Network pharmacology was used to illuminate the targets and pathways of polybrominated diphenyl ethers (PBDEs) causing thyroid dysfunction. A protein-protein interaction (PPI) network was constructed. Molecular docking was applied to analyze PBDEs and key targets according to the network pharmacology results. A total of 247 targets were found to be related to 16 PBDEs. Ten key targets with direct action were identified, including the top five PIK3R1, MAPK1, SRC, RXRA, and TP53. Gene Ontology (GO) functional enrichment analysis identified 75 biological items. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis identified 62 pathways mainly related to the regulation of the thyroid hormone signaling pathway, MAPK signaling pathway, PI3K-Akt signaling, pathways in cancer, proteoglycans in cancer, progesterone-mediated oocyte maturation, and others. The molecular docking results showed that BDE-99, BDE-153, 5-OH-BDE47, 5 ′ -OH-BDE99, 5-BDE47 sulfate, and 5 ′ -BDE99 sulfate have a good binding effect with the kernel targets. PBDEs could interfere with the thyroid hormone endocrine through multiple targets and biological pathways, and metabolites demonstrated stronger effects than the prototypes. This research provides a basis for further research on the toxicological effects and molecular mechanisms of PBDEs and their metabolites. Furthermore, the application of network pharmacology to the study of the toxicity mechanisms of environmental pollutants provides a new methodology for environmental toxicology.

Polychlorinated biphenyls (PCBs) are persistent and highly toxic pollutants, which can accumulate in organisms and produce toxic effects, especially damaging the function of thyroid hormones. So far, the molecular mechanism of PCBs mixture and their metabolites interfering with thyroid hormones has not been studied thoroughly except for individual compounds. In this study, PubMed, Web of Science, and STITCH databases were used to search PCBs and their corresponding target proteins. The intersection of PCBs and thyroid hormone dysfunction target proteins was obtained from GeneCards. The “compounds-targets-pathways” network was constructed by Cytoscape software. And KEGG and Go analyses were performed for key targets. Finally, molecular docking was used to verify the binding effect. Four major active components, five key targets, and 10 kernel pathways were successfully screened by constructing the network. Functional enrichment analysis showed that the interference was mediated by cancer, proteoglycans, PI3K-Akt, thyroid hormone, and FoxO signaling pathways. The molecular docking results showed that the binding energies were less than -5 kcal·mol-1. PCBs and their metabolites may act on the key targets of MAPK3, MAPK1, RXRA, PIK3R1, and TP53. The toxic effect of sulfated and methyl sulfone PCBs is greater. The method of screening targets based on the simultaneous action of multiple PCBs can provide a reference for other research. The targets were not found in previous metabolite toxicity studies. It also provides a bridge for the toxic effects and experimental research of PCBs and their metabolites in the future.

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Marein is the main active compound of Coreopsis tinctoria Nutt., and its main activities include antioxidant, hypoglycemic, and hypotensive. After oral administration of marein, the blood concentration of marein is low. The metabolites of marein have not been reported systematically. In this study, a rapid and systematic method based on ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS) was established to detect metabolites of marein in vivo (plasma and urine) after oral administration and injection. Sixty-one metabolites were identified. The metabolites are formed through a wide range of metabolic reactions, including hydroxylation, glucuronidation, methylation, hydrolysis, and desorption of hydrogen. The liver microsome incubation was further used to investigate the metabolic rate of marein. Network pharmacology was applied to study the targets and pathways of marein and its metabolites. Marein and its metabolites act on the same targets to enhance the therapeutic effect. This research illuminates the metabolites and metabolic reaction of marein and establishes a basis for the development and rational utilization of C. tinctoria. Meanwhile, the analysis of prototype and metabolites together by network pharmacology techniques could provide a methodology for the study of component activity.