{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T13:09:38Z","timestamp":1772456978229,"version":"3.50.1"},"reference-count":107,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2024,12,24]],"date-time":"2024-12-24T00:00:00Z","timestamp":1734998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of University and Research"},{"name":"Inv.M4.C2.1.1 PNRR"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Di-(2-ethylhexyl) phthalate (DEHP) and Cadmium (Cd) affect female reproduction. To date, toxicological research has focused on the effects of individual contaminants, whereas living beings are exposed to mixtures. This study analyzed the effects of a DEHP\/Cd mixture on nuclear and cytoplasmic maturation of sheep cumulus\u2013oocyte complexes (COCs) compared with single compounds. COCs recovered from slaughterhouses-derived sheep ovaries were in vitro exposed to 0.5 \u03bcM DEHP, 0.1 \u03bcM Cd, or DEHP\/Cd mixture at the same concentrations during 24 h of in vitro maturation (IVM). After IVM, oocyte nuclear chromatin configuration was evaluated, and bioenergetic\/oxidative parameters were assessed on expanded cumulus cells (CCs) and matured oocytes (chi-square test and one-way ANOVA; p &lt; 0.05). Under examined conditions, oocyte nuclear maturation was never impaired. However, COC bioenergetics was affected with stronger effects for the mixture than single compounds. Indeed, the percentages of matured oocytes with healthy mitochondrial distribution patterns were reduced (p &lt; 0.001 and p &lt; 0.05 for mixture and single compounds, respectively). Oocyte mitochondrial membrane potential, intracellular ROS levels, and mitochondria\/ROS co-localization were reduced, with the same significance level, in all contaminated conditions. CCs displayed increased ROS levels only upon mixture exposure (p &lt; 0.001). In conclusion, in vitro exposure to the DEHP\/Cd mixture affected COC quality in the sheep to a greater extent than separate compounds.<\/jats:p>","DOI":"10.3390\/ijms26010005","type":"journal-article","created":{"date-parts":[[2024,12,24]],"date-time":"2024-12-24T02:50:56Z","timestamp":1735008656000},"page":"5","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["In Vitro Toxicity of a DEHP and Cadmium Mixture on Sheep Cumulus\u2013Oocyte Complexes"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7136-4029","authenticated-orcid":false,"given":"Antonella","family":"Mastrorocco","sequence":"first","affiliation":[{"name":"Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, 70125 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5673-6111","authenticated-orcid":false,"given":"Letizia","family":"Temerario","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, 70125 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3549-9052","authenticated-orcid":false,"given":"Valeria","family":"Vurchio","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, 70125 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5796-0094","authenticated-orcid":false,"given":"Susanna","family":"Cotecchia","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, 70125 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6853-2757","authenticated-orcid":false,"given":"Nicola Antonio","family":"Martino","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, 70125 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Elena","family":"Dell\u2019Aquila","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, 70125 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1001\/jama.2021.4788","article-title":"Diagnosis and Management of Infertility","volume":"326","author":"Carson","year":"2021","journal-title":"JAMA"},{"key":"ref_2","unstructured":"World Health Organization (2023). Infertility Prevalence Estimates, 1990\u20132021, World Health Organization."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1061\/(ASCE)0733-9372(2002)128:1(1)","article-title":"Environmental Engineering and Endocrine Disrupting Chemicals","volume":"128","author":"Sayles","year":"2002","journal-title":"J. Environ. Eng."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1001\/jamainternmed.2016.5766","article-title":"Endocrine-Disrupting Chemicals","volume":"176","author":"Gore","year":"2016","journal-title":"JAMA Intern. Med."},{"key":"ref_5","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_6","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/S2213-8587(20)30129-7","article-title":"Endocrine-disrupting chemicals: Implications for human health","volume":"8","author":"Kahn","year":"2020","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/j.etap.2012.08.013","article-title":"Di-(2-ethylhcxyl) phthalate reduces progesterone levels and induces apoptosis of ovarian granulosa cell in adult female ICR mice","volume":"34","author":"Li","year":"2012","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","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":"ref_9","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1007\/s40618-022-01983-4","article-title":"Endocrine-disrupting chemicals (EDCs) and cancer: New perspectives on an old relationship","volume":"46","author":"Modica","year":"2022","journal-title":"J. Endocrinol. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"R87","DOI":"10.1530\/EC-20-0578","article-title":"Obesity and endocrine-disrupting chemicals","volume":"10","author":"Amato","year":"2021","journal-title":"Endocr. Connect."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Hinault, C., Caroli-Bosc, P., Bost, F., and Chevalier, N. (2023). Critical Overview on Endocrine Disruptors in Diabetes Mellitus. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24054537"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"117385","DOI":"10.1016\/j.envres.2023.117385","article-title":"Endocrine disruptors: Unravelling the link between chemical exposure and Women\u2019s reproductive health","volume":"241","author":"Hassan","year":"2023","journal-title":"Environ. Res."},{"key":"ref_13","first-page":"91","article-title":"Migration of phthalates from plastic containers into soft drinks and mineral water","volume":"45","year":"2007","journal-title":"Food Technol. Biotechnol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.scitotenv.2013.04.056","article-title":"Study on the leaching of phthalates from polyethylene terephthalate bottles into mineral water","volume":"458\u2013460","author":"Keresztes","year":"2013","journal-title":"Sci. Total Environ."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"8518","DOI":"10.1007\/s11356-015-5946-9","article-title":"Estrogenic effects in the influents and effluents of the drinking water treatment plants","volume":"23","author":"Gou","year":"2016","journal-title":"Environ. Sci. Pollut. Res."},{"key":"ref_16","doi-asserted-by":"crossref","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":"ref_17","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1080\/10934529.2019.1637207","article-title":"Human exposure to phthalates from house dust in Bangkok, Thailand","volume":"54","author":"Promtes","year":"2019","journal-title":"J. Environ. Sci. Health Part A"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"141564","DOI":"10.1016\/j.chemosphere.2024.141564","article-title":"Pollution characteristics, sources, and health risks of phthalate esters in ambient air: A daily continuous monitoring study in the central Chinese city of Nanchang","volume":"353","author":"Guo","year":"2024","journal-title":"Chemosphere"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"134423","DOI":"10.1016\/j.jhazmat.2024.134423","article-title":"A systematic review of global distribution, sources and exposure risk of phthalate esters (PAEs) in indoor dust","volume":"471","author":"Li","year":"2024","journal-title":"J. Hazard. Mater."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"150980","DOI":"10.1016\/j.scitotenv.2021.150980","article-title":"Exposure of childbearing-aged female to phthalates through the use of personal care products in China: An assessment of absorption via dermal and its risk characterization","volume":"807","author":"Li","year":"2021","journal-title":"Sci. Total Environ."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"117028","DOI":"10.1016\/j.envres.2023.117028","article-title":"Assessment of the plasticizer exposure of hospital workers regularly handling medical devices: A pilot study","volume":"237","author":"Eckert","year":"2023","journal-title":"Environ. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1289\/ehp.6202","article-title":"In utero exposure to di-(2-ethylhexyl)phthalate and duration of human pregnancy","volume":"111","author":"Latini","year":"2003","journal-title":"Environ. Health Perspect."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6626","DOI":"10.1021\/acs.est.8b00838","article-title":"Distribution of Phthalate Metabolites between Paired Maternal\u2013Fetal Samples","volume":"52","author":"Li","year":"2018","journal-title":"Environ. Sci. Technol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1093\/jat\/34.7.400","article-title":"Correlations Between Phthalate Metabolites in Urine, Serum, and Seminal Plasma from Young Danish Men Determined by Isotope Dilution Liquid Chromatography Tandem Mass Spectrometry","volume":"34","author":"Frederiksen","year":"2010","journal-title":"J. Anal. Toxicol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1016\/j.scitotenv.2017.10.189","article-title":"Associations of urinary phthalate metabolites with residential characteristics, lifestyles, and dietary habits among young children in Shanghai, China","volume":"616\u2013617","author":"Liao","year":"2018","journal-title":"Sci. Total Environ."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.envpol.2015.12.052","article-title":"Semen phthalate metabolites, semen quality parameters and serum reproductive hormones: A cross-sectional study in China","volume":"211","author":"Wang","year":"2016","journal-title":"Environ. Pollut."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"126149","DOI":"10.1016\/j.chemosphere.2020.126149","article-title":"Associations of lifestyle factors with phthalate metabolites, bisphenol A, parabens, and triclosan concentrations in breast milk of Korean mothers","volume":"249","author":"Kim","year":"2020","journal-title":"Chemosphere"},{"key":"ref_28","unstructured":"Krej\u010d\u00edkov\u00e1, M., and Jaro\u0161ov\u00e1, A. (2013, January 20\u201321). Phthalate in cow milk depending on the method of milking. Proceedings of the MENDELNET 2013, Brno, Czech Republic."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1289\/ehp.7469","article-title":"Alkyl Phenols and Diethylhexyl Phthalate in Tissues of Sheep Grazing Pastures Fertilized with Sewage Sludge or Inorganic Fertilizer","volume":"113","author":"Rhind","year":"2005","journal-title":"Environ. Health Perspect."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1007\/s00204-004-0558-z","article-title":"Kinetics of orally administered di(2-ethylhexyl) phthalate and its metabolite, mono(2-ethylhexyl) phthalate, in male pigs","volume":"78","author":"Ljungvall","year":"2004","journal-title":"Arch. Toxicol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1016\/j.fertnstert.2019.01.021","article-title":"Follicular fluid concentrations of phthalate metabolites are associated with altered intrafollicular reproductive hormones in women undergoing in vitro fertilization","volume":"111","author":"Du","year":"2019","journal-title":"Fertil. Steril."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1590","DOI":"10.1093\/humrep\/deab063","article-title":"Association between follicular fluid phthalate concentrations and extracellular vesicle microRNAs expression","volume":"36","author":"Knapp","year":"2021","journal-title":"Hum. Reprod."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.3346\/jkms.2021.36.e1","article-title":"The Association of Ovarian Reserve with Exposure to Bisphenol A and Phthalate in Reproductive-aged Women","volume":"36","author":"Park","year":"2021","journal-title":"J. Korean Med. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1038\/s41370-023-00579-1","article-title":"Associations between lifestyle factors and levels of per- and polyfluoroalkyl substances (PFASs), phthalates and parabens in follicular fluid in women undergoing fertility treatment","volume":"33","author":"Hallberg","year":"2023","journal-title":"J. Expo. Sci. Environ. Epidemiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"108383","DOI":"10.1016\/j.envint.2023.108383","article-title":"Ovarian follicular fluid levels of phthalates and benzophenones in relation to fertility outcomes","volume":"183","author":"Beck","year":"2023","journal-title":"Environ. Int."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Gokyer, D., Laws, M.J., Kleinhans, A., Riley, J.K., Flaws, J.A., and Babayev, E. (2024). Phthalates are detected in the follicular fluid of adolescents and oocyte donors with associated changes in the cumulus cell transcriptome. bioRxiv.","DOI":"10.1101\/2024.04.04.588126"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1677\/JOE-07-0238","article-title":"The influence of di-(2-ethylhexyl) phthalate on steroidogenesis by the ovarian granulosa cells of immature female rats","volume":"194","author":"Svechnikova","year":"2007","journal-title":"J. Endocrinol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Ambruosi, B., Uranio, M.F., Sardanelli, A.M., Pocar, P., Martino, N.A., Paternoster, M.S., Amati, F., and Dell\u2019Aquila, M.E. (2011). In Vitro Acute Exposure to DEHP Affects Oocyte Meiotic Maturation, Energy and Oxidative Stress Parameters in a Large Animal Model. PLoS ONE, 6.","DOI":"10.1371\/annotation\/4eeebe50-1b31-422c-94a0-effcf9eda85f"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1007\/s10565-012-9230-1","article-title":"Effect of di-(2-ethylhexyl) phthalate and mono-(2-ethylhexyl) phthalate on in vitro developmental competence of bovine oocytes","volume":"28","author":"Grossman","year":"2012","journal-title":"Cell Biol. Toxicol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.taap.2015.02.010","article-title":"Di(2-ethylhexyl) phthalate inhibits antral follicle growth, induces atresia, and inhibits steroid hormone production in cultured mouse antral follicles","volume":"284","author":"Hannon","year":"2015","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Kalo, D., Hadas, R., Furman, O., Ben-Ari, J., Maor, Y., Patterson, D.G., Tomey, C., and Roth, Z. (2015). Carryover Effects of Acute DEHP Exposure on Ovarian Function and Oocyte Developmental Competence in Lactating Cows. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0130896"},{"key":"ref_42","doi-asserted-by":"crossref","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":"ref_43","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1002\/em.22037","article-title":"Di(2-ethylhexyl)phthalate: Adverse effects on folliculogenesis that cannot be neglected","volume":"57","author":"Zhang","year":"2016","journal-title":"Environ. Mol. Mutagen."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1002\/mrd.23156","article-title":"Altered morphokinetics in equine embryos from oocytes exposed to DEHP during IVM","volume":"86","author":"Marzano","year":"2019","journal-title":"Mol. Reprod. Dev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"114629","DOI":"10.1016\/j.taap.2019.114629","article-title":"Prenatal and ancestral exposure to di(2-ethylhexyl) phthalate alters gene expression and DNA methylation in mouse ovaries","volume":"379","author":"Rattan","year":"2019","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"116088","DOI":"10.1016\/j.envpol.2020.116088","article-title":"Di (2-ethylhexyl) phthalate impairs primordial follicle assembly by increasing PDE3A expression in oocytes","volume":"270","author":"Liu","year":"2020","journal-title":"Environ. Pollut."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4992","DOI":"10.7150\/thno.55006","article-title":"Single-cell transcriptome dissection of the toxic impact of Di (2-ethylhexyl) phthalate on primordial follicle assembly","volume":"11","author":"Wang","year":"2021","journal-title":"Theranostics"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"48","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":"ref_49","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1016\/j.scitotenv.2018.12.096","article-title":"Cadmium pigments in consumer products and their health risks","volume":"657","author":"Turner","year":"2019","journal-title":"Sci. Total. Environ."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Satarug, S. (2018). Dietary Cadmium Intake and Its Effects on Kidneys. Toxics, 6.","DOI":"10.3390\/toxics6010015"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1289\/ehp.0901234","article-title":"Cadmium, Environmental Exposure, and Health Outcomes","volume":"118","author":"Satarug","year":"2010","journal-title":"Environ. Health Perspect."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.envres.2006.05.009","article-title":"House dust as possible route of environmental exposure to cadmium and lead in the adult general population","volume":"103","author":"Hogervorst","year":"2006","journal-title":"Environ. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/j.scitotenv.2017.11.144","article-title":"Characteristics and health risk assessment of heavy metals exposure via household dust from urban area in Chengdu, China","volume":"61\u2013620","author":"Cheng","year":"2018","journal-title":"Sci. Total Environ."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.envpol.2017.12.114","article-title":"Gut as a target for cadmium toxicity","volume":"235","author":"Tinkov","year":"2018","journal-title":"Environ. Pollut."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s00128-020-03088-1","article-title":"A review on Cadmium Exposure in the Population and Intervention Strategies Against Cadmium Toxicity","volume":"106","author":"Wang","year":"2021","journal-title":"Bull. Environ. Contam. Toxicol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"hoab023","DOI":"10.1093\/hropen\/hoab023","article-title":"Toxic elements in follicular fluid adversely influence the likelihood of pregnancy and live birth in women undergoing IVF","volume":"2021","author":"Butts","year":"2021","journal-title":"Hum. Reprod. Open"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Flora, S.J., and Agrawal, S. (2017). Arsenic, cadmium, and lead. Reproductive and Developmental Toxicology, Academic Press.","DOI":"10.1016\/B978-0-12-804239-7.00031-7"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.reprotox.2008.02.001","article-title":"Cadmium: Toxic effects on the reproductive system and the embryo","volume":"25","author":"Thompson","year":"2008","journal-title":"Reprod. Toxicol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/S0890-6238(01)00139-3","article-title":"Lead accumulation in the mouse ovary after treatment-induced follicular atresia","volume":"15","author":"Taupeau","year":"2001","journal-title":"Reprod. Toxicol."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Miglietta, S., Cristiano, L., Battaglione, E., Macchiarelli, G., Nottola, S.A., De Marco, M.P., Costanzi, F., Schimberni, M., Colacurci, N., and Caserta, D. (2023). Heavy Metals in Follicular Fluid Affect the Ultrastructure of the Human Mature Cumulus-Oocyte Complex. Cells, 12.","DOI":"10.20944\/preprints202310.0843.v1"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Zhao, L.-L., Ru, Y.-F., Liu, M., Tang, J.-N., Zheng, J.-F., Wu, B., Gu, Y.-H., and Shi, H.-J. (2017). Reproductive effects of cadmium on sperm function and early embryonic development in vitro. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0186727"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"158882","DOI":"10.1016\/j.scitotenv.2022.158882","article-title":"The association between exposure to multiple toxic metals and the risk of endometriosis: Evidence from the results of blood and follicular fluid","volume":"855","author":"Shen","year":"2022","journal-title":"Sci. Total Environ."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1002\/jat.3767","article-title":"Exposure to cadmium and mono-(2-ethylhexyl) phthalate induce biochemical changes in rat liver, spleen, lung and kidney as determined by attenuated total reflection-Fourier transform infrared spectroscopy","volume":"39","author":"Zhu","year":"2019","journal-title":"J. Appl. Toxicol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.reprotox.2017.02.005","article-title":"Exposure to cadmium during in vitro maturation at environmental nanomolar levels impairs oocyte fertilization through oxidative damage: A large animal model study","volume":"69","author":"Martino","year":"2017","journal-title":"Reprod. Toxicol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"S73","DOI":"10.1016\/j.ijvsm.2018.03.001","article-title":"The effect of cadmium on the Bovinein vitrooocyte maturation and early embryo development","volume":"6","author":"Akar","year":"2018","journal-title":"Int. J. Veter. Sci. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"113194","DOI":"10.1016\/j.envpol.2019.113194","article-title":"Glutathione alleviates the cadmium exposure-caused porcine oocyte meiotic defects via eliminating the excessive ROS","volume":"255","author":"Zhou","year":"2019","journal-title":"Environ. Pollut."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.reprotox.2020.06.009","article-title":"Chronic cadmium exposure causes oocyte meiotic arrest by disrupting spindle assembly checkpoint and maturation promoting factor","volume":"96","author":"Dong","year":"2020","journal-title":"Reprod. Toxicol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1186\/s13048-022-01053-6","article-title":"Expression of long noncoding RNAs in the ovarian granulosa cells of women with diminished ovarian reserve using high-throughput sequencing","volume":"15","author":"Dong","year":"2022","journal-title":"J. Ovarian Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.jhazmat.2017.10.014","article-title":"An overview of chemical additives present in plastics: Migration, release, fate and environmental impact during their use, disposal and recycling","volume":"344","author":"Hahladakis","year":"2018","journal-title":"J. Hazard. Mater."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"EFSA Scientific Committee, More, S.J., Bampidis, V., Benford, D., Bennekou, S.H., Bragard, C., Halldorsson, T.I., Hern\u00e1ndez-Jerez, A.F., Koutsoumanis, K.P., and Naegeli, H. (2019). Guidance on harmonised methodologies for human health, animal health and ecological risk assessment of combined exposure to multiple chemicals. EFSA J., 17, e05634.","DOI":"10.2903\/j.efsa.2019.5634"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1186\/s13048-024-01457-6","article-title":"Folliculogenesis and steroidogenesis alterations after chronic exposure to a human-relevant mixture of environmental toxicants spare the ovarian reserve in the rabbit model","volume":"17","author":"Frenois","year":"2024","journal-title":"J. Ovarian Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1093\/toxsci\/kfac066","article-title":"Multigenerational Effects of an Environmentally Relevant Phthalate Mixture on Reproductive Parameters and Ovarian miRNA Expression in Female Rats","volume":"189","author":"Gonsioroski","year":"2022","journal-title":"Toxicol. Sci."},{"key":"ref_73","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":"ref_74","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.reprotox.2020.10.009","article-title":"Prenatal exposure to an environmentally relevant phthalate mixture accelerates biomarkers of reproductive aging in a multiple and transgenerational manner in female mice","volume":"98","author":"Brehm","year":"2020","journal-title":"Reprod. Toxicol."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Lea, R.G., Amezaga, M.R., Loup, B., Mandon-P\u00e9pin, B., Stefansdottir, A., Filis, P., Kyle, C., Zhang, Z., Allen, C., and Purdie, L. (2016). The fetal ovary exhibits temporal sensitivity to a \u2018real-life\u2019 mixture of environmental chemicals. Sci. Rep., 6.","DOI":"10.1038\/srep22279"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1093\/molehr\/gan020","article-title":"In utero exposure to low doses of environmental pollutants disrupts fetal ovarian development in sheep","volume":"14","author":"Fowler","year":"2008","journal-title":"Mol. Hum. Reprod."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Martino, N.A., Picardi, E., Ciani, E., D\u2019erchia, A.M., Bogliolo, L., Ariu, F., Mastrorocco, A., Temerario, L., Mansi, L., and Palumbo, V. (2023). Cumulus Cell Transcriptome after Cumulus-Oocyte Complex Exposure to Nanomolar Cadmium in an In Vitro Animal Model of Prepubertal and Adult Age. Biology, 12.","DOI":"10.3390\/biology12020249"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1093\/molehr\/gat013","article-title":"The activity and copy number of mitochondrial DNA in ovine oocytes throughout oogenesis in vivo and during oocyte maturation in vitro","volume":"19","author":"Cotterill","year":"2013","journal-title":"Mol. Hum. Reprod."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Leoni, G.G., Palmerini, M.G., Satta, V., Succu, S., Pasciu, V., Zinellu, A., Carru, C., Macchiarelli, G., Nottola, S.A., and Naitana, S. (2015). Differences in the Kinetic of the First Meiotic Division and in Active Mitochondrial Distribution between Prepubertal and Adult Oocytes Mirror Differences in their Developmental Competence in a Sheep Model. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0124911"},{"key":"ref_80","first-page":"429","article-title":"Domestic ruminants as models for the elucidation of the mechanisms controlling ovarian follicle development in humans","volume":"61","author":"Campbell","year":"2019","journal-title":"Biosci. Proc."},{"key":"ref_81","first-page":"21","article-title":"Ovarian intrafollicular processes as a target for cigarette smoke components and selected environmental reproductive disruptors","volume":"39","author":"Mlynarcikova","year":"2005","journal-title":"Endocr Regul."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"116679","DOI":"10.1016\/j.ecoenv.2024.116679","article-title":"Impact of DEHP on mitochondria-associated endoplasmic reticulum membranes and reproductive toxicity in ovary","volume":"282","author":"Guo","year":"2024","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"44928","DOI":"10.1007\/s11356-022-18988-4","article-title":"Long-term exposure of the binary mixture of cadmium and mercury damages the developed ovary of adult zebrafish","volume":"29","author":"Patel","year":"2022","journal-title":"Environ. Sci. Pollut. Res."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Cao, Y., Liang, C., Shen, L., Zhang, Z., Jiang, T., Li, D., Zou, W., Wang, J., Zong, K., and Liang, D. (2022). The association between essential trace element (copper, zinc, selenium, and cobalt) status and the risk of early embryonic arrest among women undergoing assisted reproductive techniques. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.906849"},{"key":"ref_85","first-page":"217","article-title":"Effects of an environmentally relevant phthalate mixture on cultured mouse antral follicles","volume":"156","author":"Zhou","year":"2016","journal-title":"Toxicol. Sci."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"127019","DOI":"10.1289\/EHP11998","article-title":"Associations between Phthalate Metabolite Concentrations in Follicular Fluid and Reproductive Outcomes among Women Undergoing in Vitro Fertilization\/Intracytoplasmic Sperm Injection Treatment","volume":"131","author":"Yao","year":"2023","journal-title":"Environ. Health Perspect."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"116605","DOI":"10.1016\/j.ecoenv.2024.116605","article-title":"Cadmium and phthalate impacts developmental growth and mortality of Spodoptera littoralis, but not reproductive success","volume":"281","author":"Fuentes","year":"2024","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Satarug, S. (2023). Is Environmental Cadmium Exposure Causally Related to Diabetes and Obesity?. Cells, 13.","DOI":"10.20944\/preprints202311.1813.v1"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.jhazmat.2015.05.052","article-title":"DEHP exposure impairs mouse oocyte cyst breakdown and primordial follicle assembly through estrogen receptor-dependent and independent mechanisms","volume":"298","author":"Mu","year":"2015","journal-title":"J. Hazard. Mater."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1007\/s10534-024-00582-5","article-title":"Cadmium transport by mammalian ATP-binding cassette transporters","volume":"37","author":"Lee","year":"2024","journal-title":"BioMetals"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"114029","DOI":"10.1016\/j.ecoenv.2022.114029","article-title":"The environment and female reproduction: Potential mechanism of cadmium poisoning to the growth and development of ovarian follicle","volume":"244","author":"Qu","year":"2022","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1089\/ars.2019.7984","article-title":"Redox Biology of Human Cumulus Cells: Basic Concepts, Impact on Oocyte Quality, and Potential Clinical Use","volume":"32","author":"Klamt","year":"2020","journal-title":"Antioxid. Redox Signal."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1095\/biolreprod63.3.805","article-title":"Protection of Porcine Oocytes Against Apoptotic Cell Death Caused by Oxidative Stress During In Vitro Maturation: Role of Cumulus Cells1","volume":"63","author":"Tatemoto","year":"2000","journal-title":"Biol. Reprod."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.theriogenology.2023.04.009","article-title":"Oocyte-cumulus cells crosstalk: New comparative insights","volume":"205","author":"Martinez","year":"2023","journal-title":"Theriogenology"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1177\/1933719115607993","article-title":"The Defensive Role of Cumulus Cells Against Reactive Oxygen Species Insult in Metaphase II Mouse Oocytes","volume":"23","author":"Shaeib","year":"2016","journal-title":"Reprod. Sci."},{"key":"ref_96","doi-asserted-by":"crossref","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":"ref_97","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1039\/C8TX00263K","article-title":"Di-(2-ethylhexyl) phthalate (DEHP) inhibits steroidogenesis and induces mitochondria-ROS mediated apoptosis in rat ovarian granulosa cells","volume":"8","author":"Tripathi","year":"2019","journal-title":"Toxicol. Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1017\/S0967199405003126","article-title":"Presence of cumulus cells during in vitro fertilization protects the bovine oocyte against oxidative stress and improves first cleavage but does not affect further development","volume":"13","author":"Fatehi","year":"2005","journal-title":"Zygote"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1016\/j.fertnstert.2013.01.129","article-title":"Cumulus and granulosa cell markers of oocyte and embryo quality","volume":"99","author":"Uyar","year":"2013","journal-title":"Fertil. Steril."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1093\/biolre\/ioac009","article-title":"Non-invasive oocyte quality assessment","volume":"106","author":"Sciorio","year":"2022","journal-title":"Biol. Reprod."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1093\/molehr\/gaq032","article-title":"Human cumulus cells as biomarkers for embryo and pregnancy outcomes","volume":"16","author":"Assou","year":"2010","journal-title":"Mol. Hum. Reprod."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/j.fertnstert.2012.10.041","article-title":"Identification of a novel gene set in human cumulus cells predictive of an oocyte\u2019s pregnancy potential","volume":"99","author":"Iager","year":"2013","journal-title":"Fertil. Steril."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.theriogenology.2022.06.008","article-title":"Hesperetin activated SIRT1 neutralizes cadmium effects on the early bovine embryo development","volume":"189","author":"Idrees","year":"2022","journal-title":"Theriogenology"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"3194","DOI":"10.1007\/s43032-021-00817-7","article-title":"Cumulus Cell DNA Damage as an Index of Human Oocyte Competence","volume":"29","author":"Baratas","year":"2021","journal-title":"Reprod. Sci."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Mastrorocco, A., Cacopardo, L., Lamanna, D., Temerario, L., Brunetti, G., Carluccio, A., Robbe, D., and Dell\u2019aquila, M.E. (2021). Bioengineering Approaches to Improve In Vitro Performance of Prepubertal Lamb Oocytes. Cells, 10.","DOI":"10.3390\/cells10061458"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1002\/mrd.23256","article-title":"The mycotoxin beauvericin induces oocyte mitochondrial dysfunction and affects embryo development in the juvenile sheep","volume":"86","author":"Mastrorocco","year":"2019","journal-title":"Mol. Reprod. Dev."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.fertnstert.2022.04.019","article-title":"Mitochondrial dysfunction in cumulus cells is related to decreased reproductive capacity in advanced-age women","volume":"118","author":"Lu","year":"2022","journal-title":"Fertil. Steril."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/1\/5\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:58:54Z","timestamp":1760115534000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/1\/5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,24]]},"references-count":107,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["ijms26010005"],"URL":"https:\/\/doi.org\/10.3390\/ijms26010005","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,24]]}}}