{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T12:24:43Z","timestamp":1773663883716,"version":"3.50.1"},"reference-count":47,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,6,12]],"date-time":"2021-06-12T00:00:00Z","timestamp":1623456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012190","name":"Ministry of Science and Higher Education of the Russian Federation","doi-asserted-by":"publisher","award":["\u0410\u0410\u0410\u0410-\u041017-117013050048-6"],"award-info":[{"award-number":["\u0410\u0410\u0410\u0410-\u041017-117013050048-6"]}],"id":[{"id":"10.13039\/501100012190","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Dichlorodiphenyltrichloroethane (DDT) is a persistent organic pollutant and one of the most widespread endocrine disrupting chemicals. The impact of low-dose exposure to DDT on the morphogenesis of the adrenal gland is still poorly understood. The development and function of zona glomerulosa in rats has been found to be associated with changes in the expression of the transcription factor Oct4 (Octamer 4), which is the most important player in cell pluripotency. The aim of the study was to investigate the morphogenesis and function of rat adrenal zona glomerulosa in rats exposed to low doses of DDT during prenatal and postnatal development and to determine the possible role of Oct4 in DDT-mediated structural and functional changes. The DDT-exposed rats demonstrated slower development and lower functional activity of the zona glomerulosa during the pubertal period associated with higher expression of Oct4. Further, accelerated growth and restoration of hormone production was associated with, firstly, a decrease in Oct4 expressing cells and secondly, the loss of the inverse relationship between basal aldosterone levels and the number of Oct4 expressing cells. Thus, the transcriptional factor Oct4 exhibited an altered pattern of expression in the DDT-exposed rats during postnatal development. The results of the study uncover a novel putative mechanism by which low doses of DDT disrupt the development of adrenal zona glomerulosa.<\/jats:p>","DOI":"10.3390\/ijms22126324","type":"journal-article","created":{"date-parts":[[2021,6,14]],"date-time":"2021-06-14T10:30:25Z","timestamp":1623666625000},"page":"6324","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Impaired Morphogenesis and Function of Rat Adrenal Zona Glomerulosa by Developmental Low-Dose Exposure to DDT Is Associated with Altered Oct4 Expression"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8239-5039","authenticated-orcid":false,"given":"Nataliya V.","family":"Yaglova","sequence":"first","affiliation":[{"name":"Laboratory of Endocrine System Development, Federal State Budgetary Scientific Institution \u201cResearch Institute of Human Morphology\u201d, 117418 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergey S.","family":"Obernikhin","sequence":"additional","affiliation":[{"name":"Laboratory of Endocrine System Development, Federal State Budgetary Scientific Institution \u201cResearch Institute of Human Morphology\u201d, 117418 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dibakhan A.","family":"Tsomartova","sequence":"additional","affiliation":[{"name":"Laboratory of Endocrine System Development, Federal State Budgetary Scientific Institution \u201cResearch Institute of Human Morphology\u201d, 117418 Moscow, Russia"},{"name":"Department of Histology, Cytology, and Embryology, Federal State Funded Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University, 119435 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Svetlana V.","family":"Nazimova","sequence":"additional","affiliation":[{"name":"Laboratory of Endocrine System Development, Federal State Budgetary Scientific Institution \u201cResearch Institute of Human Morphology\u201d, 117418 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentin V.","family":"Yaglov","sequence":"additional","affiliation":[{"name":"Laboratory of Endocrine System Development, Federal State Budgetary Scientific Institution \u201cResearch Institute of Human Morphology\u201d, 117418 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elina S.","family":"Tsomartova","sequence":"additional","affiliation":[{"name":"Laboratory of Endocrine System Development, Federal State Budgetary Scientific Institution \u201cResearch Institute of Human Morphology\u201d, 117418 Moscow, Russia"},{"name":"Department of Histology, Cytology, and Embryology, Federal State Funded Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University, 119435 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1046-6336","authenticated-orcid":false,"given":"Elizaveta V.","family":"Chereshneva","sequence":"additional","affiliation":[{"name":"Department of Histology, Cytology, and Embryology, Federal State Funded Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University, 119435 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina Y.","family":"Ivanova","sequence":"additional","affiliation":[{"name":"Department of Histology, Cytology, and Embryology, Federal State Funded Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University, 119435 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatiana A.","family":"Lomanovskaya","sequence":"additional","affiliation":[{"name":"Department of Histology, Cytology, and Embryology, Federal State Funded Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University, 119435 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4097","DOI":"10.1210\/en.2012-1422","article-title":"Endocrine disrupting chemicals and public health protection: A statement of principles from The Endocrine Society","volume":"153","author":"Zoeller","year":"2012","journal-title":"Endocrinology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1210\/er.2009-0002","article-title":"Endocrine-disrupting chemicals: An Endocrine Society scientific statement","volume":"30","author":"Bourguignon","year":"2009","journal-title":"Endocr. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Calsolaro, V., Pasqualetti, G., Niccolai, F., Caraccio, N., and Monzani, F. (2017). Thyroid disrupting chemicals. Int. J. Mol. Sci., 18.","DOI":"10.20944\/preprints201711.0026.v1"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.etap.2017.02.024","article-title":"Human exposure to endocrine disrupting chemicals: Effects on the male and female reproductive systems","volume":"51","author":"Sifakis","year":"2017","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Street, M.E., Angelini, S., Bernasconi, S., Burgio, E., Cassio, A., Catellani, C., Cirillo, F., Deodati, A., Fabbrizi, E., and Fanos, V. (2018). Current knowledge on endocrine disrupting chemicals (EDCs) from animal biology to humans, from pregnancy to adulthood: Highlights from a national Italian meeting. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19061647"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"112","DOI":"10.3389\/fendo.2019.00112","article-title":"Endocrine disrupting chemicals: An occult mediator of metabolic disease","volume":"10","author":"Papalou","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"E1","DOI":"10.1210\/er.2015-1010","article-title":"EDC-2, The Endocrine Society\u2019s second scientific statement on endocrine-disrupting chemicals","volume":"36","author":"Gore","year":"2015","journal-title":"Endocr. Rev."},{"key":"ref_8","first-page":"45","article-title":"Consensus on the key characteristics of endocrine-disrupting chemicals as a basis for hazard identification","volume":"18","author":"Vandenberg","year":"2020","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_9","unstructured":"World Health Organization (2019). Pesticide Residues in Food\u20142018. Toxicological Evaluations, WHO. World Health Organization and Food and Agriculture Organization of the United Nations."},{"key":"ref_10","unstructured":"World Health Organization (2016). Pesticide Residues in Food\u20142016 Evaluations. Part II\u2014Toxicological, WHO."},{"key":"ref_11","unstructured":"Hayes, W.J., and Edwards, R.L. (1999). Recognized and possible exposure to pesticide. Handbook of Pesticide Toxicology, Academic Press."},{"key":"ref_12","first-page":"7","article-title":"Global surveillance of DDT and DDE levels in human tissues","volume":"16","author":"Jaga","year":"2003","journal-title":"Int. J. Occup. Med. Environ. Health"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/375581a0","article-title":"Persistent DDT metabolite p,p\u2019-DDE is a potent androgen receptor antagonist","volume":"375","author":"Kelce","year":"1995","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/j.taap.2013.09.024","article-title":"o,p\u2019-DDT-mediated uterotrophy and gene expression in immature C57BL\/6 mice and Sprague-Dawley rats","volume":"273","author":"Kwekel","year":"2013","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1289\/ehp.8741","article-title":"Persistent pesticides in human breast milk and cryptorchidism","volume":"114","author":"Damgaard","year":"2006","journal-title":"Environ. Health Perspect."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/j.chemosphere.2010.04.055","article-title":"Hypospadias and halogenated organic pollutant levels in maternal mid-pregnancy serum samples","volume":"80","author":"Carmichael","year":"2010","journal-title":"Chemosphere"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.mce.2011.01.006","article-title":"Hypospadias: Interactions between environment and genetics","volume":"335","author":"Kalfa","year":"2011","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/B978-0-12-800095-3.00002-X","article-title":"Agricultural pesticides and precocious puberty","volume":"94","author":"Ozen","year":"2014","journal-title":"Vitam. Horm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.envres.2013.09.001","article-title":"Long-term exposure to organochlorine pesticides and thyroid status in adults in a heavily contaminated area in Brazil","volume":"127","author":"Freire","year":"2013","journal-title":"Environ. Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Alsen, M., Sinclair, C., Cooke, P., Ziadkhanpour, K., Genden, E., and van Gerven, M. (2021). Endocrine Disrupting Chemicals and Thyroid Cancer: An Overview. Toxics, 9.","DOI":"10.3390\/toxics9010014"},{"key":"ref_21","first-page":"29","article-title":"Mechanisms mediating environmental chemical-induced endocrine disruption in the adrenal gland","volume":"6","author":"Papadopoulos","year":"2015","journal-title":"Front. Endocrinol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"dvx017","DOI":"10.1093\/eep\/dvx017","article-title":"Epigenetic impact of endocrine disrupting chemicals on lipid homeostasis and atherosclerosis: A pregnane X receptor-centric view","volume":"3","author":"Helsley","year":"2017","journal-title":"Environ. Epigenet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1111\/bcpt.12878","article-title":"Understanding epigenetic effects of endocrine disrupting chemicals: From mechanisms to novel test methods","volume":"122","author":"Ruegg","year":"2018","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1134\/S1062359018060122","article-title":"The role of the canonical Wnt-signaling pathway in morphogenesis and regeneration of the adrenal cortex in rats exposed to the endocrine disruptor dichlorodiphenyltrichloroethane during prenatal and postnatal development","volume":"46","author":"Yaglova","year":"2019","journal-title":"Biol. Bull."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"772","DOI":"10.3389\/fendo.2019.00772","article-title":"Stem cells, self-renewal, and lineage commitment in the endocrine system","volume":"10","author":"Mariniello","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"25438","DOI":"10.1038\/srep25438","article-title":"Nanog, Oct4 and Tet1 interplay in establishing pluripotency","volume":"6","author":"Olariu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1038\/cr.2008.309","article-title":"Yamanaka factors critically regulate the developmental signaling network in mouse embryonic stem cells","volume":"18","author":"Liu","year":"2008","journal-title":"Cell Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1634\/stemcells.2006-0611","article-title":"Oct-4 expression in adult human differentiated cells challenges its role as a pure stem cell marker","volume":"25","author":"Zangrossi","year":"2007","journal-title":"Stem Cells"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.humpath.2013.08.006","article-title":"Cytoplasmic OCT4 staining is a sensitive marker of neuroendocrine differentiation","volume":"45","author":"Alexander","year":"2014","journal-title":"Hum. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1007\/s10517-019-04573-2","article-title":"Role of transcription factor Oct4 in postnatal development and function of the adrenal cortex","volume":"167","author":"Yaglova","year":"2019","journal-title":"Bull. Exp. Biol. Med."},{"key":"ref_31","first-page":"568","article-title":"Transcriptional regulation of morphogenesis of rat adrenal zona glomerulosa during postnatal development","volume":"167","author":"Obernikhin","year":"2019","journal-title":"Clin. Exp. Morphol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/S0303-7207(98)00045-8","article-title":"The development of the adrenal gland zona glomerulosa in the rat. A morphological, immunohistochemical and biochemical study","volume":"140","author":"Pignatelli","year":"1998","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.stem.2007.07.020","article-title":"Oct4 expression is not required for mouse somatic stem cell self-renewal","volume":"1","author":"Lengner","year":"2007","journal-title":"Cell Stem Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3655","DOI":"10.1016\/j.sjbs.2020.08.009","article-title":"Developmental exposure to endocrine disrupter dichlorodiphenyltrichloroethane alters transcriptional regulation of postnatal morphogenesis of adrenal zona fasciculata","volume":"27","author":"Yaglova","year":"2020","journal-title":"Saudi J. Biol. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1002\/stem.1382","article-title":"Repression of Zeb1 and hypoxia cause sequential MET and induction of Aid, Oct4, and Dnmt1, leading to immortalization and multipotential reprogramming of fibroblasts in spheres","volume":"31","author":"Liu","year":"2013","journal-title":"Stem Cells"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/dna.2017.3780","article-title":"Networks of transcription factors for Oct4 expression in mice","volume":"36","author":"Li","year":"2017","journal-title":"DNA Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1677\/joe.0.1720595","article-title":"Oxygen-dependence of ACTH-stimulated aldosterone and corticosterone synthesis in the rat adrenal cortex: Developmental aspects","volume":"172","author":"Bruder","year":"2002","journal-title":"J. Endocrinol."},{"key":"ref_38","first-page":"185","article-title":"Chronic hypoxia induced ultrastructural changes in the rat adrenal zona glomerulosa","volume":"17","author":"Lorente","year":"2002","journal-title":"Histol. Histopathol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"163","DOI":"10.2183\/pjab.90.163","article-title":"Functional zonation of the rat adrenal cortex: The development and maintenance","volume":"90","author":"Mitani","year":"2014","journal-title":"Proc. Jpn. Acad. Ser. B Phys. Biol. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"107524","DOI":"10.1016\/j.celrep.2020.107524","article-title":"Beta-catenin causes adrenal hyperplasia by blocking zonal transdifferentiation","volume":"31","author":"Pignatti","year":"2020","journal-title":"Cell Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3908","DOI":"10.1016\/j.bbagen.2012.03.012","article-title":"Thyroid hormone receptors, cell growth and differentiation","volume":"1830","author":"Pascual","year":"2013","journal-title":"Biochem. Biophys. Acta"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"bqab047","DOI":"10.1210\/endocr\/bqab047","article-title":"Thyroid hormones regulate goblet cell differentiation and Fgf19-Fgfr4 signaling","volume":"162","author":"Blitz","year":"2021","journal-title":"Endocrinology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.envint.2015.09.004","article-title":"Prenatal DDT and DDE exposure and child IQ in the CHAMACOS cohort","volume":"85","author":"Gaspar","year":"2015","journal-title":"Environ. Int."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.envres.2017.04.013","article-title":"Effect of exposure to p,p-DDE during the first half of pregnancy in the maternal thyroid profile of female residents in a Mexican floriculture area","volume":"156","author":"Cebrian","year":"2017","journal-title":"Environ. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"743","DOI":"10.3389\/fendo.2019.00743","article-title":"Pesticides with potential thyroid hormone-disrupting effects: A review of recent data","volume":"10","author":"Leemans","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1677\/joe.1.06972","article-title":"Adrenarche in the rat","volume":"191","author":"Pignatelli","year":"2006","journal-title":"J. Endocrinol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1248\/jhs.56.566","article-title":"Human blood concentrations of dichlorodiphenyltrichloroethane (DDT) extrapolated from metabolism in rats and humans and physiologically based pharmacokinetic modeling","volume":"56","author":"Yamazaki","year":"2010","journal-title":"J. Health Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/12\/6324\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:13:49Z","timestamp":1760163229000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/12\/6324"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,12]]},"references-count":47,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["ijms22126324"],"URL":"https:\/\/doi.org\/10.3390\/ijms22126324","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,12]]}}}