{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:03:20Z","timestamp":1792785800792,"version":"4.5.0"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2023,10,9]],"date-time":"2023-10-09T00:00:00Z","timestamp":1696809600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32 ES007326"],"award-info":[{"award-number":["T32 ES007326"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 ES034112"],"award-info":[{"award-number":["R01 ES034112"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 ES028661"],"award-info":[{"award-number":["R01 ES028661"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Makowski Family Foundation"},{"name":"University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core"},{"name":"Eunice Kennedy Shriver","award":["R24HD102061"],"award-info":[{"award-number":["R24HD102061"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,1,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Di(2-ethylhexyl) phthalate and diisononyl phthalate are widely used as plasticizers in polyvinyl chloride products. Short-term exposures to phthalates affect hormone levels, ovarian follicle populations, and ovarian gene expression. However, limited data exist regarding the effects of long-term exposure to phthalates on reproductive functions. Thus, this study tested the hypothesis that short-term and long-term exposure to di(2-ethylhexyl) phthalate or diisononyl phthalate disrupts follicle dynamics, ovarian and pituitary gene expression, and hormone levels in female mice. Adult CD-1 female mice were exposed to vehicle, di(2-ethylhexyl) phthalate, or diisononyl phthalate (0.15\u00a0ppm, 1.5\u00a0ppm, or 1500\u00a0ppm) via the chow for 1 or 6\u00a0months. Short-term exposure to di(2-ethylhexyl) phthalate (0.15\u00a0ppm) and diisononyl phthalate (1.5\u00a0ppm) decreased serum follicle-stimulating hormone levels compared to control. Long-term exposure to di(2-ethylhexyl) phthalate and diisononyl phthalate (1500 ppm) increased the percentage of primordial follicles and decreased the percentages of preantral and antral follicles compared to control. Both phthalates increased follicle-stimulating hormone levels (di(2-ethylhexyl) phthalate at 1500\u00a0ppm; diisononyl phthalate at 1.5\u00a0ppm) and decreased luteinizing hormone levels (di(2-ethylhexyl) phthalate at 0.15 and 1.5\u00a0ppm; diisononyl phthalate at 1.5\u00a0ppm and 1500\u00a0ppm) compared to control. Furthermore, both phthalates altered the expression of pituitary gonadotropin subunit genes (Cga, Fshb, and Lhb) and a transcription factor (Nr5a1) that regulates gonadotropin synthesis. These data indicate that long-term exposure to di(2-ethylhexyl) phthalate and diisononyl phthalate alters follicle growth dynamics in the ovary and the expression of gonadotropin subunit genes in the pituitary and consequently luteinizing hormone and follicle-stimulating hormone synthesis.<\/jats:p>","DOI":"10.1093\/biolre\/ioad137","type":"journal-article","created":{"date-parts":[[2023,10,9]],"date-time":"2023-10-09T11:41:11Z","timestamp":1696851671000},"page":"198-210","source":"Crossref","is-referenced-by-count":20,"title":["The effects of short-term and long-term phthalate exposures on ovarian follicle growth dynamics and hormone levels in female mice"],"prefix":"10.1093","volume":"110","author":[{"given":"Rams\u00e9s","family":"Santacruz-M\u00e1rquez","sequence":"first","affiliation":[{"name":"Department of Comparative Biosciences, University of Illinois Urbana-Champaign , Urbana, Illinois , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adira M","family":"Safar","sequence":"additional","affiliation":[{"name":"Department of Comparative Biosciences, University of Illinois Urbana-Champaign , Urbana, Illinois , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary J","family":"Laws","sequence":"additional","affiliation":[{"name":"Department of Comparative Biosciences, University of Illinois Urbana-Champaign , Urbana, Illinois , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daryl D","family":"Meling","sequence":"additional","affiliation":[{"name":"Department of Comparative Biosciences, University of Illinois Urbana-Champaign , Urbana, Illinois , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenghui","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Reproductive Sciences , Division of Reproductive Endocrinology & Infertility, Department of Obstetrics & Gynecology, , Aurora, Colorado , USA"},{"name":"University of Colorado Anschutz Medical Campus , Division of Reproductive Endocrinology & Infertility, Department of Obstetrics & Gynecology, , Aurora, Colorado , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T Rajendra","family":"Kumar","sequence":"additional","affiliation":[{"name":"Division of Reproductive Sciences , Division of Reproductive Endocrinology & Infertility, Department of Obstetrics & Gynecology, , Aurora, Colorado , USA"},{"name":"University of Colorado Anschutz Medical Campus , Division of Reproductive Endocrinology & Infertility, Department of Obstetrics & Gynecology, , Aurora, Colorado , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romana A","family":"Nowak","sequence":"additional","affiliation":[{"name":"Department of Animal Sciences, University of Illinois Urbana-Champaign , Urbana, Illinois , USA"},{"name":"Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign , Urbana, Illinois , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lori T","family":"Raetzman","sequence":"additional","affiliation":[{"name":"Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign , Urbana, Illinois , USA"},{"name":"Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign , Urbana, Illinois , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jodi A","family":"Flaws","sequence":"additional","affiliation":[{"name":"Department of Comparative Biosciences, University of Illinois Urbana-Champaign , Urbana, Illinois , USA"},{"name":"Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign , Urbana, Illinois , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,10,9]]},"reference":[{"key":"2024011612162054100_ref1","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.repbio.2020.01.007","article-title":"Gonadal development and sex determination in mouse","volume":"20","author":"Yildirim","year":"2020","journal-title":"Reprod Biol"},{"key":"2024011612162054100_ref2","doi-asserted-by":"crossref","first-page":"349","DOI":"10.3390\/toxics11040349","article-title":"Imidacloprid and its bioactive metabolite, desnitro-imidacloprid, differentially affect ovarian antral follicle growth, morphology, and hormone synthesis in vitro","volume":"11","author":"Mourikes","year":"2023","journal-title":"Toxics"},{"key":"2024011612162054100_ref3","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1093\/humrep\/dei353","article-title":"The hypothalamus\u2013pituitary\u2013ovary axis and type 1 diabetes mellitus: a mini review","volume":"21","author":"Arrais","year":"2006","journal-title":"Hum Reprod"},{"key":"2024011612162054100_ref4","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1093\/glycob\/5.1.3","article-title":"Glycoprotein hormones: glycobiology of gonadotrophins, thyrotrophin and free alpha subunit","volume":"5","author":"Thotakura","year":"1995","journal-title":"Glycobiology"},{"key":"2024011612162054100_ref5","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1210\/en.2003-1047","article-title":"Regulation of luteinizing hormone-beta and follicle-stimulating hormone (FSH)-beta gene transcription by androgens: testosterone directly stimulates FSH-beta transcription independent from its role on follistatin gene expression","volume":"145","author":"Burger","year":"2004","journal-title":"Endocrinology"},{"key":"2024011612162054100_ref6","doi-asserted-by":"crossref","first-page":"R131","DOI":"10.1530\/JME-17-0308","article-title":"Molecular regulation of follicle-stimulating hormone synthesis, secretion and action","volume":"60","author":"Das","year":"2018","journal-title":"J Mol Endocrinol"},{"key":"2024011612162054100_ref7","doi-asserted-by":"crossref","first-page":"102274","DOI":"10.1016\/j.coph.2022.102274","article-title":"Pituitary gonadotroph-specific patterns of gene expression and hormone secretion","volume":"66","author":"Constantin","year":"2022","journal-title":"Curr Opin Pharmacol"},{"key":"2024011612162054100_ref8","doi-asserted-by":"crossref","first-page":"603","DOI":"10.3390\/healthcare9050603","article-title":"Phthalates and their impacts on human health","volume":"9","author":"Wang","year":"2021","journal-title":"Healthcare (Basel)"},{"key":"2024011612162054100_ref9","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1111\/j.1365-2605.2005.00567.x","article-title":"Human exposure to phthalates via consumer products","volume":"29","author":"Schettler","year":"2006","journal-title":"Int J Androl"},{"key":"2024011612162054100_ref10","volume-title":"Toxicological Profile forDi(2-Ethylhexyl)Phthalate (DEHP)","author":"ATSDR","year":"2022"},{"key":"2024011612162054100_ref11","volume-title":"Biomonitoring Summary | CDC","year":"2021"},{"key":"2024011612162054100_ref12","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1002\/mnfr.201000121","article-title":"Assessing exposure to phthalates - the human biomonitoring approach","volume":"55","author":"Wittassek","year":"2011","journal-title":"Mol Nutr Food Res"},{"key":"2024011612162054100_ref13","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1055\/s-0037-1603569","article-title":"Environmental contaminants affecting fertility and somatic health","volume":"35","author":"Chiang","year":"2017","journal-title":"Semin Reprod Med"},{"key":"2024011612162054100_ref14","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.reprotox.2019.12.006","article-title":"Late-life consequences of short-term exposure to di(2-ethylhexyl) phthalate and diisononyl phthalate during adulthood in female mice","volume":"93","author":"Chiang","year":"2020","journal-title":"Reprod Toxicol"},{"key":"2024011612162054100_ref15","doi-asserted-by":"crossref","first-page":"251","DOI":"10.3390\/toxics10050251","article-title":"Effects of phthalate mixtures on ovarian folliculogenesis and steroidogenesis","volume":"10","author":"Fletcher","year":"2022","journal-title":"Toxics"},{"key":"2024011612162054100_ref16","doi-asserted-by":"crossref","first-page":"kfad030","DOI":"10.1093\/toxsci\/kfad030","article-title":"Long-term exposure to di(2-ethylhexyl) phthalate, diisononyl phthalate, and a mixture of phthalates alters estrous cyclicity and\/or impairs gestational index and birth rate in mice","volume":"193","author":"Laws","year":"2023","journal-title":"Toxicol Sci"},{"key":"2024011612162054100_ref17","doi-asserted-by":"crossref","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":"2024011612162054100_ref18","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1093\/toxsci\/kfv317","article-title":"Acute exposure to di(2-ethylhexyl) phthalate in adulthood causes adverse reproductive outcomes later in life and accelerates reproductive aging in female mice","volume":"150","author":"Hannon","year":"2016","journal-title":"Toxicol Sci"},{"key":"2024011612162054100_ref19","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1210\/en.2017-03004","article-title":"Prenatal exposure to di(2-ethylhexyl) phthalate causes long-term transgenerational effects on female reproduction in mice","volume":"159","author":"Brehm","year":"2018","journal-title":"Endocrinology"},{"key":"2024011612162054100_ref20","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/S0890-6238(02)00032-1","article-title":"NTP Center for the Evaluation of Risks to Human Reproduction: phthalates expert panel report on the reproductive and developmental toxicity of di(2-ethylhexyl) phthalate","volume":"16","author":"Kavlock","year":"2002","journal-title":"Reprod Toxicol"},{"key":"2024011612162054100_ref21","doi-asserted-by":"crossref","first-page":"dvab010","DOI":"10.1093\/eep\/dvab010","article-title":"Prenatal exposure to a mixture of phthalates accelerates the age-related decline in reproductive capacity but may not affect direct biomarkers of ovarian aging in the F1 generation of female mice","volume":"7","author":"Brehm","year":"2021","journal-title":"Environ Epigenet"},{"key":"2024011612162054100_ref22","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.reprotox.2021.09.013","article-title":"Prenatal exposure to an environmentally relevant phthalate mixture alters ovarian steroidogenesis and folliculogenesis in the F1 generation of adult female mice","volume":"106","author":"Gill","year":"2021","journal-title":"Reprod Toxicol"},{"key":"2024011612162054100_ref23","doi-asserted-by":"crossref","first-page":"114952","DOI":"10.1016\/j.taap.2020.114952","article-title":"Exposure to di(2-ethylhexyl) phthalate and diisononyl phthalate during adulthood disrupts hormones and ovarian folliculogenesis throughout the prime reproductive life of the mouse","volume":"393","author":"Chiang","year":"2020","journal-title":"Toxicol Appl Pharmacol"},{"key":"2024011612162054100_ref24","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1093\/biolre\/ioab108","article-title":"Iodoacetic acid affects estrous cyclicity, ovarian gene expression, and hormone levels in mice","volume":"105","author":"Gonsioroski","year":"2021","journal-title":"Biol Reprod"},{"key":"2024011612162054100_ref25","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1093\/nar\/29.9.e45","article-title":"A new mathematical model for relative quantification in real-time RT-PCR","volume":"29","author":"Pfaffl","year":"2001","journal-title":"Nucleic Acids Res"},{"key":"2024011612162054100_ref26","doi-asserted-by":"crossref","first-page":"5735","DOI":"10.1073\/pnas.1321404111","article-title":"Redirecting intracellular trafficking and the secretion pattern of FSH dramatically enhances ovarian function in mice","volume":"111","author":"Wang","year":"2014","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2024011612162054100_ref27","first-page":"200","article-title":"Initial and cyclic recruitment of ovarian follicles","volume":"21","author":"McGee","year":"2000","journal-title":"Endocr Rev"},{"key":"2024011612162054100_ref28","doi-asserted-by":"crossref","first-page":"227","DOI":"10.4103\/0974-1208.126285","article-title":"Luteinizing hormone and follicle stimulating hormone synergy: a review of role in controlled ovarian hyper-stimulation","volume":"6","author":"Raju","year":"2013","journal-title":"J Hum Reprod Sci"},{"key":"2024011612162054100_ref29","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/S0015-0282(97)00557-8","article-title":"Use of the antral follicle count to predict the outcome of assisted reproductive technologies","volume":"69","author":"Chang","year":"1998","journal-title":"Fertil Steril"},{"key":"2024011612162054100_ref30","doi-asserted-by":"crossref","DOI":"10.3389\/fcell.2020.575706","article-title":"The factors and pathways regulating the activation of mammalian primordial follicles in vivo","volume":"8","author":"Chen","year":"2020","journal-title":"Frontiers in Cell and Developmental Biology"},{"key":"2024011612162054100_ref31","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1210\/mend-2-4-338","article-title":"Influence of gonadotropin-releasing hormone pulse amplitude, frequency, and treatment duration on the regulation of luteinizing hormone (LH) subunit messenger ribonucleic acids and LH secretion","volume":"2","author":"Haisenleder","year":"1988","journal-title":"Mol Endocrinol"},{"key":"2024011612162054100_ref32","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1007\/978-3-319-31973-5_7","volume-title":"Molecular Mechanisms of Cell Differentiation in Gonad Development","author":"Rimon-Dahari","year":"2016"},{"key":"2024011612162054100_ref33","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.redox.2017.07.015","article-title":"Cellular adaptation to xenobiotics: interplay between xenosensors, reactive oxygen species and FOXO transcription factors","volume":"13","author":"Klotz","year":"2017","journal-title":"Redox Biol"},{"key":"2024011612162054100_ref34","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.1098\/rstb.2008.0208","article-title":"Human body burdens of chemicals used in plastic manufacture","volume":"364","author":"Koch","year":"2009","journal-title":"Philos Trans R Soc Lond B Biol Sci"},{"key":"2024011612162054100_ref35","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.reprotox.2021.12.008","article-title":"Prenatal exposure to the phthalate DEHP impacts reproduction-related gene expression in the pituitary","volume":"108","author":"Ge","year":"2022","journal-title":"Reprod Toxicol"}],"container-title":["Biology of Reproduction"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/biolreprod\/advance-article-pdf\/doi\/10.1093\/biolre\/ioad137\/52455139\/ioad137.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/biolreprod\/article-pdf\/110\/1\/198\/55674330\/ioad137.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/biolreprod\/article-pdf\/110\/1\/198\/55674330\/ioad137.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T07:27:30Z","timestamp":1705390050000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/biolreprod\/article\/110\/1\/198\/7301513"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,9]]},"references-count":35,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,10,9]]},"published-print":{"date-parts":[[2024,1,13]]}},"URL":"https:\/\/doi.org\/10.1093\/biolre\/ioad137","relation":{},"ISSN":["0006-3363","1529-7268"],"issn-type":[{"value":"0006-3363","type":"print"},{"value":"1529-7268","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,1]]},"published":{"date-parts":[[2023,10,9]]}}}