Proteomics Laboratory, Indian Institute of Toxicology Research, Council of Scientific & Industrial Research (CSIR), India.
J Toxicol Sci. 2013;38(4):629-42. doi: 10.2131/jts.38.629.
Deltamethrin, a pyrethroid insecticide, used extensively for pest control has been reported to cause adverse health effects including carcinogenic/toxic effects in animals but the underlying mechanism remains elusive. In the present study, we investigated the effect of deltamethrin after short exposure on early protein expression changes involved in neoplastic transformation in mouse skin, validated the results in human keratinocyte HaCaT cells and thereby explore the possible underlying mechanism. Deltamethrin (4 mg/kg b.wt) and benzo[a]pyrene (B[a]P, 0.05 mg/kg b.wt) were topically applied on Swiss albino mice, respectively. The comparative protein expression profiles with vehicle control were generated by 2-dimensional gel electrophoresis (2-DE) and mass spectrometry. 2-DE maps of deltamethrin and B[a]P treated mouse skin showed 20 and 24 significant (2 fold change, p < 0.05) differentially expressed protein spots, against vehicle controls. However, comparison between them showed relatively similar expression level of 20 spots. Among them, 5 proteins (carbonic anhydrase III, peroxiredoxin-2, calcyclin, superoxide dismutase [Cu-Zn], ubiquitin) are of particular significance as these are involved in cancer-related key processes. Deregulation of these was confirmed at protein and mRNA levels by immunoblotting and RT-PCR in mouse skin and HaCaT cells. Therefore, we conclude that these preliminarily identified proteins might be responsible for the neoplastic transformation of mouse skin epidermal cells and HaCaT cells by deltamethrin. This study proposes complementary mechanism where inhibition of proteasome activator protein (PA200) is responsible for accumulation of ubiquitinated-calcyclin, regulates deltamethrin-induced neoplastic changes in mouse skin and HaCaT cells.
溴氰菊酯是一种广泛用于害虫防治的拟除虫菊酯杀虫剂，据报道它会对动物造成不良健康影响，包括致癌/毒性作用，但潜在机制仍不清楚。在本研究中，我们研究了短时间暴露于溴氰菊酯后对小鼠皮肤肿瘤转化早期相关蛋白表达变化的影响，在人角质形成细胞 HaCaT 细胞中验证了结果，从而探索了可能的潜在机制。分别用溴氰菊酯（4mg/kg 体重）和苯并[a]芘（B[a]P，0.05mg/kg 体重）对瑞士白化小鼠进行局部给药。用二维凝胶电泳（2-DE）和质谱法生成与载体对照的比较蛋白质表达谱。溴氰菊酯和 B[a]P 处理的小鼠皮肤的 2-DE 图谱显示 20 和 24 个显著（2 倍变化，p<0.05）差异表达的蛋白质斑点，与载体对照相比。然而，它们之间的比较显示相对相似的 20 个斑点的表达水平。其中，5 种蛋白质（碳酸酐酶 III、过氧化物还原酶-2、钙调蛋白、超氧化物歧化酶[Cu-Zn]、泛素）具有特别重要的意义，因为它们参与了癌症相关的关键过程。在小鼠皮肤和 HaCaT 细胞中，通过免疫印迹和 RT-PCR 证实了这些蛋白质的下调，并在蛋白质和 mRNA 水平上得到了证实。因此，我们得出结论，这些初步鉴定的蛋白质可能是溴氰菊酯导致小鼠皮肤表皮细胞和 HaCaT 细胞发生肿瘤转化的原因。本研究提出了一种补充机制，即蛋白酶体激活蛋白（PA200）抑制剂负责泛素化钙调蛋白的积累，调节溴氰菊酯诱导的小鼠皮肤和 HaCaT 细胞的肿瘤变化。
