Food Toxicology Division, Food, Drug, and Chemical Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India.; Academy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of Toxicology Research Campus, (CSIR-IITR), Lucknow 226001, Uttar Pradesh, India.
Food Toxicology Division, Food, Drug, and Chemical Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India.
Toxicol Appl Pharmacol. 2018 Oct 1;356:224-234. doi: 10.1016/j.taap.2018.08.009. Epub 2018 Aug 20.
Patulin (PAT), a mycotoxin, is a natural contaminant that is produced by certain species of Penicillium, Aspergillus and Byssochlamys. The major contamination of PAT is in apple and apple based products. PAT is known to cause glutathione depletion, oxidative DNA damage and cell proliferation. Recently, in vitro studies have indicated that PAT can also increase the intestinal epithelial permeability, modulate tight junctions and decrease transepithelial electrical resistance. Nonetheless, no previous study has evaluated the mechanisms responsible for PAT-induced intestinal toxicity or its relevance to the in vivo situation. Here, Wistar rats were orally treated with 100 μg/kg body weight (b.wt.) of PAT, either alone or along with 100 mg/kg b. wt. of celecoxib for 3 days. We found that PAT exposure led to significantly higher levels of PGE in serum and intestinal tissue and high expression of COX-2 and Ki-67 compared to controls. Interestingly, our results showed that celecoxib treatment could decrease the PAT-induced PGE and reduce the PAT-induced intestinal damage. To study the mechanistic aspect, normal rat intestinal epithelial cells (IEC-6) were treated with non-toxic concentrations (100 nM, 250 nM and 500 nM) of PAT for 6 h. It was observed that PAT exposure caused enhanced proliferation, higher expression of COX-2, and EP2 and EP4 receptors, along with increased PGE secretion. Additionally, PAT exposure caused enhanced Akt expression, which in turn inhibits GSK-3β and stabilizes β-catenin. Overall, our study suggests that the COX-2/EP2-EP4/β-catenin signaling cascades are involved in the regulation of PAT-induced intestinal cell proliferation and inflammation.
棒曲霉素（PAT）是一种真菌毒素，由某些青霉、曲霉和蝙蝠蛾属真菌产生。PAT 的主要污染来源是苹果及其制品。PAT 已知会导致谷胱甘肽耗竭、氧化 DNA 损伤和细胞增殖。最近，体外研究表明，PAT 还可以增加肠道上皮细胞通透性，调节紧密连接，降低跨上皮电阻。然而，以前没有研究评估过 PAT 诱导的肠道毒性的机制及其与体内情况的相关性。在这里，Wistar 大鼠口服给予 100μg/kg 体重（b.wt.）的 PAT，单独或与 100mg/kg b.wt.的塞来昔布连用 3 天。我们发现，与对照组相比，PAT 暴露导致血清和肠道组织中的 PGE 水平显著升高，COX-2 和 Ki-67 的表达水平也显著升高。有趣的是，我们的结果表明，塞来昔布治疗可以降低 PAT 诱导的 PGE 并减轻 PAT 诱导的肠道损伤。为了研究机制方面，用无毒浓度（100nM、250nM 和 500nM）的 PAT 处理正常大鼠肠上皮细胞（IEC-6）6 小时。结果观察到，PAT 暴露导致增殖增强、COX-2 以及 EP2 和 EP4 受体表达增加，同时 PGE 分泌增加。此外，PAT 暴露导致 Akt 表达增强，进而抑制 GSK-3β并稳定β-连环蛋白。总体而言，我们的研究表明，COX-2/EP2-EP4/β-连环蛋白信号通路参与了 PAT 诱导的肠道细胞增殖和炎症的调节。
