{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T15:10:12Z","timestamp":1793805012942,"version":"4.6.1"},"reference-count":83,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,12,20]],"date-time":"2024-12-20T00:00:00Z","timestamp":1734652800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002383","name":"King Saud University","doi-asserted-by":"publisher","award":["RSP2024R17"],"award-info":[{"award-number":["RSP2024R17"]}],"id":[{"id":"10.13039\/501100002383","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Acephate is an organophosphate foliar and soil insecticide that is used worldwide. In this study, the transgenerational ovarian developmental toxicity caused by acephate, along with its in utero reprogramming mechanisms, were explored. Thirty female virgin Wistar albino rats were randomly assigned to three groups: one control group and two acephate treatment groups. The treatment groups received daily low or high doses of acephate (34.2 mg\/kg or 68.5 mg\/kg body weight, respectively) from gestational day 6 until spontaneous labor, resulting in F1 offspring. At 28 days, a subgroup of F1 females were euthanized. The ovaries were extracted, thoroughly cleaned, and weighed before being fixed for further analysis. The remaining F1 females were mated with normal males to produce the F2 generation. The F1 female offspring presented reduced fertility and body weight, whereas the ovarian weight index and sex ratio increased in a dose-dependent manner. Structural analysis revealed altered follicular abnormalities with ovarian cells displaying pyknotic nuclei. Additionally, the gene and protein expression of Cyp19 decreased, whereas that of Gdf-9 increased in the high-dose treatment group (68.5 mg\/kg). We also observed significantly increased expression levels of ovarian estrogen receptor 1 (Esr1) and insulin-like growth factor 1 (Igf1), whereas Insl3 expression was significantly decreased. The F2 female offspring presented reproductive phenotype alterations similar to those of F1 females including decreased fertility, reduced Cyp19 gene and protein expression, and structural ovarian abnormalities similar to those of polycystic ovary syndrome (PCOS). In conclusion, acephate induced ovarian developmental toxicity across two generations of rats, which may be linked to changes in the ovarian Cyp19, Gdf9, Insl3, and Igf1 levels.<\/jats:p>","DOI":"10.3390\/biology13121075","type":"journal-article","created":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T02:39:56Z","timestamp":1734921596000},"page":"1075","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Acephate Exposure Induces Transgenerational Ovarian Developmental Toxicity by Altering the Expression of Follicular Growth Markers in Female Rats"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-6931-9848","authenticated-orcid":false,"given":"Abeer","family":"Alhazmi","sequence":"first","affiliation":[{"name":"Department of Zoology, College of Science, King Saud University, Riyadh P.O. Box 145111, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saber","family":"Nahdi","sequence":"additional","affiliation":[{"name":"Department of Zoology, College of Science, King Saud University, Riyadh P.O. Box 145111, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saleh","family":"Alwasel","sequence":"additional","affiliation":[{"name":"Department of Zoology, College of Science, King Saud University, Riyadh P.O. Box 145111, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2170-1303","authenticated-orcid":false,"given":"Abdel Halim","family":"Harrath","sequence":"additional","affiliation":[{"name":"Department of Zoology, College of Science, King Saud University, Riyadh P.O. Box 145111, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"105858","DOI":"10.1016\/j.envint.2020.105858","article-title":"Prenatal maternal organophosphorus pesticide exposures, paraoxonase 1, and childhood adiposity in the Mount Sinai Children\u2019s Environmental Health Study","volume":"142","author":"Etzel","year":"2020","journal-title":"Environ. Int."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Jalouli, M., Mofti, A., Elnakady, Y.A., Nahdi, S., Feriani, A., Alrezaki, A., Sebei, K., Bizzarri, M., Alwasel, S., and Harrath, A.H. (2022). Allethrin promotes apoptosis and autophagy associated with the oxidative stress-related PI3K\/AKT\/mTOR signaling pathway in developing rat ovaries. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23126397"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.tox.2016.10.010","article-title":"Acephate exposure during a perinatal life program to type 2 diabetes","volume":"372","author":"Ribeiro","year":"2016","journal-title":"Toxicology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/s12992-024-01040-0","article-title":"Burden of cardiovascular disease attributed to air pollution: A systematic review","volume":"20","author":"Khoshakhlagh","year":"2024","journal-title":"Glob. Health"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"152636","DOI":"10.1016\/j.tox.2020.152636","article-title":"Biochemical and histopathological responses in peripubertal male rats exposed to agrochemicals isolated or in combination: A multivariate data analysis study","volume":"447","author":"Aranha","year":"2021","journal-title":"Toxicology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.toxlet.2019.04.022","article-title":"Intrauterine programming of the glucocorticoid-insulin-like growth factor 1 (GC-IGF1) axis mediates glomerulosclerosis in female adult offspring rats induced by prenatal ethanol exposure","volume":"311","author":"He","year":"2019","journal-title":"Toxicol. Lett."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1111\/jne.12328","article-title":"Neonatal nicotine exposure leads to hypothalamic gliosis in adult overweight rats","volume":"27","author":"Moura","year":"2015","journal-title":"J. Neuroendocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"113081","DOI":"10.1016\/j.ecoenv.2021.113081","article-title":"Ethylbenzene exposure disrupts ovarian function in Wistar rats via altering folliculogenesis and steroidogenesis-related markers and activating autophagy and apoptosis","volume":"229","author":"Harrath","year":"2022","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1017\/S2040174419000060","article-title":"Intergenerational response of steroidogenesis-related genes to maternal malnutrition","volume":"10","author":"Harrath","year":"2019","journal-title":"J. Dev. Orig. Health Dis."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Alhelaisi, A., Alrezaki, A., Nahdi, S., Aldahmash, W., Alwasel, S., and Harrath, A.H. (2023). Early-Life Exposure to the Mycotoxin Fumonisin B1 and Developmental Programming of the Ovary of the Offspring: The Possible Role of Autophagy in Fertility Recovery. Toxics, 11.","DOI":"10.20944\/preprints202309.1557.v1"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"103790","DOI":"10.1016\/j.etap.2021.103790","article-title":"Pre-conceptional and prenatal exposure to pesticides and pediatric neuroblastoma. A meta-analysis of nine studies","volume":"90","author":"Khan","year":"2022","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_12","first-page":"9604","article-title":"Summary of the 2016 World Health Organization Report and 2021 Compendium on environmental diseases","volume":"11","author":"Bertolina","year":"2023","journal-title":"Work. Pap. Public Health"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3548","DOI":"10.1021\/es303525x","article-title":"Variability of pesticide dissipation half-lives in plants","volume":"47","author":"Fantke","year":"2013","journal-title":"Environ. Sci. Technol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1002\/ps.5332","article-title":"Do farmers misuse pesticides in crop production in China? Evidence from a farm household survey","volume":"75","author":"Sun","year":"2019","journal-title":"Pest Manag. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1177\/0748233712468017","article-title":"Toxicopathological evaluation in Wistar rats (Rattus norvegicus) following repeated oral exposure to acephate","volume":"31","author":"Bhadaniya","year":"2015","journal-title":"Toxicol. Ind. Health"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.foodchem.2006.05.003","article-title":"Determination of organochlorine and pyrethroid pesticides in fruit and vegetables using SAX\/PSA clean-up column","volume":"102","author":"Zawiyah","year":"2007","journal-title":"Food Chem."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Mufti, A., Jalouli, M., Nahdi, S., Tlili, N., Alqahtani, W., Mansour, L., Alwasel, S., and Harrath, A.H. (2023). Maternal Exposure to Acephate Caused Nephrotoxicity in Adult Offspring Rats Mediated by Excessive Autophagy Activation, Oxidative Stress Induction, and Altered Epithelial Sodium Channel and Na+\/K+-ATPase Gene Expression. Biology, 12.","DOI":"10.3390\/biology12020162"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1016\/j.chemosphere.2015.09.108","article-title":"Assessing the distribution and human health risk of organochlorine pesticide residues in sediments from selected rivers","volume":"144","author":"Ogbeide","year":"2016","journal-title":"Chemosphere"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1532","DOI":"10.1016\/j.scitotenv.2018.10.441","article-title":"Pesticide residues in European agricultural soils\u2013A hidden reality unfolded","volume":"653","author":"Silva","year":"2019","journal-title":"Sci. Total Environ."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S0048-9697(01)00868-3","article-title":"Association between chronic exposure to pesticides and recorded cases of human malignancy in Gaza Governorates (1990\u20131999)","volume":"284","author":"Safi","year":"2002","journal-title":"Sci. Total Environ."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"149","DOI":"10.4103\/jehp.jehp_148_19","article-title":"Chronic exposure to organophosphate pesticides as an important challenge in promoting reproductive health: A comparative study","volume":"8","author":"Ranjbar","year":"2019","journal-title":"J. Educ. Health Promot."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Mulla, S.I., Ameen, F., Talwar, M.P., Eqani, S.A.M.A.S., Bharagava, R.N., Saxena, G., Tallur, P.N., and Ninnekar, H.Z. (2020). Organophosphate pesticides: Impact on environment, toxicity, and their degradation. Bioremediation of Industrial Waste for Environmental Safety: Volume I: Industrial Waste and Its Management, Springer.","DOI":"10.1007\/978-981-13-1891-7_13"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1021\/jf504916b","article-title":"Enantioselective dissipation of acephate and its metabolite, methamidophos, during tea cultivation, manufacturing, and infusion","volume":"63","author":"Pan","year":"2015","journal-title":"J. Agric. Food Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1016\/j.arabjc.2014.12.007","article-title":"A review on sample preparation and chromatographic determination of acephate and methamidophos in different samples","volume":"8","author":"Kumar","year":"2015","journal-title":"Arab. J. Chem."},{"key":"ref_25","first-page":"155","article-title":"Association of methamidophos and sleep loss on reproductive toxicity of male mice","volume":"32","author":"Maia","year":"2011","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_26","first-page":"963","article-title":"Acephate induced oxidative damage in erythrocytes","volume":"40","author":"Thapar","year":"2002","journal-title":"Indian J. Exp. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1590\/S0102-05362005000100008","article-title":"Acephate and methamidophos residues in greenhouse and in field grown tomatoes","volume":"23","author":"Trevizan","year":"2005","journal-title":"Hortic. Bras."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1002\/ps.1667","article-title":"Dissipation of acephate, chlorpyrifos, cypermethrin and their metabolites in a humid-tropical vegetable production system","volume":"65","author":"Chai","year":"2009","journal-title":"Pest Manag. Sci. Former. Pestic. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.tox.2018.10.013","article-title":"Decreased H3K9ac level of AT2R mediates the developmental origin of glomerulosclerosis induced by prenatal dexamethasone exposure in male offspring rats","volume":"411","author":"Li","year":"2019","journal-title":"Toxicology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6887","DOI":"10.18632\/aging.204269","article-title":"Fetal programming: In utero exposure to acrylamide leads to intergenerational disrupted ovarian function and accelerated ovarian aging","volume":"14","author":"Aldawood","year":"2022","journal-title":"Aging"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1093\/toxsci\/kfl032","article-title":"Developmental neurotoxicity of organophosphorous pesticides: Fetal and neonatal exposure to chlorpyrifos alters sex-specific behaviors at adulthood in mice","volume":"93","author":"Ricceri","year":"2006","journal-title":"Toxicol. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1262\/jrd.18007","article-title":"Effect of gestational exposure to nonylphenol on the development and fertility of mouse offspring","volume":"52","author":"Kimura","year":"2006","journal-title":"J. Reprod. Dev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1292\/jvms.21-0014","article-title":"Effects of in utero and lactational exposure to the no-observed-adverse-effect level (NOAEL) dose of the neonicotinoid clothianidin on the reproductive organs of female mice","volume":"83","author":"Kitauchi","year":"2021","journal-title":"J. Vet. Med. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/s40471-016-0060-1","article-title":"Female infertility and \u201cemerging\u201d organic pollutants of concern","volume":"3","author":"Bloom","year":"2016","journal-title":"Curr. Epidemiol. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6442","DOI":"10.3390\/ijerph10126442","article-title":"Occupational pesticide exposures and respiratory health","volume":"10","author":"Ye","year":"2013","journal-title":"Int. J. Env. Res. Public Health"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Zaller, J.G. (2020). Pesticide impacts on the environment and humans. Daily Poison: Pesticides-an Underestimated Danger, Springer.","DOI":"10.1007\/978-3-030-50530-1"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Harrath, A.H., Rahman, M.A., Bhajan, S.K., Bishwas, A.K., Rahman, M.H., Alwasel, S., Jalouli, M., Kang, S., Park, M.N., and Kim, B. (2024). Autophagy and Female Fertility: Mechanisms, Clinical Implications, and Emerging Therapies. Cells, 13.","DOI":"10.3390\/cells13161354"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1186\/s13048-017-0372-x","article-title":"Food restriction during pregnancy and female offspring fertility: Adverse effects of reprogrammed reproductive lifespan","volume":"10","author":"Harrath","year":"2017","journal-title":"J. Ovarian Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"102575","DOI":"10.1016\/j.jksus.2023.102575","article-title":"Autophagy activation, histopathological damage, and altered renal epithelial sodium channel and Na+, K+-ATPase gene expression in offspring kidney after in utero exposure to allethrin","volume":"35","author":"Alqahtani","year":"2023","journal-title":"J. King Saud Univ.-Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1136\/jech.58.2.114","article-title":"Developmental origins of adult health and disease","volume":"58","author":"Barker","year":"2004","journal-title":"J. Epidemiol. Community Health"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/B978-0-444-53884-0.00022-1","article-title":"Perinatal brain damage in children: Neuroplasticity, early intervention, and molecular mechanisms of recovery","volume":"189","author":"Cioni","year":"2011","journal-title":"Prog. Brain Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1530\/rep.1.00033","article-title":"Endocrine mechanisms of intrauterine programming","volume":"127","author":"Fowden","year":"2004","journal-title":"Reproduction"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"323","DOI":"10.3923\/rjet.2011.323.335","article-title":"Effect of exposure to mixture of four organophosphate insecticides","volume":"5","author":"Mossa","year":"2011","journal-title":"Res. J. Environ. Toxicol"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.cbi.2005.08.004","article-title":"Protective effects of zinc on lipid peroxidation, antioxidant enzymes and hepatic histoarchitecture in chlorpyrifos-induced toxicity","volume":"156","author":"Goel","year":"2005","journal-title":"Chem.-Biol. Interact."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1177\/0960327109357276","article-title":"Adverse effects of lactational exposure to chlorpyrifos in suckling rats","volume":"29","author":"Mansour","year":"2010","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1002\/ajhb.22374","article-title":"Intergenerational effects of in utero exposure to Ramadan in Tunisia","volume":"25","author":"Alwasel","year":"2013","journal-title":"Am. J. Hum. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.apjr.2015.05.001","article-title":"Effects of low dose acrylamide on the rat reproductive organs structure, fertility and gene integrity","volume":"4","author":"ALKarim","year":"2015","journal-title":"Asian Pac. J. Reprod."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Duan, X., Wang, Q.-C., Chen, K.-L., Zhu, C.-C., Liu, J., and Sun, S.-C. (2015). Acrylamide toxic effects on mouse oocyte quality and fertility in vivo. Sci. Rep., 5.","DOI":"10.1038\/srep11562"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.reprotox.2009.11.002","article-title":"Reproductive toxicity of acrylamide-treated male rats","volume":"29","author":"Wang","year":"2010","journal-title":"Reprod. Toxicol."},{"key":"ref_50","first-page":"79","article-title":"Reproductive toxic effects of ingestion of sodium fluoride in female rats","volume":"33","author":"Elbetieha","year":"2000","journal-title":"Fluoride"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Zaid, S.S.M., Othman, S., and Kassim, N.M. (2014). Potential protective effect of Tualang honey on BPA-induced ovarian toxicity in prepubertal rat. BMC Complement. Altern. Med., 14.","DOI":"10.1186\/1472-6882-14-509"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s00128-014-1312-8","article-title":"Exposure assessment to glyphosate of two species of annelids","volume":"93","author":"Romaniuk","year":"2014","journal-title":"Bull. Environ. Contam. Toxicol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Parisi, C., and Guerriero, G. (2019). Antioxidative defense and fertility rate in the assessment of reprotoxicity risk posed by global warming. Antioxidants, 8.","DOI":"10.3390\/antiox8120622"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1002\/acr.20510","article-title":"Luteinized unruptured follicle syndrome increased by inactive disease and selective cyclooxygenase 2 inhibitors in women with inflammatory arthropathies","volume":"63","author":"Micu","year":"2011","journal-title":"Arthritis Care Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/S0887-2333(00)00018-7","article-title":"Screening of selected pesticides for inhibition of CYP19 aromatase activity in vitro","volume":"14","author":"Vinggaard","year":"2000","journal-title":"Toxicol. Vitr."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1080\/03602530600569984","article-title":"Organophosphorus chemicals: Potent inhibitors of the human metabolism of steroid hormones and xenobiotics","volume":"38","author":"Hodgson","year":"2006","journal-title":"Drug Metab. Rev."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/s12041-017-0741-7","article-title":"CYP\/PON genetic variations as determinant of organophosphate pesticides toxicity","volume":"96","author":"Kaur","year":"2017","journal-title":"J Genet"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1093\/humupd\/dmm040","article-title":"Oocyte-secreted factors: Regulators of cumulus cell function and oocyte quality","volume":"14","author":"Gilchrist","year":"2008","journal-title":"Hum. Reprod. Update"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2740","DOI":"10.1210\/en.2008-1536","article-title":"Growth differentiation factor 9 promotes rat preantral follicle growth by up-regulating follicular androgen biosynthesis","volume":"150","author":"Orisaka","year":"2009","journal-title":"Endocrinology"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.reprotox.2011.10.010","article-title":"Acute reproductive toxicity of 3, 3\u2032-iminodipropionitrile in female rats","volume":"33","author":"Takahashi","year":"2012","journal-title":"Reprod. Toxicol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1095\/biolreprod.105.050633","article-title":"Consequences of fetal irradiation on follicle histogenesis and early follicle development in rat ovaries","volume":"75","author":"Guigon","year":"2006","journal-title":"Biol. Reprod."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/B978-012444562-8\/50022-7","article-title":"Follicle selection in mammalian ovaries: Regulatory mechanisms of granulosa cell apoptosis during follicular atresia","volume":"2004","author":"Manabe","year":"2004","journal-title":"Ovary"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1210\/mend.13.6.0309","article-title":"Molecular characterization of the follicle defects in the growth differentiation factor 9-deficient ovary","volume":"13","author":"Elvin","year":"1999","journal-title":"Mol. Endocrinol."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Hu, Q., Gui, Y., Cao, C., Xie, J., and Tang, H. (2023). Single-cell sequencing reveals transcriptional dynamics regulated by ER\u03b1 in mouse ovaries. PLoS ONE, 19.","DOI":"10.21203\/rs.3.rs-3728959\/v1"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Uenoyama, Y., Inoue, N., Nakamura, S., and Tsukamura, H. (2021). Kisspeptin neurons and estrogen\u2013estrogen receptor \u03b1 signaling: Unraveling the mystery of steroid feedback system regulating mammalian reproduction. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22179229"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1289\/ehp.5658","article-title":"Mechanisms of phthalate ester toxicity in the female reproductive system","volume":"111","author":"Davis","year":"2003","journal-title":"Environ. Health Perspect."},{"key":"ref_67","first-page":"282","article-title":"Examination of the in vitro and in vitro estrogenic activities of eight commercial phthalate esters","volume":"46","author":"Zacharewski","year":"1998","journal-title":"Toxicol. Sci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"4277","DOI":"10.1242\/dev.127.19.4277","article-title":"Effect of single and compound knockouts of estrogen receptors \u03b1 (ER\u03b1) and \u03b2 (ER\u03b2) on mouse reproductive phenotypes","volume":"127","author":"Dupont","year":"2000","journal-title":"Development"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"3247","DOI":"10.1210\/en.2005-0213","article-title":"Estrogen receptor-\u03b2 is critical to granulosa cell differentiation and the ovulatory response to gonadotropins","volume":"146","author":"Couse","year":"2005","journal-title":"Endocrinology"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"345","DOI":"10.2486\/indhealth.40.345","article-title":"Reproductive toxicity of carbofuran to the female mice: Effects on estrous cycle and follicles","volume":"40","author":"Baligar","year":"2002","journal-title":"Ind. Health"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.taap.2008.09.010","article-title":"Developmental methoxychlor exposure affects multiple reproductive parameters and ovarian folliculogenesis and gene expression in adult rats","volume":"233","author":"Armenti","year":"2008","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"SP147","DOI":"10.2131\/jts.34.S147","article-title":"Collaborative work on evaluation of ovarian toxicity 14) Two-or four-week repeated-dose studies and fertility study of atrazine in female rats","volume":"34","author":"Shibayama","year":"2009","journal-title":"J. Toxicol. Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1093\/humupd\/dmy029","article-title":"Insulin-like peptide 3 (INSL3) is a major regulator of female reproductive physiology","volume":"24","author":"Ivell","year":"2018","journal-title":"Hum. Reprod. Update"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.fertnstert.2005.07.019","article-title":"A novel hormone known as insulin-like factor 3 (INSL3) is expressed in the human ovary and serum levels are increased in women with polycystic ovary syndrome (PCOS)","volume":"84","author":"Havelock","year":"2005","journal-title":"Fertil. Steril."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1080\/09513590.2017.1416462","article-title":"Evaluation of the correlation between insulin like factor 3, polycystic ovary syndrome, and ovarian maldescent","volume":"34","author":"Seyam","year":"2018","journal-title":"Gynecol. Endocrinol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1054\/ghir.2001.0201","article-title":"Granulosa cell proliferation is impaired in the Igf1 null ovary","volume":"11","author":"Kadakia","year":"2001","journal-title":"Growth Horm. IGF Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1071\/RD18425","article-title":"Resveratrol directly affects ovarian cell sirtuin, proliferation, apoptosis, hormone release and response to follicle-stimulating hormone (FSH) and insulin-like growth factor I (IGF-I)","volume":"31","author":"Sirotkin","year":"2019","journal-title":"Reprod. Fertil. Dev."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1210\/me.2012-1307","article-title":"IGF-I signaling is essential for FSH stimulation of AKT and steroidogenic genes in granulosa cells","volume":"27","author":"Zhou","year":"2013","journal-title":"Mol. Endocrinol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.ecoenv.2019.06.017","article-title":"The interference of DEHP in precocious puberty of females mediated by the hypothalamic IGF-1\/PI3K\/Akt\/mTOR signaling pathway","volume":"181","author":"Shao","year":"2019","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1111\/cen.12682","article-title":"The relationship between Insulin-like Growth Factor 1, sex steroids and timing of the pubertal growth spurt","volume":"82","author":"Cole","year":"2015","journal-title":"Clin. Endocrinol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1039\/C6FO01616B","article-title":"Effects of pomegranate extract in supplementing gonadotropin-releasing hormone therapy on idiopathic central precocious puberty in Chinese girls: A randomized, placebo-controlled, double-blind clinical trial","volume":"8","author":"Liu","year":"2017","journal-title":"Food Funct."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.reprotox.2016.04.014","article-title":"Regulation of arcuate genes by developmental exposures to endocrine-disrupting compounds in female rats","volume":"62","author":"Roepke","year":"2016","journal-title":"Reprod. Toxicol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1210\/jc.2015-2706","article-title":"Relating phthalate and BPA exposure to metabolism in peripubescence: The role of exposure timing, sex, and puberty","volume":"101","author":"Watkins","year":"2016","journal-title":"J. Clin. Endocrinol."}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/13\/12\/1075\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:57:09Z","timestamp":1760115429000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/13\/12\/1075"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,20]]},"references-count":83,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["biology13121075"],"URL":"https:\/\/doi.org\/10.3390\/biology13121075","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,20]]}}}