{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:54:52Z","timestamp":1790880892463,"version":"4.1.0"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T00:00:00Z","timestamp":1709164800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Precocious puberty (PP) is a prevalent endocrine disorder affecting the physical and mental wellbeing of children. Identifying the triggering factors of PP has become a central issue. This study seeks to investigate the metabolomic and transcriptomic alterations in PP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Material and methods<\/jats:title><jats:p>First, 37 school-aged girls diagnosed with PP and 25 age-matched prepubertal control girls were recruited, and the fecal samples were collected for non-targeted metabolomic analysis to screen for differentially expressed metabolites (DEMs). Subsequently, an animal model of PP was constructed by danazol administration to neonatal female rats, and both fecal non-targeted metabolomics and serum next-generation transcriptomic sequencing were performed to screen DEMs and differentially expressed genes (DEGs) in PP. Moreover, the DEM co-existing in clinical and animal models was administrated to PP rats to explore the role of the target metabolite in PP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 24 DEMs in PP clinical samples and 180 DEMs and 425 DEGs in PP animal samples were identified. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that these DEMs and DEGs were enriched in disease-associated pathways, including fatty acid synthesis, glycerolipid metabolism, pyrimidine metabolism, steroid hormone biosynthesis, progesterone-mediated oocyte maturation, and gonadotropin-releasing hormone (GnRH) signaling pathway, forming a tight DEM\u2013DEG pathway regulatory network. Further DEM validation demonstrated that thymine supplementation delayed the opening of the vagina and development of PP in model rats.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study reveals that the metabolomic and transcriptomic changes, along with enriched pathways, are implicated in PP based on clinical and animal analyses. The findings may provide new strategies and research avenues for PP treatment.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2024.1285666","type":"journal-article","created":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T05:21:21Z","timestamp":1709184081000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Multi-omic analysis of precocious puberty girls: pathway changes and metabolite validation"],"prefix":"10.3389","volume":"15","author":[{"given":"Fang","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhong","family":"Mao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenzhen","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,2,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"113907","DOI":"10.1016\/j.biopha.2022.113907","article-title":"Development of precocious puberty in children: Surmised medicinal plant treatment","volume":"156","author":"Han","year":"2022","journal-title":"Biomedicine Pharmacother."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2020.15665","article-title":"Trends in the incidence of central precocious puberty and normal variant puberty among children in Denmark, 1998 to 2017","volume":"3","author":"Br\u00e4uner","year":"2020","journal-title":"JAMA Net Open"},{"key":"B3","doi-asserted-by":"publisher","first-page":"9229153","DOI":"10.1155\/2022\/9229153","article-title":"Analysis of the incidence and risk factors of precocious puberty in girls during the COVID-19 pandemic","volume":"2022","author":"Fu","year":"2022","journal-title":"Int J Endocrinology."},{"key":"B4","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1530\/EJE-17-0379","article-title":"Marked geographic patterns in the incidence of idiopathic central precocious puberty: a nationwide study in France","volume":"178","author":"Le Moal","year":"2018","journal-title":"Eur J Endocrinol."},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s40272-015-0130-8","article-title":"Central precocious puberty: update on diagnosis and treatment","volume":"17","author":"Chen","year":"2015","journal-title":"Pediatr Drugs"},{"key":"B6","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1186\/s12887-022-03350-x","article-title":"Effects of childhood obesity and related genetic factors on precocious puberty: protocol for a multi-center prospective cohort study","volume":"22","author":"Yu","year":"2022","journal-title":"BMC Pediatr."},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1097\/MED.0b013e32835b7ec7","article-title":"Control of puberty: genetics, endocrinology, and environment","volume":"20","author":"Choi","year":"2013","journal-title":"Curr Opin Endocrinol Diabetes Obes"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-021-02630-3","article-title":"Prevalence of precocious puberty among Chinese children: a school population-based study","volume":"72","author":"Liu","year":"2021","journal-title":"Endocrine."},{"key":"B9","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1186\/s12887-023-04013-1","article-title":"The effect of environmental factors on precocious puberty in children: a case-control study","volume":"23","author":"Bigambo","year":"2023","journal-title":"BMC Pediatr."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.1056871","article-title":"Childhood obesity and central precocious puberty","volume":"13","author":"Shi","year":"2022","journal-title":"Front Endocrinol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"101579","DOI":"10.1016\/j.beem.2021.101579","article-title":"Endocrine-disrupting chemicals and their effects on puberty","volume":"35","author":"Lopez-Rodriguez","year":"2021","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"B12","doi-asserted-by":"publisher","first-page":"101300","DOI":"10.1016\/j.beem.2019.101300","article-title":"Endocrine disrupters and possible contribution to pubertal changes","volume":"33","author":"Fudvoye","year":"2019","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"B13","doi-asserted-by":"publisher","first-page":"null","DOI":"10.3390\/ijms20194781","article-title":"The need for multi-omics biomarker signatures in precision medicine","volume":"20","author":"Olivier","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.315","article-title":"Applications of multi-omics analysis in human diseases","volume":"4","author":"Chen","year":"2023","journal-title":"MedComm."},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(15)00380-0","article-title":"Causes, diagnosis, and treatment of central precocious puberty","volume":"4","author":"Latronico","year":"2016","journal-title":"Lancet Diabetes Endocrinol."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1080\/08820139.2021.1885437","article-title":"Buserelin inhibits the immunosuppressive activity of regulatory T cells through the protein kinase A signaling in a central precocious puberty model","volume":"51","author":"Li","year":"2022","journal-title":"Immunol Invest."},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1080\/01635581.2020.1856389","article-title":"Carcinogenesis and bacillus calmette-gu\u00e9rin (BCG) intravesical treatment of non-muscle-invasive bladder cancer under tryptophan and thymine supplementation","volume":"73","author":"Ossick","year":"2021","journal-title":"Nutr Cancer-An Int J"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.951552","article-title":"Integrated analysis of proteomics and metabolomics in girls with central precocious puberty","volume":"13","author":"Li","year":"2022","journal-title":"Front Endocrinol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1186\/s12967-023-04169-5","article-title":"Gut microbiome combined with metabolomics reveals biomarkers and pathways in central precocious puberty","volume":"21","author":"Huang","year":"2023","journal-title":"J Trans Med"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.envint.2018.09.001","article-title":"Phthalate exposure and childhood overweight and obesity: Urinary metabolomic evidence","volume":"121","author":"Xia","year":"2018","journal-title":"Environ Int"},{"key":"B21","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1186\/s12887-021-02936-1","article-title":"Obesity is a risk factor for central precocious puberty: a case-control study","volume":"21","author":"Liu","year":"2021","journal-title":"BMC Pediatr."},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgab064","article-title":"Total and central adiposity are associated with age at gonadarche and incidence of precocious gonadarche in boys","volume":"106","author":"Pereira","year":"2021","journal-title":"J Clin Endocrinol Metab"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-142046","article-title":"Fatty acid profiles in demented patients: identification of hexacosanoic acid (C26:0) as a blood lipid biomarker of dementia","volume":"44","author":"Zarrouk","year":"2015","journal-title":"J Alzheimers Dis."},{"key":"B24","doi-asserted-by":"publisher","first-page":"114305","DOI":"10.1016\/j.physbeh.2023.114305","article-title":"Identification of urine biomarkers associated with early puberty in children: An untargeted metabolomics analysis","volume":"270","author":"Wang","year":"2023","journal-title":"Physiol behavior."},{"key":"B25","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.reprotox.2020.04.001","article-title":"Sex- and age-dependent effects of maternal organophosphate flame-retardant exposure on neonatal hypothalamic and hepatic gene expression","volume":"94","author":"Adams","year":"2020","journal-title":"Reprod Toxicol."},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2004.05.012","article-title":"Decreased hypothalamic aromatization in female rats of true precocious puberty","volume":"366","author":"Tian","year":"2004","journal-title":"Neurosci Lett."},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(93)90636-Y","article-title":"Induction of true precocious puberty by neonatal treatment with danazol in female rats","volume":"157","author":"Morishita","year":"1993","journal-title":"Neurosci Lett."},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2826.2003.01106.x","article-title":"Puberty: a period of both organizational and activational effects of steroid hormones on neurobehavioural development","volume":"15","author":"Romeo","year":"2003","journal-title":"J Neuroendocrinol."},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.yfrne.2005.10.003","article-title":"Pubertal hormones organize the adolescent brain and behavior","volume":"26","author":"Sisk","year":"2005","journal-title":"Front Neuroendocrinol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"114003","DOI":"10.1016\/j.envpol.2020.114003","article-title":"Associations of fluoride exposure with sex steroid hormones among U.S. children and adolescents, NHANES 2013-2016","volume":"260","author":"Bai","year":"2020","journal-title":"Environ Pollut."},{"key":"B31","doi-asserted-by":"publisher","first-page":"153548","DOI":"10.1016\/j.scitotenv.2022.153548","article-title":"Associations between exposure to a mixture of phenols, parabens, and phthalates and sex steroid hormones in children 6-19 years from NHANES, 2013-2016","volume":"822","author":"Hu","year":"2022","journal-title":"Sci Total Environ."},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1515\/jpem-2021-0691","article-title":"A preliminary study on the relationship between environmental endocrine disruptors and precocious puberty in girls","volume":"35","author":"Zhou","year":"2022","journal-title":"J Pediatr Endocrinol Metab"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2023.1157272","article-title":"Comprehensive analysis of untargeted metabolomics and lipidomics in girls with central precocious puberty","volume":"11","author":"Zhao","year":"2023","journal-title":"Front Pediatr."},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2022.885030","article-title":"Integrated proteomic and metabolomic analyses of chicken ovary revealed the crucial role of lipoprotein lipase on lipid metabolism and steroidogenesis during sexual maturity","volume":"13","author":"Cui","year":"2022","journal-title":"Front Physiol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-019-0123-5","article-title":"Metabolic regulation of cell growth and proliferation","volume":"20","author":"Zhu","year":"2019","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"null","DOI":"10.3390\/ijms221910253","article-title":"Pyrimidine biosynthetic enzyme CAD: its function, regulation, and diagnostic potential","volume":"22","author":"Li","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2005.07.003","article-title":"Pyrimidine pathways in health and disease","volume":"11","author":"L\u00f6ffler","year":"2005","journal-title":"Trends Mol Med"},{"key":"B38","doi-asserted-by":"publisher","first-page":"6877541","DOI":"10.1155\/2022\/6877541","article-title":"Identification of the metabolomics signature of human follicular fluid from PCOS women with insulin resistance","volume":"2022","author":"Liu","year":"2022","journal-title":"Dis Markers."},{"key":"B39","doi-asserted-by":"publisher","first-page":"29","DOI":"10.2147\/HMER.S7860","article-title":"Scavenger receptor class B member 1 protein: hepatic regulation and its effects on lipids, reverse cholesterol transport, and atherosclerosis","volume":"3","author":"Kent","year":"2011","journal-title":"Hepatic Med evidence Res"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-020-01076-8","article-title":"Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia","volume":"23","author":"Muir","year":"2021","journal-title":"Genet Med"},{"key":"B41","doi-asserted-by":"publisher","first-page":"6904769","DOI":"10.1155\/2022\/6904769","article-title":"Role of phosphatidylinositol 3-kinase and its catalytic unit PIK3CA in cervical cancer: a mini-review","volume":"2022","author":"Sun","year":"2022","journal-title":"Appl Bionics Biomechanics."}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2024.1285666\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T05:21:23Z","timestamp":1709184083000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2024.1285666\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,29]]},"references-count":41,"alternative-id":["10.3389\/fendo.2024.1285666"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2024.1285666","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,29]]},"article-number":"1285666"}}