{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T17:01:50Z","timestamp":1784221310472,"version":"3.55.0"},"reference-count":67,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2023,11,5]],"date-time":"2023-11-05T00:00:00Z","timestamp":1699142400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sapienza University, Rome","award":["RM11715C54A7D4F0"],"award-info":[{"award-number":["RM11715C54A7D4F0"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>It is known that exposure to heavy metal such as lead (Pb) and cadmium (Cd) has several adverse effects, particularly on the human reproductive system. Pb and Cd have been associated with infertility in both men and women. In pregnant women, they have been associated with spontaneous abortion, preterm birth, and impairment of the development of the fetus. Since these heavy metals come from both natural and anthropogenic activities and their harmful effects have been observed even at low levels of exposure, exposure to them remains a public health issue, especially for the reproductive system. Given this, the present study aimed to investigate the potential reproductive effects of Pb and Cd levels in the follicular fluid (FF) of infertile women and non-smokers exposed to heavy metals for professional reasons or as a result of living in rural areas near landfills and waste disposal areas in order to correlate the intrafollicular presence of these metals with possible alterations in the ultrastructure of human cumulus-oocyte complexes (COCs), which are probably responsible for infertility. Blood and FF metals were measured using atomic absorption spectrometry. COCs corresponding to each FF analyzed were subjected to ultrastructural analyses using transmission electron microscopy. We demonstrated for the first time that intrafollicular levels of Pb (0.66 \u00b5g\/dL\u20130.85 \u00b5g\/dL) and Cd (0.26 \u00b5g\/L\u20130.41 \u00b5g\/L) could be associated with morphological alterations of both the oocyte and cumulus cells\u2019 (CCs) ultrastructure. Since blood Cd levels (0.54 \u00b5g\/L\u20131.87 \u00b5g\/L) were above the current reference values established by the guidelines of the Agency for Toxic Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA) (0.4 \u00b5g\/L), whereas blood Pb levels (1.28 \u00b5g\/dL\u20133.98 \u00b5g\/dL) were below the ATSDR reference values (\u22645 \u00b5g\/dL), we believe that these alterations could be due especially to Cd, even if we cannot exclude a possible additional effect of Pb. Our results highlighted that oocytes were affected in maturation and quality, whereas CCs showed scarcely active steroidogenic elements. Regressing CCs, with cytoplasmic alterations, were also numerous. According to Cd\u2019s endocrine-disrupting activity, the poor steroidogenic activity of CCs might correlate with delayed oocyte cytoplasmic maturation. So, we conclude that levels of heavy metals in the blood and the FF might negatively affect fertilization, embryo development, and pregnancy, compromising oocyte competence in fertilization both directly and indirectly, impairing CC steroidogenic activity, and inducing CC apoptosis.<\/jats:p>","DOI":"10.3390\/cells12212577","type":"journal-article","created":{"date-parts":[[2023,11,5]],"date-time":"2023-11-05T07:35:06Z","timestamp":1699169706000},"page":"2577","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Heavy Metals in Follicular Fluid Affect the Ultrastructure of the Human Mature Cumulus-Oocyte Complex"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8692-9184","authenticated-orcid":false,"given":"Selenia","family":"Miglietta","sequence":"first","affiliation":[{"name":"Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Sapienza University, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0539-0736","authenticated-orcid":false,"given":"Loredana","family":"Cristiano","sequence":"additional","affiliation":[{"name":"Department of Life Health and Environmental Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ezio","family":"Battaglione","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Sapienza University, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9182-0586","authenticated-orcid":false,"given":"Guido","family":"Macchiarelli","sequence":"additional","affiliation":[{"name":"Department of Life Health and Environmental Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4626-6328","authenticated-orcid":false,"given":"Stefania Annarita","family":"Nottola","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Sapienza University, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Paola","family":"De Marco","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences and Translational Medicine, Sapienza University of Rome, Sant\u2019Andrea University Hospital, Via di Grottarossa 1035, 00189 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavia","family":"Costanzi","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences and Translational Medicine, Sapienza University of Rome, Sant\u2019Andrea University Hospital, Via di Grottarossa 1035, 00189 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Schimberni","sequence":"additional","affiliation":[{"name":"GENERA Centers for Reproductive Medicine, Clinica Valle Giulia, 00197 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Colacurci","sequence":"additional","affiliation":[{"name":"Department of Woman Child and General and Specialized Surgery, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donatella","family":"Caserta","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences and Translational Medicine, Sapienza University of Rome, Sant\u2019Andrea University Hospital, Via di Grottarossa 1035, 00189 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3456-1434","authenticated-orcid":false,"given":"Giuseppe","family":"Familiari","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Sapienza University, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e04691","DOI":"10.1016\/j.heliyon.2020.e04691","article-title":"Heavy metal pollution in the environment and their toxicological effects on humans","volume":"6","author":"Briffa","year":"2020","journal-title":"Heliyon"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1080\/15376516.2019.1701594","article-title":"The effects of heavy metals on human metabolism","volume":"3","author":"Fu","year":"2020","journal-title":"Toxicol. 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