Food Drug and Chemical Toxicology, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), P.O. Box No. 80, Mahatma Gandhi Marg, Lucknow 226 001, India; Department of Biochemistry, Banaras Hindu University (BHU), Varanasi, India.
Food Drug and Chemical Toxicology, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), P.O. Box No. 80, Mahatma Gandhi Marg, Lucknow 226 001, India.
Toxicol Appl Pharmacol. 2014 Sep 1;279(2):186-97. doi: 10.1016/j.taap.2014.06.003. Epub 2014 Jun 15.
Several toxicological manifestations of deoxynivalenol (DON), a mycotoxin, are well documented; however, dermal toxicity is not yet explored. The effect of topical application of DON to mice was studied using markers of skin proliferation, inflammation and tumor promotion. Single topical application of DON (84-672nmol/mouse) significantly enhanced dermal hyperplasia and skin edema. DON (336 and 672nmol) caused significant enhancement in [(3)H]-thymidine uptake in DNA along with increased myeloperoxidase and ornithine decarboxylase activities, suggesting tissue inflammation and cell proliferation. Furthermore, DON (168nmol) caused enhanced expression of RAS, and phosphorylation of PI3K/Akt, ERK, JNK and p38 MAPKs. DON exposure also showed activation of transcription factors, c-fos, c-jun and NF-κB along with phosphorylation of IkBα. Enhanced phosphorylation of NF-κB by DON caused over expression of target proteins, COX-2, cyclin D1 and iNOS in skin. Though a single topical application of DMBA followed by twice weekly application of DON (84 and 168nmol) showed no tumorigenesis after 24weeks, however, histopathological studies suggested hyperplasia of the epidermis and hypertrophy of hair follicles. Interestingly, intestine was also found to be affected as enlarged Peyer's patches were observed, suggesting inflammatory effects which were supported by elevation of inflammatory cytokines after 24weeks of topical application of DON. These results suggest that DON induced cell proliferation in mouse skin is through the activation of MAPK signaling pathway involving transcription factors NFκB and AP-1, further leading to transcriptional activation of downstream target proteins c-fos, c-jun, cyclin D1, iNOS and COX-2 which might be responsible for its inflammatory potential.
脱氧雪腐镰刀菌烯醇（DON）是一种真菌毒素，其多种毒理学表现已得到充分证实；然而，其皮肤毒性尚未得到研究。本研究采用皮肤增殖、炎症和肿瘤促进标志物，研究了 DON 经皮给药对小鼠的影响。单次经皮应用 DON（84-672nmol/只小鼠）可显著增强皮肤增生和皮肤水肿。DON（336 和 672nmol）可显著增强[（3）H]胸苷在 DNA 中的摄取，并伴有髓过氧化物酶和鸟氨酸脱羧酶活性增加，提示组织炎症和细胞增殖。此外，DON（168nmol）可增强 RAS 的表达和 PI3K/Akt、ERK、JNK 和 p38MAPKs 的磷酸化。DON 暴露还显示转录因子 c-fos、c-jun 和 NF-κB 的激活以及 IkBα 的磷酸化。DON 增强 NF-κB 的磷酸化导致 COX-2、cyclin D1 和 iNOS 等靶蛋白在皮肤中的过度表达。虽然单次经皮应用 DMBA 后每周两次应用 DON（84 和 168nmol），在 24 周后未显示肿瘤发生，但组织病理学研究表明表皮增生和毛囊肥大。有趣的是，还发现肠道受到影响，因为观察到派尔集合淋巴结增大，这表明炎症反应，24 周经皮应用 DON 后炎症细胞因子水平升高支持这一观点。这些结果表明，DON 诱导的小鼠皮肤细胞增殖是通过 MAPK 信号通路的激活实现的，该通路涉及转录因子 NFκB 和 AP-1，进一步导致下游靶蛋白 c-fos、c-jun、cyclin D1、iNOS 和 COX-2 的转录激活，这可能是其炎症潜能的原因。
