Details

Autor(en) / Beteiligte

• Cui, Yuan
• Xiao, Qianqian
• Wang, Zhenyu
• Zhang, Qiong
• Liu, Yuetong
• Hao, Weidong
• Jiang, Jianjun
• Meng, Qinghe
• Wei, Xuetao

Titel

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

Ist Teil von

• Journal of hazardous materials, 2024-01, Vol.461, p.132597-132597, Article 132597

Ort / Verlag

Elsevier B.V

Erscheinungsjahr

2024

Quelle

Access via ScienceDirect (Elsevier)

Beschreibungen/Notizen

• 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. BTBPE is widely present in natural environments, including water, air, and soil, as well as in daily life-associated activities. Widespread exposure and long-term accumulation of BTBPE make it impossible to ignore its toxic effects. The digestive tract is a common route of BTBPE exposure. However, there is currently a lack of research on the mechanisms underlying the intestinal toxicity of BTBPE. Our study is the first to explore the mechanism of intestinal damage caused by BTBPE exposure and discover new biological functions regulated by the IRX3/NOS2 axis. [Display omitted] •The mechanism of BTBPE intestinal toxicity has been explored for the first time.•BTBPE caused inflammation, necroptosis, and destruction of tight junction and mucus layer in rat small intestine.•Activation of the IRX3/NOS2 axis leading to necroptosis was first discovered.•It was first found that the activation of IRX3/NOS2 axis would destroy the tight junction.•NOS2 is a key downstream gene that IRX3 plays roles in inducing necroptosis and destroying tight junction.