PMID- 37804762 OWN - NLM STAT- MEDLINE DCOM- 20231023 LR - 20231030 IS - 1873-3336 (Electronic) IS - 0304-3894 (Linking) VI - 461 DP - 2024 Jan 5 TI - 1,2-bis(2,4,6-tribromophenoxy) ethane, a novel brominated flame retardant, disrupts intestinal barrier function via the IRX3/NOS2 axis in rat small intestine. PG - 132597 LID - S0304-3894(23)01880-0 [pii] LID - 10.1016/j.jhazmat.2023.132597 [doi] AB - Novel brominated flame retardants are widely used in electronics, textiles, furniture, and other products; they can enter the human body through ingestion and respiration and cause harm to the human body, and have been proven to have potential biological toxicity and accumulation effects. 1,2-bis(2,4,6-tribromophenoxy) ethane (BTBPE) is a widely used novel brominated flame retardant; however, there is a lack of research on its mechanism of toxicity, particularly that of intestinal toxicity. Currently, studies on the functionality of iroquois homeobox 3 (IRX3) are extremely limited. In our study, BTBPE was administered to Sprague-Dawley (SD) rats and rat small intestinal crypt epithelial cells (IEC6 cells) in vivo and in vitro, respectively, and hematoxylin and eosin (HE), immunohistochemical, Alcian blue-periodic acid-Schiff (AB-PAS), CCK8, acridine orange/ethidium bromide (AO/EB), fluorescent probes, qPCR, western blotting, and immunofluorescence analyses were performed. To explore the damage mechanism of BTBPE, we used siRNA to silence IRX3 and iNOs-IN-1 (yeast extract-peptone-wheat; YPW) to inhibit nitric oxide synthase 2 (NOS2). The results showed that BTBPE exposure caused inflammation and necroptosis in the jejunum and ileum, as well as destruction of the tight junctions and mucus layer. Moreover, BTBPE activated the IRX3/NOS2 axis both in vivo and in vitro. Silencing IRX3 or inhibiting NOS2 inhibits necroptosis and restores tight junctions in IEC6 cells. In conclusion, our study found that in the jejunum, ileum, and IEC6 cells, BTBPE exposure caused necroptosis and tight junction destruction by activating the IRX3/NOS2 axis. Blocking the IRX3/NOS2 axis can effectively inhibit necroptosis and restore tight junction. In addition, BTBPE exposure caused inflammation and loss of the mucous layer in the jejunum and ileum. Our study is the first to explore the mechanism of intestinal damage caused by BTBPE exposure and to discover new biological functions regulated by the IRX3/NOS2 axis, providing new research directions for necroptosis and tight junctions. CI - Copyright (c) 2023 Elsevier B.V. All rights reserved. FAU - Cui, Yuan AU - Cui Y AD - Department of Toxicology, School of Public Health, Peking University, Beijing 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing 100191, PR China. FAU - Xiao, Qianqian AU - Xiao Q AD - Department of Toxicology, School of Public Health, Peking University, Beijing 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing 100191, PR China. FAU - Wang, Zhenyu AU - Wang Z AD - Department of Toxicology, School of Public Health, Peking University, Beijing 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing 100191, PR China. FAU - Zhang, Qiong AU - Zhang Q AD - Department of Toxicology, School of Public Health, Peking University, Beijing 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing 100191, PR China. FAU - Liu, Yuetong AU - Liu Y AD - Department of Toxicology, School of Public Health, Peking University, Beijing 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing 100191, PR China. FAU - Hao, Weidong AU - Hao W AD - Department of Toxicology, School of Public Health, Peking University, Beijing 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing 100191, PR China. FAU - Jiang, Jianjun AU - Jiang J AD - Department of Toxicology, School of Public Health, Peking University, Beijing 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing 100191, PR China. FAU - Meng, Qinghe AU - Meng Q AD - Department of Toxicology, School of Public Health, Peking University, Beijing 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing 100191, PR China. FAU - Wei, Xuetao AU - Wei X AD - Department of Toxicology, School of Public Health, Peking University, Beijing 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing 100191, PR China. Electronic address: weixt@bjmu.edu.cn. LA - eng PT - Journal Article DEP - 20230921 PL - Netherlands TA - J Hazard Mater JT - Journal of hazardous materials JID - 9422688 RN - 0 (Flame Retardants) RN - L99N5N533T (Ethane) RN - 0 (Halogenated Diphenyl Ethers) RN - 0 (Hydrocarbons, Brominated) RN - EC 1.14.13.39 (NOS2 protein, human) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type II) RN - 0 (IRX3 protein, human) RN - 0 (Transcription Factors) RN - 0 (Homeodomain Proteins) SB - IM MH - Rats MH - Humans MH - Animals MH - *Flame Retardants/toxicity/analysis MH - Ethane/analysis MH - Rats, Sprague-Dawley MH - Inflammation MH - Intestine, Small/chemistry MH - Halogenated Diphenyl Ethers/analysis MH - *Hydrocarbons, Brominated/analysis MH - Environmental Monitoring MH - Nitric Oxide Synthase Type II MH - Transcription Factors MH - Homeodomain Proteins/genetics OTO - NOTNLM OT - BTBPE OT - IRX3 OT - Intestinal barrier OT - NOS2 OT - Necroptosis OT - Tight junction COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/10/08 02:42 MHDA- 2023/10/23 01:18 CRDT- 2023/10/07 18:09 PHST- 2023/07/04 00:00 [received] PHST- 2023/09/15 00:00 [revised] PHST- 2023/09/19 00:00 [accepted] PHST- 2023/10/23 01:18 [medline] PHST- 2023/10/08 02:42 [pubmed] PHST- 2023/10/07 18:09 [entrez] AID - S0304-3894(23)01880-0 [pii] AID - 10.1016/j.jhazmat.2023.132597 [doi] PST - ppublish SO - J Hazard Mater. 2024 Jan 5;461:132597. doi: 10.1016/j.jhazmat.2023.132597. Epub 2023 Sep 21.