-ras oncogene and a promoter/enhancer region on the genetic background of a BALB/cByj Â C57BL/6 J F1 mouse. A 26-week short-term carcinogenicity study using rasH2 mice, performed with a large number of chemicals, was found to give appropriate results for both genotoxic and nongenotoxic carcinogens. 20,[25][26][27][28] On the basis of these results, the US, European, and Japanese pharmaceutical regulatory bodies have approved a short-term carcinogenesis study using the rasH2 mouse to replace a long-term carcinogenicity study. 10 It is known ...

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“…10,27 Bir veya daha fazla geni susturulmuş fareler, genin hangi dokuyu hedeflediğinin anlaşıl-ması ve özel hastalıklara karşı kullanılacak tedavi yaklaşımlarını belirlemek için değerli araçlar olarak öne çıkmaktadır. GDF'lerin ayrıca ilaç hedefleri, reseptörleri, molekülün taşınma yolları ve metabolizmasını değerlendirmek için de kullanıla-bildiği belirtilmiştir.…”

Section: Geneti̇ği̇ Deği̇şti̇ri̇lmi̇ş Hayvanlarin In Vi̇vo Farmakoloji̇ Ve Etunclassified

“…Özellikle ilacın metabolizması ve atılması gibi farmakokinetik parametreler ile metabolitlerinin belirlenmesi, ilaç-ilaç etkileşimleri ve konakçının ilaca olan direncinin ancak insan genlerinin transgenik olarak yerleştirilme-siyle, sitokrom P450 ve diğer ksenobiyotikleri metabolize eden enzim genlerinin ve reseptörlerinin inaktivasyonuyla ve insan hepatositleriyle yeniden oluşturulan insani özellikler verilmiş farelerin kullanılmasıyla özel metabolik profil oluşturulan GDF'ler kullanılarak belirlenebileceği ifade edilmiştir. 27,48 Bu amaçla bireysel ksenobiyotik metabolize eden enzimleri veya yolakları değiştirilen GDF'ler kullanışlı olmasına rağmen, bu modellerde metabolizmanın tüm ögeleri bulunmaz. Mekanistik ve güvenlik çalışmaları için çoklu komponentlerin yerleştirilmesi veya silinmesi gerekebilir.…”

Section: Geneti̇ği̇ Deği̇şti̇ri̇lmi̇ş Hayvanlarin Farmakoki̇neti̇k Ve İlaç-i̇lunclassified

“…ABD Gıda ve İlaç İdaresine ilaç tescili için yapılan başvurularda, bu tip farelerin sınırlı bir şekilde kullanıldığı ve bu raporlarda en çok kullanılan GDF modelinin rasH2 ve daha az olarak da p53 +/− tip modeller olduğu, Tg.AC ve XPA −/−/ p53 +/− modellerinin ise sadece birkaç çalışmayla sınırlı olduğu bildirilmiştir. 27,67 Aynı durumun, büyük olasılıkla hayvan haklarına olan duyarlılığın fazla olması ve çeşitli etik nedenlerle AB için de söz konusu olduğu belirtilmiştir. 75 Ancak konuyla ilgili olarak uygun kanser modelleri geliştirme çalışmalarının ILSI/HESI, NTP ve diğer organizasyonlar tarafından araştırılması ve test edilmesine devam edilmektedir.…”

Section: Geneti̇ği̇ Deği̇şti̇ri̇lmi̇ş Hayvanlarin Kanser Araştirmalarinda Kunclassified

See 1 more Smart Citation

Genetically Modified Animals in Pharmacology and Toxicology Research: Review

Filazı¹,

Özhanci²

2017

Turkiye Klinikleri J Lab Anim

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Transgenic Animal Models in Toxicology: Historical Perspectives and Future Outlook

Cited by 90 publications

References 181 publications

Animal Models That Best Reproduce the Clinical Manifestations of Human Intoxication with Organophosphorus Compounds

Animal Models That Best Reproduce the Clinical Manifestations of Human Intoxication with Organophosphorus Compounds

Tumor Promotion by 12-O-Tetradecanoylphorbol-13-Acetate in an Ultra-Short-Term Skin Carcinogenesis Bioassay Using rasH2 Mice

Genetically Modified Animals in Pharmacology and Toxicology Research: Review

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