Aryl-phosphate flame retardants (APFRs), a subcategory of organophosphate flame retardants (OPFRs), are present in a diverse range of materials including plastic, and foam products, furniture, and electronic waste. Despite their widespread use, research on the toxicity of APFRs remains limited. In order to clarify more clearly the environmental and health risks caused by APFRs, this review provides a comprehensive overview of the occurrence and toxicity of four environmental APFRs: triphenyl phosphate (TPHP), 2-ethylhexyl diphenyl phosphate (EHDPP), isobutyl diphenyl phosphate (IDPP), and diphenyl phosphate (DPHP). Regarding the toxicity of APFRs, it seems that EHDPP and TPHP act in different ways in the intestine, but both cause disorders of lipid metabolism in the liver. On the contrary, the toxic effects of EHDPP and IDPP in the liver may be similar, but the specific mechanisms require further study. At the same time, DPHP, as the main biotransformation of APFRs, should receive more attention for its toxicity. Prioritizing the investigation of in vivo transformation products, particularly DPHP and enhancing the study of APFRs' biodegradation are crucial to comprehensively assess the toxicity of APFRs.

The higher prevalence of ulcerative colitis (UC) and the side effects of its therapeutic agents contribute to finding novel treatments. This study aimed to investigate whether kynurenine (KYN), a tryptophan metabolite, has the possibility of alleviating UC and further clarifying the underlying mechanism. The effect of KYN on treating UC was evaluated by intestinal pathology, inflammatory cytokines, and tight-junction proteins in colitis mice and LPS-stimulated Caco-2 cells. Our results revealed that KYN relieved pathological symptoms of UC, improved intestinal barrier function, enhanced AhR expression, and inhibited NF-κB signaling pathway activation in the colon of colitis mice. Moreover, the improved intestinal barrier function, the decreased inflammasome production, and the inhibited activation of the NF-κB signaling pathway by KYN were dependent on AhR in Caco-2 cells. KYN could trigger AhR activation, inactivate the NF-κB signaling pathway, and inhibit NLRP3 inflammasome production, thus alleviating intestinal epithelial barrier dysfunction and reducing intestinal inflammation. In conclusion, the present study reveals that KYN ameliorates UC by improving the intestinal epithelial barrier and activating the AhR-NF-κB-NLRP3 signaling pathway, and it can be a promising therapeutic agent and dietary supplement for alleviating UC.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease characterized by intestinal barrier dysfunction, inflammatory synergistic effects and excessive tissue injury. Gallic acid (GA) is renowned for its remarkable biological activity, encompassing anti-inflammatory and antioxidant properties. However, the underlying mechanisms by which GA protects against intestinal inflammation have not been fully elucidated. The aim of this study is to investigate the effect of GA on the inflammation of a lipopolysaccharide (LPS)-stimulated human colon carcinoma cell line (Caco-2) and on the intestinal barrier dysfunction, and explore the underlying molecular mechanism involved. Our findings demonstrate that 5 mu g/mL GA restores the downregulation of the mRNA and protein levels of Claudin-1, Occludin, and ZO-1 and decreases the expressions of inflammatory factors such as IL-6, IL-1 beta and TNF-alpha induced by LPS. In addition, GA exhibits a protective effect by reducing the LPS-enhanced early and late apoptotic ratios, downregulating the mRNA levels of pro-apoptotic factors ( Bax, Bad, Caspase- 3, Caspase- 8, and Caspase- 9), and upregulating the mRNA levels of anti-apoptotic factor Bcl- 2 in Caco-2 cells. GA also reduces the levels of reactive oxygen species increased by LPS and restores the activity of antioxidant enzymes, namely, superoxide dismutase and catalase, as well as the level of glutathione. More importantly, GA exerts its anti-inflammatory effects by inhibiting the LPS-induced phosphorylation of key signaling molecules in the NF-kappa B/MAPK pathway, including p65, I kappa B-alpha, p38, JNK, and ERK, in Caco-2 cells. Overall, our findings show that GA increases the expressions of tight junction proteins, reduces cell apoptosis, relieves oxidative stress and suppresses the activation of the NF-kappa B/MAPK pathway to reduce LPS-induced intestinal inflammation in Caco-2 cells, indicating that GA has potential as a therapeutic agent for intestinal inflammation.

2-Ethylhexyl diphenyl phosphate (EHDPP) is an organophosphorus type of flame retardant. It is mainly used as a flame-retardant plasticizer in the production of flexible polyvinyl chloride. EHDPP is widely present in environment, particularly in aquatic environment. In this study, we reported that EHDPP exposure significantly affected glucose and lipid metabolism in zebrafish larvae, which was reflected by changes in the transcription of relevant genes and decreased levels of glucose, pyruvate, and triglycerides. In addition, the transcriptomic analysis revealed that the differentially expressed genes could enrich various endpoints in zebrafish larvae. Interestingly, EHDPP exposure could not only change the transcription of genes related to glucolipid metabolism but also cause cardiotoxicity by affecting the transcription of genes related to calcium signaling pathways in zebrafish larvae. To support these findings, we confirmed that these genes involved in cardiac morphology and development were significantly upregulated in zebrafish larvae after EHDPP exposure. More importantly, the distance and overlapping area of the atrium and ventricle were also changed in the EHDPP-exposed zebrafish larvae of transgenic Tg (myl7: EGFP). Overall, our study revealed that EHDPP exposure could affect various endpoints related to glucolipid metabolism and cardiac development in the early developmental stages of zebrafish.

N-(1,3-dimethylbutyl)-N '-phenyl-p-phenylenediamine (6PPD) is a type of p-phenylenediamine (PPD), which is widely used in the manufacture of rubber tires owing to its excellent antiozonant properties. In this study, the developmental cardiotoxicity of 6PPD was evaluated in zebrafish larvae, and the LC50 was approximately 737 mu g/L for the larvae at 96 h post fertilization (hpf). In the 6PPD treatment of 100 mu g/L, the accumulation concentrations of 6PPD were up to 2658 ng/g in zebrafish larvae, and 6PPD induced significant oxidative stress and cell apoptosis in the early developmental stages of zebrafish. Transcriptome analysis showed that 6PPD exposure could potentially cause cardiotoxicity in larval zebrafish by affecting the transcription of the genes related to the calcium signal pathway and cardiac muscle contraction. The genes related to calcium signaling pathway (slc8a2b, cacna1ab, cacna1da, and pln) were verified by qRT-PCR, which were significantly downregulated in larval zebrafish after exposing to 100 mu g/L of 6PPD. Simultaneously, the mRNA levels of the genes related to cardiac functions (myl7, sox9, bmp10, and myh71) also respond accordingly. H&E staining and heart morphology investigation indicated that cardiac malformation occurred in zebrafish larvae exposed to 100 mu g/L of 6PPD. Furthermore, the phenotypic observation of transgenic Tg (myl7: EGFP) zebrafish also confirmed that 100 mu g/L of 6PPD exposure could change the distance of atria and ventricles of the heart and inhibit some key genes (cacnb3a, ATP2a1l, ryr1b) related to cardiac function in larval zebrafish. These results revealed the toxic effects of 6PPD on the cardiac system of zebrafish larvae.

Epoxiconazole (EPX), a triazole fungicide, is widely used in agriculture to control pests and diseases. High residual and occupational exposure to EPX increases health risks, and evidence of potential harm to mammals remains to be added. In the present study, 6-week-old male mice were exposed to 10 and 50 mg/kg bw EPX for 28 days. The results showed that EPX significantly increased the liver weights. EPX also decreased the mucus secretion of the colon and altered intestinal barrier function in mice including a reduced expression of some genes (Muc2, meprinβ, tjp1). Moreover, EPX altered the composition and abundance of gut microbiota in the colon of mice. The alpha diversity indices (Shannon, Simpson) in the gut microbiota increased after exposure to EPX for 28 days. Interestingly, EPX increased the ratio of Firmicutes to Bacteroides and the abundance of other harmful bacteria including Helicobacter and Alistipes. Based on the untargeted metabolomic analysis, it was found that EPX altered the metabolic profiles of the liver in mice. KEGG analysis of differential metabolites revealed that EPX disrupted the pathway related to glycolipid metabolism, and the mRNA levels of related genes were also confirmed. In addition, the correlation analysis showed that the most altered harmful bacteria were associated with some significantly altered metabolites. The findings highlight that EPX exposure changed the micro-environment and lipid metabolism disturbance. These results also suggest that the potential toxicity of triazole fungicides to mammals cannot be ignored.

Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation with no cure. The intestine is fundamental in controlling human health. Disruption of the microbial ecosystem in the intestine is considered an important cause of IBD. The interaction between the host and microbiota significantly impacts the intestinal epithelial barrier and immune function. Bacterial membrane vesicles (MVs) are vital participants in bacteria-bacteria and host-microbiota communication. Currently, MVs have been found to exhibit many important regulating effects for intestinal microecology and have excellent application potential in clinical disease therapies. In the present review, we review the current knowledge on MVs, and specifically focus on gut bacterial MVs and their roles in the IBD. In addition, we summarized the potential utility of MVs as a novel therapeutic approach in IBD patients.

Chlorinated polyfluorinated ether sulfonate (F-53 B) is a distinct substitute for perfluorooctane sulphonate. It has been reported to be biologically toxic to mammals, causing enteric toxicity, liver toxicity and neurotoxicity. However, studies about the effects of F-53 B on patients with gastrointestinal diseases such as inflammatory bowel disease are very limited. In this study, whether the toxic impacts of F-53 B on the gut and liver can be exacerbated in mice with colitis was explored. The sensitivity of mice with acute colitis caused by dextran sulfate sodium salt (DSS) to F-53 B was compared with that of healthy mice. The mice were administered water containing F-53 B at doses of 10 and 100 μg/L sequentially for two weeks, respectively. F-53 B exposure exacerbated DSS-induced colonic inflammation, including inducing shortening of colon length, inflammatory cell infiltration and more severe histopathological symptoms. In addition, F-53 B administration significantly increased the levels of inflammatory cytokines, including interleukin (IL)-1, IL-6 and tumour necrosis factor-α, in the plasma of mice with enteritis compared with control group. F-53 B impaired intestinal integrity of mice with colitis by downregulating Claudin-1 and antimicrobial peptide-related genes while elevating serum lipopolysaccharide levels. In addition, in mice with colitis, F-53 B increased the levels of serum total cholesterol, triglyceride, low-density lipoprotein cholesterol, aspartate aminotransferase, and alanine aminotransferase, resulted in more severe liver inflammation and increased the level of genes related to the Gasdermin D-mediated pyrolysis. Conclusively, our results indicated that F-53 B delayed the self-healing of ulcerative colitis (UC) and caused liver inflammation in mice. This study provided some new insights into the health risks of F-53 B and raises concerns about the health of individuals with UC.

The toxicity of perfluorinated compounds (PFCs) to mammals has recently received increasing attention. However, the effects of maternal sodium p-perfluorous nonenoxybenzene sulfonate (OBS) exposure during pregnancy and lactation on the liver function of dams (F0) and offspring (F1) mice are still unknown. The results demonstrated that maternal OBS treatment could not only induce lipid metabolism dysfunction but also disrupt amino acid metabolism in the liver of F0 and F1 generations. OBS had marked accumulation in the liver, and the serum and liver triglyceride (TG) levels increased in the F0 and F1 generations after maternal OBS exposure. Moreover, maternal OBS exposure changed the transcriptional levels of genes related to lipid metabolism (fatty acid (FA) synthesis, TG synthesis, and transport) and induced changes in the amino acid level in dams and 20-day-old mice offspring (F1-20 d). Additionally, the regulation of lipid metabolism by OBS was mainly dependent on the activation of peroxisome proliferator-activated receptor γ (PPARγ) and cluster of differentiation 36 (CD36). Interestingly, OBS could also disturb tyrosine (TYR) metabolism by increasing the TYR level and downregulating fumarate acetoacetate hydrolase (FAH). Together, these results indicated that the liver can be perceived as the major target tissue of OBS, which strongly affected metabolic function and ultimately led to an imbalance in the metabolism of lipids and TYR. In summary, maternal OBS exposure during pregnancy and lactation has toxic effects on the hepatic metabolism of dams and offspring, indicating that the toxic effects could obviously cross generations of mice, and we should pay more attention to understanding the health risk to both dams and offspring.