APPLICATION OF TRANSGENIC MODELS FOR TOXICOLOGICAL CHARACTERIZATION

识别潜在人类致癌物的主要检测方法仍然是两年啮齿动物生物测定法，其中使用近交系小鼠和大鼠作为人类风险的潜在替代物。我们建议在选定的转基因小鼠模型中进行短期生物测定，以补充为期两年的癌症生物测定。对癌症的分子理解和直接参与瘤形成的基因的鉴定的快速进展为控制细胞增殖的基因、肿瘤表型的抑制或这些基因的调节剂之间的关系提供了具体的见解。今天使用的转基因模型集中在这些领域。为此，单倍不足的p53基因敲除（p53+/-）和zetaglobin v-Ha- ras（Tg.AC）转基因小鼠模型已与传统的，两个啮齿动物物种致癌物生物测定的结果进行了比较。这些研究的结果表明，某些明确的能力，以确定一组选定的已知的人类致癌物，从转基因模型的结果提供了直接的机械见解化学品的行动。例如，p53+/-模型已证明优先鉴定遗传毒性/致突变致癌物，其中野生型等位基因的分子变化可被证明并与化学暴露直接相关。此外，在合作实验中，有可能证明植入用于动物识别的应答器会诱发皮下肉瘤。这些肿瘤的后续分子分析表明，特定的p53等位基因丢失。Tg.AC模型对非遗传毒性致癌物表现出优先反应。在与常规两阶段启动/促进模型平行的研究中，已获得的数据表明，两阶段模型和Tg.AC转基因模型都有能力在比常规生物测定短得多的时间内鉴定潜在的非遗传毒性致癌物和肿瘤促进剂。此外，对肿瘤促进模型长期获得的数据进行分析和长期生物测定分析表明，肿瘤促进特性是完全非遗传毒性致癌物的一个组成部分。因此，化学品在Tg.AC模型中的作用机制是优先诱导转基因表达，这导致皮肤乳头状瘤的报告表型的发展。在常规啮齿动物生物测定中与这些转基因模型进行的研究的直接前瞻性比较表明，转基因模型不是超灵敏的，因为它们不能检测在小鼠或大鼠中引起优先种属特异性效应的药剂。许多关键的问题仍然有待回答，以促进科学共识，使用这些转基因系的识别潜在的人类致癌物，但迄今为止开发的数据表明，这些模型可以发挥重要作用，化学和药物安全性评估。

The primary testing method for the identification of potential human carcinogens remains the two-year rodent bioassay where in-bred mice and rats are used as potential surrogates for human risk. We have proposed to supplement the two-year cancer bioassays with short-term bioassays conducted in selected transgenic mouse models. The rapid progress in the molecular understanding of cancer and the identification of genes that are directly involved in neoplasia have provided specific insights into the relationship between genes which control cell proliferation, suppression of tumor phenotype or modulators of these genes. The transgenic models utilized today are focused in these areas. To this end, the haploinsufficient p53 knockout (p53+/-) and zetaglobin v-Ha- ras (Tg.AC) transgenic mouse models have been compared with the results of conventional, two rodent species carcinogen bioassays. The results of these studies have shown some definitive capacity to identify a selected group of known human carcinogens, and that the results from the transgenic models provide direct mechanistic insights into the action of chemicals. For example, the p53+/- model has demonstrated the preferential identification of genotoxic/mutagenic carcinogens in which molecular changes in the wildtype allele can be demonstrated and associated directly with chemical exposure. In addition, in collaborative experiments, it has been possible to demonstrate the induction of subcutaneous sarcomas by implantation of transponders used for animal identification. Subsequent molecular analysis of these tumors has demonstrated specific p53 allelic loss. The Tg.AC model has demonstrated preferential responsive to nongenotoxic carcinogens. In studies in parallel with the conventional two-stage initiation/promotion model, data have been obtained to suggest that both the two-stage model and the Tg.AC transgenic model have the capacity to identify potential nongenotoxic carcinogens and tumor promoters in a much shorter period of time than conventional bioassays. In addition, the analysis of data obtained over a long period of time with tumor promotion models and analysis of long-term bioassays suggests that the property of tumor promotion is one component of complete nongenotoxic carcinogens. Thus, the mechanism of action of chemicals in the Tg.AC model is the preferential induction of transgene expression which leads to the development of a reporter phenotype of skin papillomas. Direct prospective comparison of studies conducted in conventional rodent bioassays with these transgenic models has demonstrated that the transgenic models are not supersensitive in that they do not detect agents which cause preferential species-specific effects in either mice or rats. Many critical questions remain to be answered in order to promote a scientific consensus on the use of these transgenic lines for the identification of potential human carcinogens, but the data developed to date suggests that these models can play an important role in chemical and drug safety assessments.