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

Shiqi Li,Jinwen Yuan,Siyan Che,Li Zhang,Zheng Ruan,Xiaoming Sun

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. Highlights Long-time exposure to decabromodiphenyl ether (PBDE-209) causes oxidative stress and induced intestinal damage in mice. PBDE-209 induces cell apoptosis via upregulation of FAS expression in Caco-2 cells. PBDE-209 inhibits the Keap1-Nrf2 antioxidant defense pathway in Caco-2 cells.