Genomic signatures and dose-dependent transitions in nasal epithelial responses to inhaled formaldehyde in the rat
Genomic signatures and dose-dependent transitions in nasal epithelial responses to inhaled formaldehyde in the rat
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DOI：
10.1093/toxsci/kfn097
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发表时间：
2008-10-01
影响因子：
3.8
通讯作者：
Thomas, Russell S.
中科院分区：
文献类型：
--
作者：
Andersen, Melvin E.;Clewell, Harvey J., III;Thomas, Russell S.
重复和急性暴露研究评估了鼻腔对甲醛反应的时间和浓度依赖性。暴露于0、0.7、2和6 ppm，持续6小时/天，5天/周，持续3周。在0.7 ppm时未观察到细胞增殖或组织病理学。在6 ppm时，细胞增殖在第一周结束时（第5天）增加，但在第3周结束时（第15天）没有增加。鳞状化生发生在第5天;上皮增生发生在第5天和第15天。在微阵列研究中，在0.7 ppm时没有基因改变。在2 ppm时，15个基因在第5天发生了变化;在6 ppm时，只有一半发生了变化。在第15天，在2 ppm下没有基因显著改变。在2和6 ppm时的基因变化模式，在第5天出现一过性鳞状化生，表明组织适应性，并在第15天降低组织敏感性。急性研究包括额外浓度（15 ppm）和滴注组（40 μ l，400 mM/ml）。受滴注影响的基因是吸入的三倍。在急性研究中观察到许多基因的U形剂量反应，这些基因在第5天也在2 ppm时发生改变。基于细胞成分基因本体基准剂量分析，与细胞外成分和质膜相关的基因变化最为敏感。对于甲醛，在0.7至6 ppm之间，上皮反应和基因组特征存在时间和浓度依赖性转变。低浓度主要影响细胞外基质或上皮细胞的外质膜部分。
Repeated and acute exposure studies assessed time and concentration-dependencies of nasal responses to formaldehyde. Exposures were to 0, 0.7, 2, and 6 ppm for 6 h/day, 5 days/week for up to 3 weeks. Neither cell proliferation nor histopathology was observed at 0.7 ppm. At 6 ppm, cell proliferation increased at the end of the first week (day 5), but not at the end of week 3 (day 15). Squamous metaplasia occurred at day 5; epithelial hyperplasia occurred at both day 5 and day 15. In microarray studies, no genes were altered at 0.7 ppm. At 2 ppm, 15 genes were changed on day 5; only half of them were changed at 6 ppm. No genes were changed significantly at 2 ppm at day 15. The pattern of gene changes at 2 and 6 ppm, with transient squamous metaplasia at day 5, indicated tissue adaptation and reduced tissue sensitivity by day 15. The acute study included an additional concentration (15 ppm) and an instillation group (40 mu l, 400mM per nostril). Three times more genes were affected by instillation than inhalation. U-shaped dose responses were noted in the acute study for many genes that were also altered at 2 ppm on day 5. On the basis of cellular component gene ontology benchmark dose analysis, the most sensitive changes were for genes were associated with extracellular components and plasma membrane. With formaldehyde, there are temporal and concentration-dependent transitions in epithelial responses and genomic signatures between 0.7 and 6 ppm. Low concentrations primarily affect extracellular matrix or external plasma membrane portions of the epithelium.