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首页> 美国卫生研究院文献>Springer Open Choice >Benchmark dose analyses of multiple genetic toxicity endpoints permit robust cross-tissue comparisons of MutaMouse responses to orally delivered benzoapyrene
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Benchmark dose analyses of multiple genetic toxicity endpoints permit robust cross-tissue comparisons of MutaMouse responses to orally delivered benzoapyrene

机译：多个遗传毒性终点的基准剂量分析可对MutaMouse对口服递送的苯并a py的反应进行可靠的跨组织比较

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摘要

Genetic damage is a key event in tumorigenesis, and chemically induced genotoxic effects are a human health concern. Although genetic toxicity data have historically been interpreted using a qualitative screen-and-bin approach, there is increasing interest in quantitative analysis of genetic toxicity dose–response data. We demonstrate an emerging use of the benchmark dose (BMD)-approach for empirically ranking cross-tissue sensitivity. Using a model environmental carcinogen, we quantitatively examined responses for four genetic damage endpoints over an extended dose range, and conducted cross-tissue sensitivity rankings using BMD100 values and their 90% confidence intervals (CIs). MutaMouse specimens were orally exposed to 11 doses of benzo[a]pyrene. DNA adduct frequency and lacZ mutant frequency (MF) were measured in up to 8 tissues, and Pig-a MF and micronuclei (MN) were assessed in immature (RETs) and mature red blood cells (RBCs). The cross-tissue BMD pattern for lacZ MF is similar to that observed for DNA adducts, and is consistent with an oral route-of-exposure and differences in tissue-specific metabolism and proliferation. The lacZ MF BMDs were significantly correlated with the tissue-matched adduct BMDs, demonstrating a consistent adduct conversion rate across tissues. The BMD CIs, for both the Pig-a and the MN endpoints, overlapped for RETs and RBCs, suggesting comparable utility of both cell populations for protracted exposures. Examination of endpoint-specific response maxima illustrates the difficulty of comparing BMD values for a fixed benchmark response across endpoints. Overall, the BMD-approach permitted robust comparisons of responses across tissues/endpoints, which is valuable to our mechanistic understanding of how benzo[a]pyrene induces genetic damage.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-017-2099-2) contains supplementary material, which is available to authorized users.
机译：基因损伤是肿瘤发生中的关键事件，化学诱导的遗传毒性作用是人类健康的关注点。尽管历史上已经使用定性筛选和结合方法解释了遗传毒性数据，但是人们对遗传毒性剂量反应数据的定量分析越来越感兴趣。我们证明了基准剂量（BMD）方法在根据经验对跨组织敏感性进行排名方面的新兴应用。使用模型环境致癌物，我们定量研究了扩展剂量范围内四个遗传损伤终点的反应，并使用BMD100值及其90％置信区间（CI）进行了跨组织敏感性排名。将MutaMouse标本口服暴露于11剂量的苯并[a] re。在多达8个组织中测量了DNA加合物频率和lacZ突变体频率（MF），并在未成熟（RET）和成熟红细胞（RBC）中评估了Pig-a MF和微核（MN）。 lacZ MF的跨组织BMD模式类似于DNA加合物所观察到的模式，并且与口服接触途径以及组织特异性代谢和增殖的差异相一致。 lacZ MF BMD与组织匹配的加合物BMD显着相关，表明跨组织一致的加合物转化率。对于Pig-a和MN端点，BMD CI对于RETs和RBCs都是重叠的，这表明两种细胞群在长期暴露中具有可比的效用。端点特定响应最大值的检查说明了比较跨端点的固定基准响应的BMD值的困难。总体而言，BMD方法允许对组织/端点之间的反应进行强有力的比较，这对于我们对苯并[a] how如何诱发遗传损伤的机理的理解非常有价值。电子补充材料本文的在线版本（doi：10.1007 / s00204-017 -2099-2）包含补充材料，授权用户可以使用。

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