Prenatal triphenyl phosphate exposure impairs placentation and induces preeclampsia-like symptoms in mice.

Triphenyl phosphate (TPhP) is an organophosphate flame retardant that is widely used in many commercial products. The United States Environmental Protection Agency has listed TPhP as a priority compound that requires health risk assessment. We previously found that TPhP could accumulate in the placentae of mice and impair birth outcomes by activating peroxisome proliferator-activated receptor gamma (PPARγ) in the placental trophoblast. However, the underlying mechanism remains unknown. In this study, we used a mouse intrauterine exposure model and found that TPhP induced preeclampsia (PE)-like symptoms, including new on-set gestational hypertension and proteinuria. Immunofluorescence analysis showed that during placentation, PPARγ was mainly expressed in the labyrinth layer and decidua of the placenta. TPhP significantly decreased placental implantation depth and impeded uterine spiral artery remodeling by activating PPARγ. The results of the in vitro experiments confirmed that TPhP inhibited extravillous trophoblast (EVT) cell migration and invasion by activating PPARγ and inhibiting the PI3K-AKT signaling pathway. Overall, our data demonstrated that TPhP could activate PPARγ in EVT cells, inhibit cell migration and invasion, impede placental implantation and uterine spiral artery remodeling, then induce PE-like symptom and impair birth outcomes. Although the exposure doses used in this study was several orders of magnitude higher than human daily intake, our study highlights the placenta as a potential target organ of TPhP worthy of further research.

Effects of dietary arsenic exposure on liver metabolism in mice.

Arsenic, a ubiquitous environmental toxicant with various forms and complex food matrix interactions, can reportedly exert differential effects on the liver compared to drinking water exposure. To examine its specific liver-related harms, we targeted the liver in C57BL/6 J mice (n=48, 8-week-old) fed with arsenic-contaminated food (30 mg/kg) for 60 days, mimicking the rice arsenic composition observed in real-world scenarios (iAsV: 7.3%, iAsIII: 72.7%, MMA: 1.0%, DMA: 19.0%). We then comprehensively evaluated liver histopathology, metabolic changes, and the potential role of the gut-liver axis using human hepatocellular carcinoma cells (HepG2) and microbiota/metabolite analyses. Rice arsenic exposure significantly altered hepatic lipid (fatty acids, glycerol lipids, phospholipids, sphingolipids) and metabolite (glutathione, thioneine, spermidine, inosine, indole-derivatives, etc.) profiles, disrupting 33 metabolic pathways (bile secretion, unsaturated fatty acid biosynthesis, glutathione metabolism, ferroptosis, etc.). Pathological examination revealed liver cell necrosis/apoptosis, further confirmed by ferroptosis induction in HepG2 cells. Gut microbiome analysis showed enrichment of pathogenic bacteria linked to liver diseases and depletion of beneficial strains. Fecal primary and secondary bile acids, short-chain fatty acids, and branched-chain amino acids were also elevated. Importantly, mediation analysis revealed significant correlations between gut microbiota, fecal metabolites, and liver metabolic alterations, suggesting fecal metabolites may mediate the impact of gut microbiota and liver metabolic disorders. Gut microbiota and its metabolites may play significant roles in arsenic-induced gut-liver injuries. Overall, our findings demonstrate that rice arsenic exposure triggers oxidative stress, disrupts liver metabolism, and induces ferroptosis.

Design of a Robust Synchronization-Based Topology Observer for Complex Delayed Networks with Fixed and Adaptive Coupling Strength.

Network topology plays a key role in determining the characteristics and dynamical behaviors of a network. But in practice, network topology is sometimes hidden or uncertain ahead of time because of network complexity. In this paper, a robust-synchronization-based topology observer (STO) is proposed and applied to solve the problem of identifying the topology of complex delayed networks (TICDNs). In comparison to the existing literature, the proposed STO does not require any prior knowledge about the range of topological parameters and does not have strict limits on topology type. Furthermore, the proposed STO is suitable not only for networks with fixed coupling strength, but also for networks with adaptive coupling strength. Finally, a few comparison examples for TICDNs are used to verify the feasibility and efficiency of the proposed STO, and the results show that the proposed STO outperforms the other methods.

Small animal PET imaging with the 68Ga-labeled pH (low) insertion peptide-like peptide YJL-4 in a triple-negative breast cancer mouse model.

BACKGROUND: The aim of this study was to prepare a novel 68Ga-labeled pH (low) insertion peptide (pHLIP)-like peptide, YJL-4, and determine its value for the early diagnosis of triple-negative breast cancer (TNBC) via in vivo imaging of tumor-bearing nude mice. The novel peptide YJL-4 was designed using a template-assisted method and synthesized by solid-phase peptide synthesis. After modification with the chelator 1,4,7­triazacyclononane-N,N',N″-triacetic acid (NOTA), the peptide was labeled with 68Ga. Then, the biodistribution of 68Ga-YJL-4 in tumor-bearing nude mice was investigated, and the mice were imaged by small animal positron emission tomography (PET). RESULTS: The radiochemical yield and radiochemical purity of 68Ga-YJL-4 were 89.5 ± 0.16% and 97.95 ± 0.06%, respectively. The biodistribution of 68Ga-YJL-4 in tumors (5.94 ± 1.27% ID/g, 6.72 ± 1.69% ID/g and 4.54 ± 0.58% ID/g at 1, 2 and 4 h after injection, respectively) was significantly greater than that of the control peptide in tumors at the corresponding time points (P < 0.01). Of the measured off-target organs, 68Ga-YJL-4 was highly distributed in the liver and blood. The small animal PET imaging results were consistent with the biodistribution results. The tumors were visualized by PET at 2 and 4 h after the injection of 68Ga-YJL-4. No tumors were observed in the control group. CONCLUSIONS: The novel pHLIP family peptide YJL-4 can adopt an α-helical structure for easy insertion into the cell membrane in an acidic environment. 68Ga-YJL-4 was produced in high radiochemical yield with good stability and can target TNBC tissue. Moreover, the strong concentration of radioactive 68Ga-YJL-4 in the abdomen does not hinder the imaging of early TNBC.