Transgenic Animal Models in Toxicology: Historical Perspectives and Future Outlook
Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan 48674, USA. Toxicological Sciences
(Impact Factor: 3.85).
03/2011; 121(2):207-33. DOI: 10.1093/toxsci/kfr075
Transgenic animal models are powerful tools for developing a more detailed understanding on the roles of specific genes in biological pathways and systems. Applications of these models have been made within the field of toxicology, most notably for the screening of mutagenic and carcinogenic potential and for the characterization of toxic mechanisms of action. It has long been a goal of research toxicologists to use the data from these models to refine hazard identification and characterization to better inform human health risk assessments. This review provides an overview on the applications of transgenic animal models in the assessment of mutagenicity and carcinogenicity, their use as reporter systems, and as tools for understanding the roles of xenobiotic-metabolizing enzymes and biological receptors in the etiology of chemical toxicity. Perspectives are also shared on the future outlook for these models in toxicology and risk assessment and how transgenic technologies are likely to be an integral tool for toxicity testing in the 21st century.
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Available from: J. Craig Rowlands
- "In addition to these in vivo models, transgenic animals are also increasingly being used to understand the mechanisms of biological processes (diseases) and toxicological endpoints (carcinogenicity and mutagenicity) (Boverhof et al., 2011; Gonzalez et al., 1998); however, these transgenic models are not developed specifically to study inhibition of apoptosis in hepatocarcinogenesis, thus is beyond the scope of this review. Some of the limitations of in vivo models are as follows: (1) rate of apoptosis: in the normal rodent liver rate of apoptosis varies from 0.01 to 0.05% (Chopra et al., 2009). "
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ABSTRACT: Abstract Non-genotoxic carcinogens act by promoting the clonal expansion of preneoplastic cells by directly or indirectly stimulating cell division or inhibiting cell loss in the target organ. The specific mode-of-action (MoA) by which some non-genotoxic carcinogens ultimately cause cancer is not completely understood. To date, there are several proposed MoAs for non-genotoxic carcinogens and some of these propose inhibition of apoptosis as one of the Key Events. In general, inhibition of apoptosis is considered a necessary step for cell survival and in theory can occur in combination or in association with other key promotional events, such as cell proliferation, oxidative stress, and inhibition of intercellular communication to promote carcinogenesis. However, the evidence supporting the role of inhibition of apoptosis as a necessary step in promoting specific chemically-induced tumors is often debated. To address this evidence, we reviewed studies that utilized prototypical nuclear receptor- mediated hepatocarcinogens. Based on this review, it is proposed that the ability to determine the importance of inhibition of apoptosis as a Key Event in the MoA for tumor promotion is hampered by the limitations of the methods utilized for its detection. This review provides an assessment of the strengths and limitations of the current methodology used for detection of apoptosis and provide suggestions for improving its detection, thereby strengthening the weight of evidence supporting inhibition of apoptosis as a Key Event in a MoA for tumor promotion.
Available from: Nancy Bower
- "This greatly reduces animal use in accordance with the 3Rs (reduce/refine/replace) principles and lowers costs compared with a 2-year rodent study. The p53þ/À mouse model may be the single preferred model for compounds with evidence or residual concerns of genotoxicity; however, the rasH2 model is the only alternative model that is acceptable for compounds with positive, equivocal, or negative genotoxicity findings (Boverhof et al. 2011; MacDonald et al. 2004). "
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ABSTRACT: International regulatory and pharmaceutical industry scientists are discussing revision of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) S1 guidance on rodent carcinogenicity assessment of small molecule pharmaceuticals. A weight-of-evidence approach is proposed to determine the need for rodent carcinogenicity studies. For compounds with high human cancer risk, the product may be labeled appropriately without conducting rodent carcinogenicity studies. For compounds with minimal cancer risk, only a 6-month transgenic mouse study (rasH2 mouse or p53+/- mouse) or a 2-year mouse study would be needed. If rodent carcinogenicity testing may add significant value to cancer risk assessment, a 2-year rat study and either a 6-month transgenic mouse or a 2-year mouse study is appropriate. In many cases, therefore, one rodent carcinogenicity study could be sufficient. The rasH2 model predicts neoplastic findings relevant to human cancer risk assessment as well as 2-year rodent models, produces fewer irrelevant neoplastic outcomes, and often will be preferable to a 2-year rodent study. Before revising ICH S1 guidance, a prospective evaluation will be conducted to test the proposed weight-of-evidence approach. This evaluation offers an opportunity for a secondary analysis comparing the value of alternative mouse models and 2-year rodent studies in the proposed ICH S1 weight-of-evidence approach for human cancer risk assessment.
Available from: Shyra J Gardai
- "The strong genetic association identified between LRRK2 mutations and Parkinson’s disease has captured the attention of the research community , , with much interest focusing on whether LRRK2 modulation will be a viable strategy for treating the disease . The use of knockout and transgenic animal models may be useful in generating hypotheses for further exploration, particularly in the absence of pharmacologic tools , . In the case of LRRK2, several groups observed that mice of different lineages lacking LRRK2 all exhibited perturbations in kidney homeostasis –. "
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ABSTRACT: Genetic evidence links mutations in the LRRK2 gene with an increased risk of Parkinson's disease, for which no neuroprotective or neurorestorative therapies currently exist. While the role of LRRK2 in normal cellular function has yet to be fully described, evidence suggests involvement with immune and kidney functions. A comparative study of LRRK2-deficient and wild type rats investigated the influence that this gene has on the phenotype of these rats. Significant weight gain in the LRRK2 null rats was observed and was accompanied by significant increases in insulin and insulin-like growth factors. Additionally, LRRK2-deficient rats displayed kidney morphological and histopathological alterations in the renal tubule epithelial cells of all animals assessed. These perturbations in renal morphology were accompanied by significant decreases of lipocalin-2, in both the urine and plasma of knockout animals. Significant alterations in the cellular composition of the spleen between LRRK2 knockout and wild type animals were identified by immunophenotyping and were associated with subtle differences in response to dual infection with rat-adapted influenza virus (RAIV) and Streptococcus pneumoniae. Ontological pathway analysis of LRRK2 across metabolic and kidney processes and pathological categories suggested that the thioredoxin network may play a role in perturbing these organ systems. The phenotype of the LRRK2 null rat is suggestive of a complex biology influencing metabolism, immune function and kidney homeostasis. These data need to be extended to better understand the role of the kinase domain or other biological functions of the gene to better inform the development of pharmacological inhibitors.
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