Département Polluants et Santé, Institut National de Recherche et de Sécurité, Rue du Morvan, CS 60027, 54519, Vandoeuvre lès Nancy cedex, France.
Département Polluants et Santé, Institut National de Recherche et de Sécurité, Rue du Morvan, CS 60027, 54519, Vandoeuvre lès Nancy cedex, France.
Neurotoxicology. 2014 Mar;41:9-19. doi: 10.1016/j.neuro.2013.12.007. Epub 2013 Dec 25.
1,2-Diethylbenzene (1,2-DEB) is used in the manufacture of some plastics. Exposure to 1,2-DEB has been shown to induce peripheral neuropathy in rats. This neurotoxicity is thought to be caused by a metabolite, 1,2-diacetylbenzene (1,2-DAB), a γ-diketone-like compound. 1,2-DEB was previously shown to be extensively and rapidly taken up by the nasal mucosa in male rats. In the present study, the nasal mucosa in rats exposed to 1,2-DEB and 1,2-DAB were examined histologically. Results were compared to sections from rats exposed to two other DEB isomers - 1,3-diethylbenzene (1,3-DEB) and 1,4-diethylbenzene (1,4-DEB) - and to two other neurotoxic compounds - n-hexane and its γ-diketone metabolite, 2,5-hexanedione (2,5-HD). A single intraperitoneal dose of 1,2-DEB (200mg/kg) induced time-dependent necrosis in the olfactory epithelium and Bowman's glands, with lesions appearing from the earliest observation time (4h) in the dorsomedial olfactory mucosa. Lesions spread through the lateral and ventral parts of the ethmoturbinates over the following days. The dorsal and medial zones of the nasal cavity started to regenerate from 72h after treatment, with the new epithelium showing metaplasia. One month after treatment, most of the olfactory epithelium had returned to normal. 1,2-DAB (40mg/kg) caused the same lesions as those observed after treatment with 1,2-DEB. Treatment with 2,5-HD (1g/kg) also caused lesions of the olfactory epithelium, mainly at level IV. However, these were comparatively less severe than those observed after exposure to 1,2-DEB. In contrast, intraperitoneal injection of 1,3-DEB (800mg/kg), 1,4-DEB (800mg/kg) and n-hexane (2g/kg) did not affect the nasal mucosa. Pretreatment of rats with 5-phenyl-1-pentyne, an inhibitor of CYP2F2 and CYP2E1 completely inhibited the olfactory toxicity caused by 1,2-DEB. These results suggest that metabolic activation of 1,2-DEB may be responsible for the toxicity observed.
1,2-二乙基苯（1,2-DEB）用于制造某些塑料。已经证明，接触 1,2-DEB 会导致大鼠周围神经病。这种神经毒性被认为是由代谢物 1,2-二乙酰苯（1,2-DAB）引起的，1,2-DAB 是一种γ-二酮样化合物。以前的研究表明，1,2-DEB 会被雄性大鼠的鼻腔黏膜广泛且快速地吸收。在本研究中，观察了暴露于 1,2-DEB 和 1,2-DAB 的大鼠的鼻腔黏膜组织学变化。结果与暴露于两种其他 DEB 异构体（1,3-二乙基苯（1,3-DEB）和 1,4-二乙基苯（1,4-DEB））以及两种其他神经毒性化合物（正己烷及其γ-二酮代谢物 2,5-己二酮（2,5-HD））的大鼠切片进行了比较。单次腹腔注射 1,2-DEB（200mg/kg）会引起嗅上皮和 Bowman 腺的时间依赖性坏死，最早观察到的病变（4 小时）出现在嗅黏膜背内侧。病变在接下来的几天内通过鼻甲的外侧和腹侧扩散。治疗后 72 小时，鼻腔的背侧和内侧区域开始再生，新上皮出现化生。治疗后 1 个月，嗅上皮大部分恢复正常。1,2-DAB（40mg/kg）引起的病变与 1,2-DEB 治疗后观察到的病变相同。2,5-HD（1g/kg）也会引起嗅上皮病变，主要在 IV 级。然而，与接触 1,2-DEB 相比，这些病变相对较轻。相比之下，腹腔注射 1,3-DEB（800mg/kg）、1,4-DEB（800mg/kg）和正己烷（2g/kg）均未影响鼻腔黏膜。用 CYP2F2 和 CYP2E1 的抑制剂 5-苯基-1-戊炔预处理大鼠可完全抑制 1,2-DEB 引起的嗅毒性。这些结果表明，1,2-DEB 的代谢激活可能是导致观察到的毒性的原因。
