A new mouse model for ozone health effects research.

IF 10.1 1区 环境科学与生态学 Q1 ENVIRONMENTAL SCIENCES
Gregory J Smith, Robert M Immormino, Martin T Ferris, Sarah A Lester, Timothy P Moran, Jack R Harkema, Samir N P Kelada
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引用次数: 0

Abstract

Background: Exposure to the ambient air pollutant ozone (O3) is associated with adverse respiratory health outcomes. Rodent models have been used to identify mechanisms of response to O3 but their utility has been questioned owing to species differences in physiologic response, most notably exposure-induced hypothermia, which renders rodents relatively resistant to O3 compared to humans.

Objectives: First, to test whether a recombinant inbred mouse strain from the Collaborative Cross population, CC002/Unc, provides a sensitive model of ozone response by benchmarking it to the most commonly used inbred strain, C57BL/6J. Second, to identify the genetic basis of CC002/Unc's sensitivity.

Methods: We examined the responses of CC002/Unc and C57BL/6J mice to either acute (0.4 or 0.8 ppm O3 x 4 hours) or repeated (0.8 ppm O3 x 4 hours/day x 3 or 9 weekdays) O3 exposure. Then, we mapped quantitative trait loci (QTL) for responses to 9 days of O3 in a CC002/Unc x CC005/TauUnc (O3-resistant) backcross population.

Results: CC002/Unc was far more responsive to acute O3 than C57BL/6J, exhibiting significant inflammation following a single 0.4 ppm O3 exposure and greater inflammation and injury after 0.8 ppm O3. Enhanced sensitivity of CC002/Unc mice was associated with decreased breathing frequency and diminished hypothermic responses. Following repeated exposure, C57BL/6J lungs appeared normal, while CC002/Unc lungs had eosinophilic inflammation and centriacinar fibrosis. We identified five QTLs for airway eosinophilia, including a large-effect QTL on chromosome 11 that accounted for 18% of phenotypic variation and contains genes with plausible links to aberrant immune responses.

Discussion: The CC002/Unc strain provides an improved model to study the effects of acute and repeated O3 exposure due to its enhanced sensitivity vs. C57BL/6J and more human-like thermoregulatory response. Further genetic analysis to pinpoint causal genes underlying CC002/Unc's susceptibility will provide new insights into mechanisms of O3-induced lung disease. https://doi.org/10.1289/EHP15745.

臭氧对健康影响研究的新小鼠模型。
背景:暴露于环境空气污染物臭氧(O3)与不良呼吸健康结果相关。啮齿类动物模型已被用于确定对O3的反应机制,但由于物种在生理反应上的差异,尤其是暴露诱导的低温,它们的效用受到质疑,这使得啮齿类动物与人类相比对O3具有相对抗性。目的:首先,通过将来自协作杂交群体的重组自交系小鼠CC002/Unc与最常用的自交系小鼠C57BL/6J进行比较,测试其是否提供了臭氧反应的敏感模型。其次,确定CC002/Unc敏感性的遗传基础。方法:我们检测了CC002/Unc和C57BL/6J小鼠对急性(0.4或0.8 ppm O3 × 4小时)或重复(0.8 ppm O3 × 4小时/天× 3或9个工作日)O3暴露的反应。然后,我们绘制了CC002/Unc x CC005/TauUnc (O3抗性)回交群体对O3 9天反应的数量性状位点(QTL)。结果:CC002/Unc对急性O3的反应远比C57BL/6J灵敏,在单次0.4 ppm O3暴露后表现出明显的炎症反应,而在0.8 ppm O3暴露后表现出更大的炎症和损伤。CC002/Unc小鼠的敏感性增强与呼吸频率降低和低体温反应减少有关。反复暴露后,C57BL/6J肺表现正常,CC002/Unc肺出现嗜酸性炎症和中心胞性纤维化。我们确定了5个与气道嗜酸性粒细胞相关的QTL,包括11号染色体上的一个大效应QTL,该QTL占表型变异的18%,并且包含与异常免疫反应相关的基因。讨论:CC002/Unc菌株提供了一个改进的模型来研究急性和重复暴露于O3的影响,因为它比C57BL/6J具有更高的敏感性和更类似人类的体温调节反应。进一步的遗传分析,以确定CC002/Unc易感性的致病基因,将为臭氧诱发肺部疾病的机制提供新的见解。https://doi.org/10.1289/EHP15745。
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来源期刊
Environmental Health Perspectives
Environmental Health Perspectives 环境科学-公共卫生、环境卫生与职业卫生
CiteScore
14.40
自引率
2.90%
发文量
388
审稿时长
6 months
期刊介绍: Environmental Health Perspectives (EHP) is a monthly peer-reviewed journal supported by the National Institute of Environmental Health Sciences, part of the National Institutes of Health under the U.S. Department of Health and Human Services. Its mission is to facilitate discussions on the connections between the environment and human health by publishing top-notch research and news. EHP ranks third in Public, Environmental, and Occupational Health, fourth in Toxicology, and fifth in Environmental Sciences.
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