{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T03:32:48Z","timestamp":1792726368788,"version":"4.5.0"},"reference-count":41,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,5,31]],"date-time":"2021-05-31T00:00:00Z","timestamp":1622419200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["41991314"],"award-info":[{"award-number":["41991314"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>A representative congener of polybrominated diphenyl ethers in the environment, 2,2\u2032,4,4\u2032-tetrabromodiphenyl ether (BDE-47), is associated with male reproductive toxicity, yet the underlying mechanisms remain largely unclear. In this study, mice were administered environmentally relevant concentrations of BDE-47 for six weeks. Histopathological observations showed that BDE-47 induced inflammatory reactions and damaged the testes. By conducting an integrated proteomic and metabolomic analysis coupled with a bioinformatic analysis using ingenuity pathway analysis (IPA) methods, we found that BDE-47 mainly affected the molecules involved in free radical scavenging, cell death and survival, neurological disease, and inflammatory response. IPA canonical pathways showed inflammatory and apoptosis pathways, including hepatic fibrosis\/hepatic stellate cell activation, the GP6 signaling pathway, tight junction signaling, acute phase response signaling, LXR\/RXR activation, unfolded protein response, and FXR\/RXR activation, which are related to male reproductive toxicity. Key transcriptional regulator networks were activated via a focus on upstream regulator analysis. The expression of MYC and Clu as the core transcriptional factor and targeted protein, respectively, was verified. It is further proposed that MYC may contribute to the etiology of male reproductive toxicity. These findings will improve our understanding of the mechanisms responsible for BDE-47-induced male reproductive toxicity, which may promote the discovery of useful biomarkers indicative of BDE-47 exposure.<\/jats:p>","DOI":"10.3390\/biom11060821","type":"journal-article","created":{"date-parts":[[2021,5,31]],"date-time":"2021-05-31T21:42:06Z","timestamp":1622497326000},"page":"821","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Integrated Proteomic and Metabolomic Analysis of the Testes Characterizes BDE-47-Induced Reproductive Toxicity in Mice"],"prefix":"10.3390","volume":"11","author":[{"given":"Liang","family":"Xu","sequence":"first","affiliation":[{"name":"School of Public Health, Hongqiao International Institute of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China"},{"name":"Shanghai Integrated Biotech Solutions Co., Ltd., Shanghai 201100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songyan","family":"Gao","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Shanghai University, Shanghai 200444, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongxia","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Medicine, Shanghai University, Shanghai 200444, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liupeng","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Public Health, Hongqiao International Institute of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiyi","family":"Cao","sequence":"additional","affiliation":[{"name":"School of Public Health, Hongqiao International Institute of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Xi","sequence":"additional","affiliation":[{"name":"School of Public Health, Hongqiao International Institute of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3472-8393","authenticated-orcid":false,"given":"Xinyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Public Health, Hongqiao International Institute of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Dong","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Shanghai University, Shanghai 200444, China"},{"name":"School of Medicine, Shanghai University, Shanghai 200444, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2211-7803","authenticated-orcid":false,"given":"Yang","family":"Luan","sequence":"additional","affiliation":[{"name":"School of Public Health, Hongqiao International Institute of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1021\/es035082g","article-title":"Polybrominated Diphenyl Ethers in the Environment and in People: A Meta-Analysis of Concentrations","volume":"38","author":"Hites","year":"2004","journal-title":"Environ. Sci. Technol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1016\/j.envpol.2011.02.054","article-title":"Polybrominated diphenyl ethers (PBDEs) and alternative brominated flame retardants in air and seawater of the European Arctic","volume":"159","author":"Xie","year":"2011","journal-title":"Environ. Pollut."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1016\/j.envpol.2017.07.009","article-title":"Critical review of soil contamination by polybrominated diphenyl ethers (PBDEs) and novel brominated flame retardants (NBFRs); concentrations, sources and congener profiles","volume":"230","author":"McGrath","year":"2017","journal-title":"Environ. Pollut."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5744","DOI":"10.1007\/s11356-020-07598-7","article-title":"Levels and distribution of polybrominated diphenyl ethers in humans and environmental compartments: A comprehensive review of the last five years of research","volume":"27","year":"2020","journal-title":"Environ. Sci. Pollut. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"109531","DOI":"10.1016\/j.envres.2020.109531","article-title":"Exposure pathways, levels and toxicity of polybromin-ated diphenyl ethers in humans: A review","volume":"187","author":"Wu","year":"2020","journal-title":"Environ. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.tox.2017.07.006","article-title":"Peri-natal exposure to 2,2\u2032,4\u2032,4\u2032-Tetrabromodiphenyl ether induces testicular toxicity in adult rats","volume":"389","author":"Khalil","year":"2017","journal-title":"Toxicology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"087016","DOI":"10.1289\/EHP826","article-title":"A Human Mixture Risk Assessment for Neurodevelopmental Toxicity Associated with Polybrominated Diphenyl Ethers Used as Flame Retardants","volume":"125","author":"Martin","year":"2017","journal-title":"Environ. Health Perspect."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.marpolbul.2011.02.008","article-title":"Polybrominated diphenyl ethers and their hydroxylated\/methoxylated analogs: Environmental sources, metabolic relationships, and relative toxicities","volume":"63","author":"Wiseman","year":"2011","journal-title":"Mar. Pollut. Bull."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/S0160-4120(03)00123-5","article-title":"Environmental release and behavior of brominated flame retardants","volume":"29","author":"Watanabe","year":"2004","journal-title":"Environ. Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5003","DOI":"10.1021\/es104344e","article-title":"Genotoxicity of Several Polybrominated Diphenyl Ethers (PBDEs) and Hydroxylated PBDEs, and Their Mechanisms of Toxicity","volume":"45","author":"Ji","year":"2011","journal-title":"Environ. Sci. Technol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1093\/toxsci\/kfp296","article-title":"Comparative cytotoxicity and intracellular accumulation of five polybro-minated diphenyl ether congeners in mouse cerebellar granule neurons","volume":"114","author":"Huang","year":"2010","journal-title":"Toxicol. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1016\/j.reprotox.2011.02.005","article-title":"Polybrominated diphenyl ethers and sperm quality","volume":"31","author":"Abdelouahab","year":"2011","journal-title":"Reprod. Toxicol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1289\/ehp.0901450","article-title":"PBDE concentrations in women\u2019s serum and fecundability","volume":"118","author":"Harley","year":"2010","journal-title":"Environ. Health Perspect."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s00128-012-0867-5","article-title":"Adverse effects of 2, 2\u2032, 4, 4\u2032-tetrabromodiphenyl ether on se-men quality and spermatogenesis in male mice","volume":"90","author":"Wang","year":"2013","journal-title":"Bull. Environ. Contam. Toxicol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.reprotox.2015.01.009","article-title":"2,2\u2032,4,4\u2032-Tetrabromodiphenyl ether disrupts spermatogenesis, impairs mitochondrial function and induces apoptosis of early leptotene spermatocytes in rats","volume":"51","author":"Huang","year":"2015","journal-title":"Reprod. Toxicol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"137419","DOI":"10.1016\/j.scitotenv.2020.137419","article-title":"Toxicity of polybrominated diphenyl ethers (PBDEs) on rodent male reproductive system: A systematic review and meta-analysis of randomized control studies","volume":"720","author":"Zhang","year":"2020","journal-title":"Sci. Total Environ."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Zhang, Z., Zhang, X., Sun, Z., Dong, H., Qiu, L., Gu, J., Zhou, J., Wang, X., and Wang, S.L. (2013). Cytochrome P450 3A1 medi-ates 2, 2\u2032, 4, 4\u2032-tetrabromodiphenyl ether-induced reduction of spermatogenesis in adult rats. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0066301"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"7896","DOI":"10.1021\/es200422b","article-title":"Polybrominated Diphenyl Ethers, Hydroxylated Polybrominated Diphenyl Ethers, and Measures of Thyroid Function in Second Trimester Pregnant Women in California","volume":"45","author":"Zota","year":"2011","journal-title":"Environ. Sci. Technol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1002\/etc.2562","article-title":"En-docrine disruption and reproduction impairment in zebrafish after long-term exposure to DE-71","volume":"33","author":"Yu","year":"2014","journal-title":"Environ. Toxicol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1038\/10343","article-title":"Systematic determination of genetic network architecture","volume":"22","author":"Tavazoie","year":"1999","journal-title":"Nat. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1080\/004982599238047","article-title":"\u2018Metabonomics\u2019: Understanding the metabolic responses of living sys-tems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data","volume":"29","author":"Nicholson","year":"1999","journal-title":"Xenobiotica"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.cca.2020.04.015","article-title":"Recent advances in robotic protein sample preparation for clinical analysis and other biomedical applications","volume":"507","author":"Urban","year":"2020","journal-title":"Clin. Chim. Acta"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1093\/chromsci\/bmw167","article-title":"Proteomics: Technologies and Their Applications","volume":"55","author":"Aslam","year":"2017","journal-title":"J. Chromatogr. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5293","DOI":"10.1021\/pr500880b","article-title":"Isobaric labeling-based relative quantification in shotgun proteomics","volume":"13","author":"Rauniyar","year":"2014","journal-title":"J. Proteome Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1152\/physrev.00035.2018","article-title":"Metabolomics for Investigating Physiological and Pathophysiological Processes","volume":"99","author":"Wishart","year":"2019","journal-title":"Physiol. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1021\/acs.jproteome.7b00724","article-title":"Integrative Proteomics\u2013Metabolomics Strategy for Pathological Mechanism of Vascular Depression Mouse Model","volume":"17","author":"Zhao","year":"2017","journal-title":"J. Proteome Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Jim\u00e9nez-Mar\u00edn, \u00c1., Collado-Romero, M., Ramirez-Boo, M., Arce, C., and Garrido, J.J. (2009). Biological pathway analysis by ArrayUnlock and Ingenuity Pathway Analysis. BMC Proc., 3.","DOI":"10.1186\/1753-6561-3-S4-S6"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Deng, W., Wang, Y., Liu, Z., Cheng, H., and Xue, Y. (2014). HemI: A Toolkit for Illustrating Heatmaps. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0111988"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2167","DOI":"10.1002\/etc.3025","article-title":"High-throughput concentration-response analysis for omics datasets","volume":"34","author":"Riedl","year":"2015","journal-title":"Environ. Toxicol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.molmed.2019.09.006","article-title":"Crosstalk between Sertoli and Germ Cells in Male Fertility","volume":"26","author":"Wu","year":"2020","journal-title":"Trends Mol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2247","DOI":"10.1242\/dev.01112","article-title":"Compositional and structural requirements for laminin and basement membranes during mouse embryo implantation and gastrulation","volume":"131","author":"Miner","year":"2004","journal-title":"Development"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12610-018-0071-5","article-title":"Understanding the seminal plasma proteome and its role in male fertility","volume":"28","author":"Camargo","year":"2018","journal-title":"Basic Clin. Androl."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1006\/cbir.1994.1046","article-title":"Expression in situ of c-myc mRNA and c-myc protein during spermatogenesis in the adult mouse","volume":"18","author":"Uetani","year":"1994","journal-title":"Cell Biol. Int."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/S0010-7824(98)00010-9","article-title":"Biphasic c-Myc protein expression during gossypol-induced apoptosis in rat spermatocytes","volume":"57","author":"Teng","year":"1998","journal-title":"Contraception"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1038\/nrc2231","article-title":"Reflecting on 25 years with MYC","volume":"8","author":"Meyer","year":"2008","journal-title":"Nat. Rev. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"skaa313","DOI":"10.1093\/jas\/skaa313","article-title":"Bta-miR-34b inhibits proliferation and promotes apoptosis via the MEK\/ERK pathway by targeting MAP2K1 in bovine primary Sertoli cells","volume":"98","author":"Zhang","year":"2020","journal-title":"J. Anim. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1111\/rda.13626","article-title":"miR-362 knock-down promotes proliferation and inhibits apoptosis in porcine immature Sertoli cells by targeting the RMI1 gene","volume":"55","author":"Ran","year":"2020","journal-title":"Reprod. Domest. Anim."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"224","DOI":"10.3389\/fendo.2019.00224","article-title":"Molecular mechanisms and signaling pathways involved in sertoli cell proliferation","volume":"10","author":"Meroni","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2637","DOI":"10.1101\/gad.287045.116","article-title":"Myc\/Mycn-mediated glycolysis enhances mouse spermatogonial stem cell self-renewal","volume":"30","author":"Tanaka","year":"2016","journal-title":"Genes Dev."},{"key":"ref_40","first-page":"3208","article-title":"Regulation and role of clusterin, a secretory chaperone protein, on intraocular pressure","volume":"61","author":"Soundararajan","year":"2020","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.taap.2017.02.001","article-title":"Identification of sperm mRNA biomarkers associated with testis injury during preclinical testing of pharmaceutical compounds","volume":"320","author":"Dere","year":"2017","journal-title":"Toxicol. Appl. Pharmacol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/6\/821\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:09:28Z","timestamp":1760162968000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/6\/821"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,31]]},"references-count":41,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["biom11060821"],"URL":"https:\/\/doi.org\/10.3390\/biom11060821","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,31]]}}}