{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T16:06:12Z","timestamp":1789056372988,"version":"build-2803163510"},"reference-count":25,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100008247","name":"University of Otago","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100008247","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Reprod. Sci."],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Animal models have shown that prenatal exposure to excess androgens is associated with the development of polycystic ovary syndrome (PCOS) features. We have identified that prenatally androgenized (PNA) mice modelling PCOS show suppressed androgen receptor mRNA (\n                    <jats:italic>Ar<\/jats:italic>\n                    ) expression in the arcuate nucleus (ARC) across development. This could contribute to PCOS-related impaired gonadal steroid hormone feedback to GnRH neurons. However, the mechanism of\n                    <jats:italic>Ar<\/jats:italic>\n                    mRNA suppression following PNA is not determined. We performed a chromatin immunoprecipitation (ChIP) assay coupled with quantitative PCR (qPCR) to investigate histone and transcription factor binding within the\n                    <jats:italic>Ar<\/jats:italic>\n                    gene promoter or enhancer regions in the ARC of female mice at postnatal day (P)60 or gestational day (GD)18.5. In comparison to adult vehicle control (VEH) mice, our ChIP-qPCR revealed that H3K9me3, a repressive histone mark, was increased in adult PNA mice at the promoter regions of the\n                    <jats:italic>Ar<\/jats:italic>\n                    gene. H3K27ac, an active histone mark, and SP1, a transcription factor that acts as a positive regulator of gene expression, were unchanged in the same regions. Increased H3K9me3 seen at the promoter region in adult PNA mice, however, was not observed in the GD18.5 mice ARC following PNA. These results suggest that the deposition of H3K9me3 on the\n                    <jats:italic>Ar<\/jats:italic>\n                    promoter is unlikely to be established by PNA at the time of excess androgen exposure, and instead is likely to be established later in postnatal development or in adulthood. These data provide greater understanding of the developmental mechanisms and timeline underpinning PNA-mediated female dysfunction and PCOS-like reproductive physiology.\n                  <\/jats:p>","DOI":"10.1007\/s43032-026-02174-9","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T14:22:17Z","timestamp":1787322137000},"page":"1775-1782","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Prenatal Androgenization Modifies H3K9me3 Binding in the Promoter of the Androgen Receptor Gene in the Arcuate Nucleus of the Adult Female Mouse"],"prefix":"10.1007","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6920-5360","authenticated-orcid":false,"given":"Yugo","family":"Watanabe","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly A.","family":"Glendining","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorryn","family":"Fisher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca E.","family":"Campbell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine L.","family":"Jasoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"2174_CR1","doi-asserted-by":"publisher","DOI":"10.1210\/endrev\/bnaa010","author":"E Stener-Victorin","year":"2020","unstructured":"Stener-Victorin E, Padmanabhan V, Walters KA, Campbell RE, Benrick A, Giacobini P, et al. Animal models to understand the etiology and pathophysiology of polycystic ovary syndrome. Endocr Rev. 2020. https:\/\/doi.org\/10.1210\/endrev\/bnaa010.","journal-title":"Endocr Rev"},{"issue":"12","key":"2174_CR2","doi-asserted-by":"publisher","first-page":"1894","DOI":"10.1038\/s41591-019-0666-1","volume":"25","author":"S Risal","year":"2019","unstructured":"Risal S, Pei Y, Lu H, Manti M, Fornes R, Pui HP, et al. Prenatal androgen exposure and transgenerational susceptibility to polycystic ovary syndrome. Nat Med. 2019;25(12):1894\u2013904.","journal-title":"Nat Med"},{"key":"2174_CR3","doi-asserted-by":"crossref","unstructured":"Herbison AE. Physiology of the adult gonadotropin-releasing hormone neuronal network. In: Plant TM, Zeleznik AJ, editors. Knobil and Neil\u2019s physiology of reproduction, vol. 4th edn. Amsterdam, Netherlands: Elsevier; 2015. p. 399\u2013468.","DOI":"10.1016\/B978-0-12-397175-3.00011-9"},{"issue":"18","key":"2174_CR4","doi-asserted-by":"publisher","first-page":"7129","DOI":"10.1073\/pnas.0308058101","volume":"101","author":"SD Sullivan","year":"2004","unstructured":"Sullivan SD, Moenter SM. Prenatal androgens alter GABAergic drive to gonadotropin-releasing hormone neurons: implications for a common fertility disorder. Proc Natl Acad Sci USA. 2004;101(18):7129\u201334.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"2174_CR5","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1210\/en.2012-1954","volume":"154","author":"AM Moore","year":"2013","unstructured":"Moore AM, Prescott M, Campbell RE. Estradiol negative and positive feedback in a prenatal androgen-induced mouse model of polycystic ovarian syndrome. Endocrinology. 2013;154(2):796\u2013806.","journal-title":"Endocrinology"},{"issue":"2","key":"2174_CR6","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1073\/pnas.1415038112","volume":"112","author":"AM Moore","year":"2015","unstructured":"Moore AM, Prescott M, Marshall CJ, Yip SH, Campbell RE. Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome. Proc Natl Acad Sci U S A. 2015;112(2):596\u2013601.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"12","key":"2174_CR7","doi-asserted-by":"publisher","DOI":"10.1111\/jne.13058","volume":"33","author":"Y Watanabe","year":"2021","unstructured":"Watanabe Y, Prescott M, Campbell RE, Jasoni CL. Prenatal androgenization causes expression changes of progesterone and androgen receptor mRNAs in the arcuate nucleus of female mice across development. J Neuroendocrinol. 2021;33(12):e13058.","journal-title":"J Neuroendocrinol"},{"issue":"12","key":"2174_CR8","doi-asserted-by":"publisher","first-page":"5531","DOI":"10.1172\/JCI99159","volume":"128","author":"A Clocchiatti","year":"2018","unstructured":"Clocchiatti A, Ghosh S, Procopio MG, Mazzeo L, Bordignon P, Ostano P, et al. Androgen receptor functions as transcriptional repressor of cancer-associated fibroblast activation. J Clin Invest. 2018;128(12):5531\u201348.","journal-title":"J Clin Invest"},{"issue":"5","key":"2174_CR9","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1093\/biolre\/ioaa007","volume":"102","author":"N Sinha","year":"2020","unstructured":"Sinha N, Roy S, Huang B, Wang J, Padmanabhan V, Sen A. Developmental programming: prenatal testosterone-induced epigenetic modulation and its effect on gene expression in sheep ovary. Biol Reprod. 2020;102(5):1045\u201354.","journal-title":"Biol Reprod"},{"issue":"10","key":"2174_CR10","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1186\/s12864-018-5278-5","volume":"19","author":"L Zhang","year":"2018","unstructured":"Zhang L, Xue G, Liu J, Li Q, Wang Y. Revealing transcription factor and histone modification co-localization and dynamics across cell lines by integrating ChIP-seq and RNA-seq data. BMC Genomics. 2018;19(10):79\u201394.","journal-title":"BMC Genomics"},{"key":"2174_CR11","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1002\/jcp.1111","volume":"188","author":"AR Black","year":"2001","unstructured":"Black AR, Black JD, Azizkhan-Clifford J. Sp1 and Kr\u00fcppel-like factor family of transcription factors in cell growth regulation and cancer. J Cell Physio. 2001;188:143\u201360.","journal-title":"J Cell Physio"},{"key":"2174_CR12","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1093\/carcin\/bgi021","volume":"26","author":"H Yuan","year":"2005","unstructured":"Yuan H, Gong A, Young CY. Involvement of transcription factor Sp1 in quercetin-mediated inhibitory effect on the androgen receptor in human prostate cancer cells. Carcinogenesis. 2005;26:793\u2013801.","journal-title":"Carcinogenesis"},{"key":"2174_CR13","doi-asserted-by":"crossref","unstructured":"Peral-Sanchez I, Hojeij B, Ojeda DA, Steegers-Theunissen RP, Willaime-Morawek S. Epigenetics in the uterine environment: how maternal diet and ART may influence the epigenome in the offspring with long-term health consequences. Genes. 2021;23:13(1),31.","DOI":"10.3390\/genes13010031"},{"key":"2174_CR14","doi-asserted-by":"crossref","unstructured":"Tora\u00f1o EG, Garc\u00eda MG, Fern\u00e1ndez-Morera JL, Ni\u00f1o-Garc\u00eda P, Fern\u00e1ndez AF. The impact of external factors on the epigenome: in utero and over lifetime. BioMed Res. 2016;Int:2568635.","DOI":"10.1155\/2016\/2568635"},{"issue":"2","key":"2174_CR15","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2021.100589","volume":"2","author":"X Han","year":"2021","unstructured":"Han X, Burger LL, Garcia-Galiano D, Moenter SM, Myers JMG, Olson DP, et al. Protocol to extract actively translated mRNAs from mouse hypothalamus by translating ribosome affinity purification. STAR Protoc. 2021;2(2):100589.","journal-title":"STAR Protoc"},{"issue":"1","key":"2174_CR16","doi-asserted-by":"publisher","first-page":"48","DOI":"10.2399\/ana.11.212","volume":"7","author":"MS Salehi","year":"2013","unstructured":"Salehi MS, Namavar MR, Shirazi MR, Rahmanifar F, Tamadon A. A simple method for isolation of the anteroventral periventricular and arcuate nuclei of the rat hypothalamus. Anatomy. 2013;7(1):48\u201351.","journal-title":"Anatomy"},{"issue":"7","key":"2174_CR17","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1046\/j.1432-0436.2003.7107004.x","volume":"71","author":"A Staack","year":"2003","unstructured":"Staack A, Donjacour AA, Brody J, Cunha GR, Carroll P. Mouse urogenital development: a practical approach. Differentiation. 2003;71(7):402\u201313.","journal-title":"Differentiation"},{"issue":"6","key":"2174_CR18","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1016\/S0092-8674(01)00598-0","volume":"107","author":"E Heard","year":"2001","unstructured":"Heard E, Rougeulle C, Arnaud D, Avner P, Allis CD, Spector DL. Methylation of histone H3 at Lys-9 is an early mark on the X chromosome during X inactivation. Cell. 2001;107(6):727\u201338.","journal-title":"Cell"},{"issue":"12","key":"2174_CR19","doi-asserted-by":"publisher","first-page":"5475","DOI":"10.1128\/MCB.24.12.5475-5484.2004","volume":"24","author":"C Rougeulle","year":"2004","unstructured":"Rougeulle C, Chaumeil J, Sarma K, Allis CD, Reinberg D, Avner P, et al. Differential histone H3 Lys-9 and Lys-27 methylation profiles on the X chromosome. Mol Cell Biol. 2004;24(12):5475\u201384.","journal-title":"Mol Cell Biol"},{"issue":"4","key":"2174_CR20","doi-asserted-by":"publisher","first-page":"887","DOI":"10.5114\/aoms.2019.86060","volume":"15","author":"E Hosseini","year":"2019","unstructured":"Hosseini E, Shahhoseini M, Afsharian P, Karimian L, Ashrafi M, Mehraein F, et al. Role of epigenetic modifications in the aberrant CYP19A1 gene expression in polycystic ovary syndrome. Arch Med Sci. 2019;15(4):887\u201395.","journal-title":"Arch Med Sci"},{"issue":"8","key":"2174_CR21","first-page":"769","volume":"12","author":"Y Pan","year":"2003","unstructured":"Pan Y, Zhang JS, Gazi MH, Young CY. The cyclooxygenase 2-specific nonsteroidal anti-inflammatory drugs celecoxib and nimesulide inhibit androgen receptor activity via induction of c-Jun in prostate cancer cells. CEBP. 2003;12(8):769\u201374.","journal-title":"CEBP"},{"issue":"2","key":"2174_CR22","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/j.canlet.2004.04.003","volume":"213","author":"H Yuan","year":"2004","unstructured":"Yuan H, Pan Y, Young CY. Overexpression of c-Jun induced by quercetin and resverol inhibits the expression and function of the androgen receptor in human prostate cancer cells. Cancer Lett. 2004;213(2):155\u201363.","journal-title":"Cancer Lett"},{"issue":"12","key":"2174_CR23","doi-asserted-by":"publisher","first-page":"1152","DOI":"10.1593\/neo.07769","volume":"9","author":"F Alimirah","year":"2007","unstructured":"Alimirah F, Panchanathan R, Chen J, Zhang X, Ho SM, Choubey D. Expression of androgen receptor is negatively regulated by p53. Neoplasia. 2007;9(12):1152\u20139.","journal-title":"Neoplasia"},{"issue":"1","key":"2174_CR24","doi-asserted-by":"publisher","first-page":"5364","DOI":"10.1038\/s41467-019-13339-3","volume":"10","author":"H MacKay","year":"2019","unstructured":"MacKay H, Scott CA, Duryea JD, Baker MS, Laritsky E, Elson AE, et al. DNA methylation in AgRP neurons regulates voluntary exercise behavior in mice. Nat Commun. 2019;10(1):5364.","journal-title":"Nat Commun"},{"issue":"1","key":"2174_CR25","doi-asserted-by":"publisher","first-page":"5464","DOI":"10.1038\/ncomms6464","volume":"5","author":"A Fukuda","year":"2014","unstructured":"Fukuda A, Tomikawa J, Miura T, Hata K, Nakabayashi K, Eggan K, et al. The role of maternal-specific H3K9me3 modification in establishing imprinted X-chromosome inactivation and embryogenesis in mice. Nat Commun. 2014;5(1):5464.","journal-title":"Nat Commun"}],"container-title":["Reproductive Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s43032-026-02174-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s43032-026-02174-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s43032-026-02174-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T15:09:14Z","timestamp":1789052954000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s43032-026-02174-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,21]]},"references-count":25,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["2174"],"URL":"https:\/\/doi.org\/10.1007\/s43032-026-02174-9","relation":{},"ISSN":["1933-7191","1933-7205"],"issn-type":[{"value":"1933-7191","type":"print"},{"value":"1933-7205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,21]]},"assertion":[{"value":"25 November 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 August 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 August 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All experiments and protocols were approved by the Animal Ethics Committee of the University of Otago, and adhered to National Animal Welfare Advisory Committee, New Zealand guidelines.","order":1,"name":"Ethics","label":"Ethical Approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent to Participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":3,"name":"Ethics","label":"Consent for Publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors have no relevant financial or non-financial interests to disclose.","order":4,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}]}}