Transgenic Animal Models in Toxicology: Historical Perspectives and Future Outlook
ABSTRACT 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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- "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). "
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.Toxicology mechanisms and methods 01/2015; 25(3):1-26. DOI:10.3109/15376516.2015.1007541 · 1.55 Impact Factor
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- "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). "
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.Toxicologic Pathology 08/2013; 42(5). DOI:10.1177/0192623313502130 · 1.92 Impact Factor
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ABSTRACT: In vitro studies have suggested that nanosized titanium dioxide (TiO(2)) is genotoxic. The significance of these findings with respect to in vivo effects is unclear, as few in vivo studies on TiO(2) genotoxicity exist. Recently, nanosized TiO(2) administered in drinking water was reported to increase, e.g., micronuclei (MN) in peripheral blood polychromatic erythrocytes (PCEs) and DNA damage in leukocytes. Induction of micronuclei in mouse PCEs was earlier also described for pigment-grade TiO(2) administered intraperitoneally. The apparent systemic genotoxic effects have been suggested to reflect secondary genotoxicity of TiO(2) due to inflammation. However, a recent study suggested that induction of DNA damage in mouse bronchoalveolar lavage (BAL) cells after intratracheal instillation of nanosized or fine TiO(2) is independent of inflammation. We examined here, if inhalation of freshly generated nanosized TiO(2) (74% anatase, 26% brookite; 5 days, 4 h/day) at 0.8, 7.2, and (the highest concentration allowing stable aerosol production) 28.5 mg/m(3) could induce genotoxic effects in C57BL/6J mice locally in the lungs or systematically in peripheral PCEs. DNA damage was assessed by the comet assay in lung epithelial alveolar type II and Clara cells sampled immediately following the exposure. MN were analyzed by acridine orange staining in blood PCEs collected 48 h after the last exposure. A dose-dependent deposition of Ti in lung tissue was seen. Although the highest exposure level produced a clear increase in neutrophils in BAL fluid, indicating an inflammatory effect, no significant effect on the level of DNA damage in lung epithelial cells or micronuclei in PCEs was observed, suggesting no genotoxic effects by the 5-day inhalation exposure to nanosized TiO(2) anatase. Our inhalation exposure resulted in much lower systemic TiO(2) doses than the previous oral and intraperitoneal treatments, and lung epithelial cells probably received considerably less TiO(2) than BAL cells in the earlier intratracheal study.Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 11/2011; 745(1-2):58-64. DOI:10.1016/j.mrgentox.2011.10.011 · 4.44 Impact Factor