Inflammatory bowel disease (IBD) is an important risk factor for gastrointestinal cancers. Inflammation and other carcinogenesis-related effects at distal, tissue-specific sites require further study. In order to better understand if systemic genotoxicity is associated with IBD, we exposed mice to dextran sulfate sodium salt (DSS) and measured the incidence of micronucleated cells (MN) and Pig-a mutant phenotype cells in blood erythrocyte populations. In one study, 8-week-old male CD-1 mice were exposed to 0, 1, 2, 3 or 4% w/v DSS in drinking water. The 4-week in-life period was divided into four 1-week intervals-alternately on then off DSS treatment. Low volume blood samples were collected for MN analysis at the end of each week, and cardiac blood samples were collected at the end of the 4-week period for Pig-a analyses. The two highest doses of DSS were observed to induce significant increases in reticulocyte frequencies. Even so, no statistically significant treatment-related effects on the genotoxicity biomarkers were evident. While one high-dose mouse showed modestly elevated MN frequencies during the DSS treatment cycles, it also exhibited exceptionally high reticulocyte frequencies (e.g. 18.7% at the end of the second DSS cycle). In a second study, mice were treated with 0 or 4% DSS for 9-18 consecutive days. Exposure was continued until rectal bleeding or morbidity was evident, at which point the treatment was terminated and blood was collected for MN analysis. The Pig-a assay was conducted on samples collected 29 days after the start of treatment. The initial blood specimens showed highly elevated reticulocyte frequencies in DSS-exposed mice (mean ± SEM = 1.75 ± 0.10% vs. 13.04 ± 3.66% for 0 vs. 4% mice, respectively). Statistical analyses showed no treatment-related effect on MN or Pig-a mutant frequencies. Even so, the incidence of MN versus reticulocytes in the DSS-exposed mice were positively correlated (linear fit R2 = 0.657, P = 0.0044). Collectively, these results suggest that in the case of the DSS CD-1 mouse model, systemic effects include stress erythropoiesis but not remarkable genotoxicity. To the extent MN may have been slightly elevated in a minority of individual mice, these effects appear to be secondary, likely attributable to stimulated erythropoiesis.

中文翻译：

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通过血液微核和 Pig-a 基因突变测定评估炎症性肠病的葡聚糖硫酸钠小鼠模型的全身遗传毒性。

炎症性肠病（IBD）是胃肠道癌症的重要危险因素。远端组织特异性位点的炎症和其他致癌作用需要进一步研究。为了更好地了解全身基因毒性是否与 IBD 相关，我们将小鼠暴露于葡聚糖硫酸钠盐 (DSS) 并测量了血红细胞群中微核细胞 (MN) 和 Pig-a 突变表型细胞的发生率。在一项研究中，8 周大的雄性 CD-1 小鼠在饮用水中暴露于 0、1、2、3 或 4% w/v DSS。4 周的生命周期被分成四个 1 周的间隔——交替进行 DSS 治疗。在每周结束时收集少量血样用于 MN 分析，并在 4 周结束时收集心脏血样用于 Pig-a 分析。观察到两个最高剂量的 DSS 诱导网织红细胞频率显着增加。即便如此，对基因毒性生物标志物的治疗相关影响没有统计学意义。虽然一只高剂量小鼠在 DSS 治疗周期中显示出适度升高的 MN 频率，但它也表现出异常高的网织红细胞频率（例如，在第二个 DSS 周期结束时为 18.7%）。在第二项研究中，小鼠连续 9-18 天接受 0% 或 4% DSS 治疗。持续暴露直至直肠出血或发病率明显，此时终止治疗并收集血液用于 MN 分析。Pig-a 检测是在治疗开始后 29 天收集的样品上进行的。最初的血液样本在 DSS 暴露的小鼠中显示出高度升高的网织红细胞频率（平均值 ± SEM = 1.75 ± 0.10% 与 13.04 ± 3.66%，分别为 0 和 4% 小鼠）。统计分析显示对 MN 或 Pig-a 突变频率没有治疗相关影响。即便如此，暴露于 DSS 的小鼠中 MN 与网织红细胞的发生率呈正相关（线性拟合 R2 = 0.657，P = 0.0044）。总的来说，这些结果表明，在 DSS CD-1 小鼠模型的情况下，全身效应包括应激性红细胞生成，但没有显着的遗传毒性。就少数个体小鼠的 MN 可能略有升高而言，这些影响似乎是次要的，可能归因于刺激的红细胞生成。统计分析显示对 MN 或 Pig-a 突变频率没有治疗相关影响。即便如此，暴露于 DSS 的小鼠中 MN 与网织红细胞的发生率呈正相关（线性拟合 R2 = 0.657，P = 0.0044）。总的来说，这些结果表明，在 DSS CD-1 小鼠模型的情况下，全身效应包括应激性红细胞生成，但没有显着的遗传毒性。就少数个体小鼠的 MN 可能略有升高而言，这些影响似乎是次要的，可能归因于刺激的红细胞生成。统计分析显示对 MN 或 Pig-a 突变频率没有治疗相关影响。即便如此，暴露于 DSS 的小鼠中 MN 与网织红细胞的发生率呈正相关（线性拟合 R2 = 0.657，P = 0.0044）。总的来说，这些结果表明，在 DSS CD-1 小鼠模型的情况下，全身效应包括应激性红细胞生成，但没有显着的遗传毒性。就少数个体小鼠的 MN 可能略有升高而言，这些影响似乎是次要的，可能归因于刺激的红细胞生成。全身效应包括应激性红细胞生成，但不显着的遗传毒性。就少数个体小鼠的 MN 可能略有升高而言，这些影响似乎是次要的，可能归因于刺激的红细胞生成。全身效应包括应激性红细胞生成，但不显着的遗传毒性。就少数个体小鼠的 MN 可能略有升高而言，这些影响似乎是次要的，可能归因于刺激的红细胞生成。