{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T17:03:17Z","timestamp":1786381397232,"version":"build-2736575974"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T00:00:00Z","timestamp":1690243200000},"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. Cell Dev. Biol."],"abstract":"<jats:p><jats:bold>Objective:<\/jats:bold> We aimed to explore the correlations between and possible mechanisms of common environmental endocrine disruptors, phthalates, and ovarian dysfunction in endometriosis.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Subjects were included in the case group (<jats:italic>n<\/jats:italic> = 107) who were diagnosed with endometriosis by postoperative pathology in Fujian Maternal and Child Hospital from February 2018 to February 2021, and the women who were excluded from endometriosis by surgery were as the control group (<jats:italic>n<\/jats:italic> = 70). The demographic information of the subjects were evaluated by questionnaire, and the clinical characteristics were evaluated by medical records and 3-year follow-up results. Gas chromatography\u2012mass spectrometry was used to quantify 10 metabolites of phthalates, including dimethyl ortho-phthalate (DMP), mono-n-methyl phthalate (MMP), dioctyl ortho-phthalate (DEP), mono-ethyl phthalate (MEP), di-n-butyl ortho-phthalate (DBP), mono-butyl phthalate (MBP), benzylbutyl phthalate (BBzP), mono-benzyl; phthalate (MBzP), diethylhexyl phthalate (DEHP) and mono-ethylhexyl phthalate (MEHP), in the urine samples of the subjects. Furthermore, a total of 54 SD rats were exposed to DEHP 0, 5, 50, 100, 250, 500, 1,000, 2000, and 3,000\u00a0mg\/kg\/day for 2\u00a0weeks. The SD rats\u2019 body weight, oestrus cycle changes, and serum anti-mullerian hormone (AMH) levels were evaluated. After sacrifice, the mass index of the rat uterus and bilateral ovaries were calculated. Finally, bioinformatics analysis of rat ovarian tissues was performed to explore the possible mechanism. SPSS 24.0 (IBM, United States) was used for data analysis. <jats:italic>p<\/jats:italic>-value &amp;lt;0.05 was considered statistically significant.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> The human urinary levels of DMP (<jats:italic>p<\/jats:italic> &amp;lt; 0.001), MMP (<jats:italic>p<\/jats:italic> = 0.001), DEP (<jats:italic>p<\/jats:italic> = 0.003), MEP (<jats:italic>p<\/jats:italic> = 0.002), DBP (<jats:italic>p<\/jats:italic> = 0.041), MBP (<jats:italic>p<\/jats:italic> &amp;lt; 0.001), BBzP (<jats:italic>p<\/jats:italic> = 0.009), DEHP (<jats:italic>p<\/jats:italic> &amp;lt; 0.001), and MEHP (<jats:italic>p<\/jats:italic> &amp;lt; 0.001) were significantly higher in women with endometriosis than in controls. Notably, DEHP was a significant risk factor for endometriosis (OR: 11.0, 95% CI: 5.4\u201322.6). The area under the ROC curve increased when multiple phthalates were diagnosed jointly, reaching 0.974 as the highest value, which was helpful for the diagnosis of endometriosis. <jats:italic>In vivo<\/jats:italic> experiments showed that after DEHP exposure in rats, the mass index of the ovary and uterus decreased in a dose-dependent manner; the oestrus cycle of SD rats was irregularly prolonged and disordered; and the serum AMH level was negatively correlated with the DEHP exposure dose (Rho = \u22120.8, <jats:italic>p<\/jats:italic> &amp;lt; 0.001). Bioinformatics analysis of rat ovarian tissues showed that seven genes involved in the steroid biosynthesis pathway were upregulated and may play a negative role in ovarian function.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Exposure to phthalates, especially DEHP, is associated with the occurrence of endometriosis and affects women\u2019s reproductive prognosis and ovarian function. The steroid biosynthesis pathway may be related to ovarian dysfunction. The detection of phthalate in urine may become a new biological target for the diagnosis of endometriosis.<\/jats:p>","DOI":"10.3389\/fcell.2023.1154923","type":"journal-article","created":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T11:11:51Z","timestamp":1690283511000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Phthalate exposure and risk of ovarian dysfunction in endometriosis: human and animal data"],"prefix":"10.3389","volume":"11","author":[{"given":"Huan","family":"Yi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huamin","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbin","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixiang","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danmei","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,7,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"152665","DOI":"10.1016\/j.tox.2020.152665","article-title":"Polystyrene microplastics cause granulosa cells apoptosis and fibrosis in ovary through oxidative stress in rats","volume":"449","author":"An","year":"2021","journal-title":"Toxicology"},{"key":"B2","doi-asserted-by":"publisher","first-page":"273","DOI":"10.5935\/1518-0557.20190029","article-title":"Ethiopathogenic mechanisms of endometriosis-related infertility","volume":"23","author":"Broi","year":"2019","journal-title":"JBRA Assist. Reprod."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1048","DOI":"10.1210\/er.2018-00242","article-title":"Endometriosis","volume":"40","author":"Bulun","year":"2019","journal-title":"Endocr. Rev."},{"key":"B4","doi-asserted-by":"publisher","first-page":"855","DOI":"10.1071\/RD13061","article-title":"Cumulus cell gene expression associated with pre-ovulatory acquisition of developmental competence in bovine oocytes","volume":"26","author":"Bunel","year":"2014","journal-title":"Reprod. Fert. Dev."},{"key":"B5","doi-asserted-by":"publisher","first-page":"3678","DOI":"10.3390\/ijerph16193678","article-title":"Association between phthalate metabolites and risk of endometriosis: A meta-analysis","volume":"16","author":"Cai","year":"2019","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"B6","doi-asserted-by":"publisher","first-page":"6162","DOI":"10.3390\/ijerph19106162","article-title":"Endometriosis and infertility: A long-life approach to preserve reproductive integrity","volume":"19","author":"Coccia","year":"2022","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"B7","doi-asserted-by":"publisher","first-page":"2589","DOI":"10.3390\/ijms24032589","article-title":"Follicular fluid components in reduced ovarian reserve, endometriosis, and idiopathic infertility","volume":"24","author":"Collodel","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2847","DOI":"10.4049\/jimmunol.1701464","article-title":"Identification of MHC class ib ligands for stimulatory and inhibitory Ly49 receptors and induction of potent NK cell alloresponses in rats","volume":"200","author":"Dai","year":"2018","journal-title":"J. Immunol."},{"key":"B9","first-page":"143","article-title":"Endometriosis and infertility","volume":"58","author":"Donnez","year":"2016","journal-title":"Panminerva Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"405","DOI":"10.3389\/fgene.2020.00405","article-title":"Phthalate exposure and long-term epigenomic consequences: A review","volume":"11","author":"Dutta","year":"2020","journal-title":"Front. Genet."},{"key":"B11","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1177\/0036850419826802","article-title":"Endocrine disrupting chemicals: Impact on human health, wildlife and the environment","volume":"102","author":"Encarna\u00e7\u00e3o","year":"2019","journal-title":"Sci. progress-uk"},{"key":"B12","doi-asserted-by":"publisher","first-page":"836","DOI":"10.3760\/cma.j.issn.0529-567x.2018.12.007","article-title":"Chinese consensus on the long term management of endometriosis","volume":"53","year":"2018","journal-title":"Zhonghua Fu Chan Ke Za Zhi"},{"key":"B13","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1002\/ijgo.14519","article-title":"Combined effects of age and endometriosis on ovarian reserve in women with infertility","volume":"161","author":"Feferkorn","year":"2023","journal-title":"Int. J. Gynecol. Obstet."},{"key":"B14","doi-asserted-by":"publisher","first-page":"589.e1","DOI":"10.1016\/j.ajog.2016.05.029","article-title":"Effect of surgery on ovarian reserve in women with endometriomas, endometriosis and controls","volume":"215","author":"Goodman","year":"2016","journal-title":"Am. J. Obstet. Gynecol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1095\/biolreprod.114.119032","article-title":"Daily exposure to Di(2-ethylhexyl) phthalate alters estrous cyclicity and accelerates primordial follicle recruitment potentially via dysregulation of the phosphatidylinositol 3-kinase signaling pathway in adult mice","volume":"90","author":"Hannon","year":"2014","journal-title":"Biol. Reprod."},{"key":"B16","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1289\/ehp.1509760","article-title":"Urinary phthalate metabolite concentrations and reproductive outcomes among women undergoing in vitro fertilization: Results from the EARTH study","volume":"124","author":"Hauser","year":"2016","journal-title":"Environ. health persp"},{"key":"B17","doi-asserted-by":"publisher","first-page":"e9812","DOI":"10.7717\/peerj.9812","article-title":"Using bioinformatics and metabolomics to identify altered granulosa cells in patients with diminished ovarian reserve","volume":"8","author":"He","year":"2020","journal-title":"PeerJ"},{"key":"B18","doi-asserted-by":"publisher","first-page":"200","DOI":"10.3109\/10408444.2013.766149","article-title":"Reproductive and developmental effects of phthalate diesters in females","volume":"43","author":"Kay","year":"2013","journal-title":"Crit. Rev. Toxicol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1177\/1933719116678687","article-title":"Effects of supplementation of human endometriotic fluids on in vitro mouse preantral follicle culture","volume":"25","author":"Kim","year":"2018","journal-title":"Reprod. Sci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"92","DOI":"10.2741\/e810","article-title":"Association between ovarian endometrioma and ovarian reserve","volume":"10","author":"Kitajima","year":"2018","journal-title":"Front. Biosci. (Elite Ed."},{"key":"B45","doi-asserted-by":"publisher","first-page":"685\u2013691","DOI":"10.1016\/j.fertnstert.2011.06.064","article-title":"Endometriomas as a possible cause of reduced ovarian reserve in women with endometriosis","author":"Kitajima","year":"2011","journal-title":"Fertil. Steril."},{"key":"B21","doi-asserted-by":"publisher","first-page":"134406","DOI":"10.1016\/j.scitotenv.2019.134406","article-title":"Role of the 17\u03b2-hydroxysteroid dehydrogenase signalling pathway in di-(2-ethylhexyl) phthalate-induced ovarian dysfunction: An in vivo study","volume":"712","author":"Li","year":"2020","journal-title":"Sci. total Environ."},{"key":"B22","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.reprotox.2014.03.006","article-title":"Effects of di-(2-ethylhexyl) phthalate on the hypothalamus-pituitary-ovarian axis in adult female rats","volume":"46","author":"Liu","year":"2014","journal-title":"Reprod. Toxicol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1130","DOI":"10.3390\/ijerph13111130","article-title":"Effects of di-(2-ethylhexyl) phthalate on the hypothalamus-uterus in pubertal female rats","volume":"13","author":"Liu","year":"2016","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"B24","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.reprotox.2014.12.005","article-title":"In utero exposure to the endocrine disruptor di(2-ethylhexyl) phthalate targets ovarian theca cells and steroidogenesis in the adult female rat","volume":"51","author":"Meltzer","year":"2015","journal-title":"Reprod. Toxicol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"3361","DOI":"10.1210\/clinem\/dgaa513","article-title":"Anti-m\u00fcllerian hormone and ovarian reserve: Update on assessing ovarian function","volume":"105","author":"Moolhuijsen","year":"2020","journal-title":"J. Clin. Endocr. Metab."},{"key":"B26","doi-asserted-by":"publisher","first-page":"131","DOI":"10.4103\/jhrs.JHRS_137_17","article-title":"Women diagnosed with endometriosis show high serum levels of diethyl hexyl phthalate","volume":"11","author":"Nazir","year":"2018","journal-title":"J. Hum. Reprod. Sci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"101552","DOI":"10.1016\/j.beem.2021.101552","article-title":"Phthalates, ovarian function and fertility in adulthood","volume":"35","author":"Panagiotou","year":"2021","journal-title":"Best. Pract. Res. Clin. Endocrinol. Metab."},{"key":"B28","doi-asserted-by":"publisher","first-page":"734","DOI":"10.4103\/ijmr.IJMR_2077_16","article-title":"Estimation of plasma levels of bisphenol-A and phthalates in fertile and infertile women by gas chromatography-mass spectrometry","volume":"148","author":"Pednekar","year":"2018","journal-title":"Indian J. Med. Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"546","DOI":"10.3967\/bes2019.071","article-title":"Di-2-Ethylhexyl phthalate induces ovarian toxicity and alters protein expression of hormone-regulated receptors in rats","volume":"32","author":"Qin","year":"2019","journal-title":"Biomed. Environ. Sci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1111\/j.1471-0528.2006.00925.x","article-title":"Association of phthalate esters with endometriosis in Indian women","volume":"113","author":"Reddy","year":"2006","journal-title":"Bjog-int J. Obstet. gy"},{"key":"B31","doi-asserted-by":"publisher","first-page":"25285","DOI":"10.3390\/ijms161025285","article-title":"Integrated bioinformatics, environmental epidemiologic and genomic approaches to identify environmental and molecular links between endometriosis and breast cancer","volume":"16","author":"Roy","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"B32","first-page":"719","article-title":"Investigation of anti-mullerian hormone (AMH) level and ovarian response in infertile women with endometriosis in IVF cycles","volume":"16","author":"Safdarian","year":"2018","journal-title":"Int. J. Reprod. Biomed."},{"key":"B33","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1186\/s13048-017-0341-4","article-title":"Is the oocyte quality affected by endometriosis? A review of the literature","volume":"10","author":"Sanchez","year":"2017","journal-title":"J. Ovarian Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1186\/1476-069X-13-43","article-title":"Phthalates and diet: A review of the food monitoring and epidemiology data","volume":"13","author":"Serrano","year":"2014","journal-title":"Environ. Health"},{"key":"B35","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1002\/jat.3302","article-title":"Stereoselectivity and the potential endocrine disrupting activity of di-(2-ethylhexyl)phthalate (DEHP) against human progesterone receptor: A computational perspective","volume":"36","author":"Sheikh","year":"2016","journal-title":"J. Appl. Toxicol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1515\/reveh-2020-0046","article-title":"Environmental exposures to endocrine disrupting chemicals (EDCs) and their role in endometriosis: A systematic literature review","volume":"36","author":"Sirohi","year":"2021","journal-title":"Rev. Environ. health"},{"key":"B37","doi-asserted-by":"publisher","first-page":"Sp111","DOI":"10.2131\/jts.34.s111","article-title":"Collaborative work on evaluation of ovarian toxicity 10) Two- or four-week repeated dose studies and fertility study of di-(2-ethylhexyl) phthalate (DEHP) in female rats","volume":"34","author":"Takai","year":"2009","journal-title":"J. Toxicol. Sci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1017\/S0967199419000121","article-title":"Encircling granulosa cells protects against di-(2-ethylhexyl)phthalate-induced apoptosis in rat oocytes cultured in vitro","volume":"27","author":"Tripathi","year":"2019","journal-title":"Zygote"},{"key":"B39","doi-asserted-by":"publisher","first-page":"1837","DOI":"10.1093\/humrep\/dem101","article-title":"Stable serum levels of anti-m\u00fcllerian hormone during the menstrual cycle: A prospective study in normo-ovulatory women","volume":"22","author":"Tsepelidis","year":"2007","journal-title":"Hum. Reprod."},{"key":"B40","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.envres.2013.07.003","article-title":"Phthalates and risk of endometriosis","volume":"126","author":"Upson","year":"2013","journal-title":"Environ. Res."},{"key":"B41","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1186\/s12940-017-0242-4","article-title":"Environmental pollutants, a possible etiology for premature ovarian insufficiency: A narrative review of animal and human data","volume":"16","author":"Vabre","year":"2017","journal-title":"Environ. Health"},{"key":"B42","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1038\/nrendo.2013.255","article-title":"Endometriosis: Pathogenesis and treatment","volume":"10","author":"Vercellini","year":"2014","journal-title":"Nat. Rev. Endocrinol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.theriogenology.2019.07.012","article-title":"Effect of hypothyroidism on CYP51 and FSHR expression in rat ovary","volume":"138","author":"Weng","year":"2019","journal-title":"Theriogenology"},{"key":"B44","first-page":"151","article-title":"Endometrioma and ovarian reserve: Effects of endometriomata per se and its surgical treatment on the ovarian reserve","volume":"11","author":"Y\u0131lmaz Hanege","year":"2019","journal-title":"Facts views Vis. obgy"}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2023.1154923\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T11:12:01Z","timestamp":1690283521000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2023.1154923\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,25]]},"references-count":45,"alternative-id":["10.3389\/fcell.2023.1154923"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2023.1154923","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,25]]},"article-number":"1154923"}}