RESUMO
Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is an organophosphorus flame retardant that has been utilized in recent years as a primary replacement for polybrominated diphenyl ethers (PBDEs) in a wide variety of fire-sensitive applications. However, the impact of TDCPP on the immune system has not been fully determined. As the largest secondary immune organ in the body, the spleen is considered to be an important study endpoint for determining immune defects in the body. The aim of this study is to investigate the effect of TDCPP toxicity on the spleen and its possible molecular mechanisms. In this study, for 28 consecutive days, TDCPP was administered intragastrically (i.g), and we assessed the general condition of mice by evaluating their 24 h water and food intake. Pathological changes in spleen tissues were also evaluated at the end of the 28-day exposure. To measure the TDCPP-induced inflammatory response in the spleen and its consequences, the expression of the critical players in the NF-κB pathway and mitochondrial apoptosis were detected. Lastly, RNA-seq was performed to identify the crucial signaling pathways of TDCPP-induced splenic injury. The results showed that TDCPP intragastric exposure triggered an inflammatory response in the spleen, likely through activating the NF-κB/IFN-γ/TNF-α/IL-1ß pathway. TDCPP also led to mitochondrial-related apoptosis in the spleen. Further RNA-seq analysis suggested that the TDCPP-mediated immunosuppressive effect is associated with the inhibition of chemokines and the expression of their receptor genes in the cytokine-cytokine receptor interaction pathway, including four genes of the CC subfamily, four genes of the CXC subfamily, and one gene of the C subfamily. Taken together, the present study identifies the sub-chronic splenic toxicity of TDCPP and provides insights on the potential mechanisms of TDCPP-induced splenic injury and immune suppression.
RESUMO
An average daily increase of 10 µg/m3 in NO2 concentrations could lead to an increased mortality in cardiovascular, cerebrovascular of 1.89%, 2.07%, but the mechanism by which NO2 contributes to cardiotoxicity is rarely reported. In order to assess the cardiotoxicity of NO2 inhalation (5 ppm), we firstly investigate the change of gut microbiota, serum metabonomics and cardiac proteome. Non-targeted LC-MS/MS metabonomics showed that NO2 stress could perturb the glycerophospholipid metabolism in the serum, which might destabilize the bilayer configuration of cardiac lipid membranes. Furthermore, we observed that NO2 inhalation caused augmented intercellular gap and inflammatory infiltration in the heart. Although 16 S rRNA gene amplification sequencing demonstrated that NO2 exposure did not influence the intestinal microbial abundance and diversity, but glycerophospholipid metabolism disruption might be finally reflected in gut microbiom dysregulation, such as Sphingomonas, Koribacter, Actinomarina and Bradyrhizobium Turicibacter, Rothia, Globicatella and Aerococcus. Proteome mining revealed that differentially expressed genes (DEGs) in the heart after NO2 stress were involved in necroptosis, mitophagy and ferroptosis. We further revealed that NO2 increased the number of cardiac mitochondria with depletion of cristae by regulating the expression of Mfn2 and Hsp70. This study indicating Mfn2-meidcated imbalanced mitochondrial dynamics as a potential mechanism after NO2-induced heart injury and suggesting microbiome dysregulation/glycerophospholipid metabolism exerts critical roles in cardiotoxicity caused by NO2.
