Garry Sébastien, Nesslany Fabrice, Aliouat El Moukhtar, Haguenoer Jean-Marie, Marzin Daniel
Laboratoire de Toxicologie Génétique, Institut Pasteur de Lille, 1 Rue du Pr. Calmette, BP 245, 59019 Lille Cedex, France.
Mutagenesis. 2003 Sep;18(5):449-55. doi: 10.1093/mutage/geg016.
Since epidemiological studies have firmly implicated co-exposure to iron oxides and polycyclic aromatic hydrocarbons as a potential etiological factor involved in the excess mortality due to lung cancer in miners, experimental studies have been performed to investigate the role of iron particles in benzo[a]pyrene (B[a]P)-induced lung pathogenesis. In a previous study using the Comet assay in vivo in the rat, we demonstrated that iron particles enhanced B[a]P genotoxicity. To determine whether co-exposure (B[a]P/iron oxides) induces a real genotoxic activity or is only due to inhibition of DNA repair, the unscheduled DNA synthesis (UDS) assay was implemented in vivo in the rat. The UDS assay was used to measure DNA repair in two cell types (lung cells and hepatocytes) of OFA Sprague-Dawley rats, 24 h after endotracheal administration of a single dose of an iron oxide (hematite, Fe2O3) (0.75 mg), of B[a]P (0.75 mg) or of B[a]P (0.75 mg) coated on hematite particles (0.75 mg). No difference in UDS was observed in the two organs investigated in rats treated with iron oxide alone compared with control animals, while a significant increase in UDS was observed in lungs and liver of rats treated with B[a]P alone compared with control animals. The main finding was a significant increase in UDS observed in both lung and liver cells of rats treated with B[a]P coated on hematite when compared with those treated with B[a]P alone. The current study demonstrates (i) that iron particles did not inhibit UDS in lung cells and hepatocytes of OFA Sprague-Dawley treated rats with B[a]P coated on hematite and (ii) a potent genotoxic activity of co-exposure to B[a]P coated on hematite. Therefore, our data may contribute to explaining the excess mortality due to lung cancer in epidemiological studies and overall why exposure to B[a]P coated on Fe2O3 particles resulted in a higher tumor incidence in rodents compared with exposure to B[a]P alone.
由于流行病学研究已确凿地表明，同时接触氧化铁和多环芳烃是导致矿工肺癌超额死亡率的一个潜在病因，因此已开展实验研究来探究铁颗粒在苯并[a]芘（B[a]P）诱发的肺部病变中的作用。在之前一项对大鼠进行体内彗星试验的研究中，我们证明铁颗粒增强了B[a]P的遗传毒性。为了确定同时接触（B[a]P/氧化铁）是诱导了真正的遗传毒性活性还是仅仅由于抑制了DNA修复，在大鼠体内进行了非程序性DNA合成（UDS）试验。UDS试验用于测量经气管内单次给予一剂氧化铁（赤铁矿，Fe2O3）（0.75毫克）、B[a]P（0.75毫克）或包裹在赤铁矿颗粒上的B[a]P（0.75毫克）24小时后，OFA斯普拉格-道利大鼠两种细胞类型（肺细胞和肝细胞）中的DNA修复情况。与对照动物相比，单独用氧化铁处理的大鼠所研究的两个器官中未观察到UDS有差异，而与对照动物相比，单独用B[a]P处理的大鼠的肺和肝脏中观察到UDS显著增加。主要发现是，与单独用B[a]P处理的大鼠相比，用包裹在赤铁矿上的B[a]P处理的大鼠的肺和肝细胞中观察到UDS显著增加。当前研究表明：（i）铁颗粒不会抑制用包裹有B[a]P的赤铁矿处理的OFA斯普拉格-道利大鼠的肺细胞和肝细胞中的UDS；（ii）同时接触包裹在赤铁矿上的B[a]P具有强大的遗传毒性活性。因此，我们的数据可能有助于解释流行病学研究中肺癌导致的超额死亡率，以及总体上为什么与单独接触B[a]P相比，接触包裹在Fe2O3颗粒上的B[a]P会导致啮齿动物中更高的肿瘤发生率。
