十溴二苯醚通过 Keap1-Nrf2 通路诱导 ROS 介导的肠道毒性,Journal of Biochemical and Molecular Toxicology

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十溴二苯醚通过 Keap1-Nrf2 通路诱导 ROS 介导的肠道毒性
Journal of Biochemical and Molecular Toxicology ( IF 3.2 ) Pub Date : 2022-03-09 , DOI: 10.1002/jbt.22995
Shiqi Li ₁ , Jinwen Yuan ₁ , Siyan Che ₁ , Li Zhang ₁ , Zheng Ruan ₁ , Xiaoming Sun ₁

Affiliation

多溴二苯醚 (PBDEs) 是作为商业产品广泛使用的溴化阻燃剂。PBDEs 已被证明可诱导肝脏、生殖、神经和甲状腺毒性作用。本研究旨在阐明十溴二苯醚 (PBDE-209) 在体内和体外的潜在肠道毒性作用。首先，我们研究了 PBDE-209 对小鼠肠道氧化应激的影响。随后，研究了 PBDE-209 在体外的潜在毒性机制。Caco-2 细胞用不同浓度的 PBDE-209（1、5 和 25 μmol/L）处理 24 和 48 小时。我们确定了细胞活力、活性氧 (ROS) 水平、多个细胞参数和相对 mRNA 表达。结果表明，PBDE-209显着损伤小鼠结肠，增加肠道丙二醛（MDA）水平，改变抗氧化酶活性。PBDE-209 抑制 Caco-2 细胞的增殖和诱导细胞毒性。ROS 产生和线粒体膜电位 (MMP) 的变化表明 PBDE-209 在 Caco-2 细胞中引起氧化应激。实时荧光定量 PCR 分析显示 PBDE-209 抑制抗氧化防御因子、核因子红细胞 2 相关因子 2 (Nrf2) 的 mRNA 表达水平。此外，FAS 和细胞色素 P450 1A1 (CYP1A1) mRNA 表达水平在 Caco-2 细胞中增加。这些结果表明，PBDE-209 在体内和体外均具有肠道毒性作用，并抑制 Caco-2 细胞中抗氧化防御基因的表达。

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Decabromodiphenyl ether induces ROS-mediated intestinal toxicity through the Keap1-Nrf2 pathway

Polybrominated diphenyl ethers (PBDEs) are widely used brominated flame retardants as commercial products. PBDEs have been demonstrated to induce hepatic, reproductive, neural, and thyroid toxicity effects. This study aimed to clarify the potential intestinal toxicity effects of decabrominated diphenyl ether (PBDE-209) in vivo and in vitro. First, we investigated the change of PBDE-209 on oxidative stress in the intestine of mice. Subsequently, the potential toxicity mechanism of PBDE-209 in vitro was investigated. Caco-2 cells were treated with different concentrations of PBDE-209 (1, 5, and 25 μmol/L) for 24 and 48 h. We determined the cell viability, reactive oxygen species (ROS) level, multiple cellular parameters, and relative mRNA expressions. The results showed that PBDE-209 significantly injured the colon of mice, increased the intestinal levels of malondialdehyde (MDA), and changed the antioxidant enzyme activities. PBDE-209 inhibited the proliferation and induced cytotoxicity of Caco-2 cells. The change in ROS production and mitochondrial membrane potential (MMP) revealed that PBDE-209 caused oxidative stress in Caco-2 cells. The real-time PCR assays revealed that PBDE-209 inhibited the mRNA expression level of antioxidative defense factor, nuclear factor erythroid 2-related factor 2 (Nrf2). Furthermore, the FAS and Cytochrome P450 1A1 (CYP1A1) mRNA expression levels were increased in Caco-2 cells. These results suggested that PBDE-209 exerts intestinal toxicity effects in vivo and in vitro and inhibits the antioxidative defense gene expression in Caco-2 cells. This study provides an opportunity to advance the understanding of toxicity by the persistent environmental pollutant PBDE-209 to the intestine.

更新日期：2022-03-09

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