title: The fungicide mancozeb induces toxic effects on mammalian granulosa cells.
abstract: The ethylene-bis-dithiocarbamate mancozeb is a widely used fungicide with low reported toxicity in mammals. In mice, mancozeb induces embryo apoptosis, affects oocyte meiotic spindle morphology and impairs fertilization rate even when used at very low concentrations. We evaluated the toxic effects of mancozeb on the mouse and human ovarian somatic granulosa cells. We examined parameters such as cell morphology, induction of apoptosis, and p53 expression levels. Mouse granulosa cells exposed to mancozeb underwent a time- and dose-dependent modification of their morphology, and acquired the ability to migrate but not to proliferate. The expression level of p53, in terms of mRNA and protein content, decreased significantly in comparison with unexposed cells, but no change in apoptosis was recorded. Toxic effects could be attributed, at least in part, to the presence of ethylenthiourea (ETU), the main mancozeb catabolite, which was found in culture medium. Human granulosa cells also showed dose-dependent morphological changes and reduced p53 expression levels after exposure to mancozeb. Altogether, these results indicate that mancozeb affects the somatic cells of the mammalian ovarian follicles by inducing a premalignant-like status, and that such damage occurs to the same extent in both mouse and human GC. These results further substantiate the concept that mancozeb should be regarded as a reproductive toxicant.
authors.affiliation: Department of Health Sciences, University of L'Aquila, Via Vetoio, L'Aquila, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Paro
authors.forename: Gian Mario
authors.initials: GM
authors.lastname: Tiboni
authors.forename: Roberto
authors.initials: R
authors.lastname: Buccione
authors.forename: Gianna
authors.initials: G
authors.lastname: Rossi
authors.forename: Valerio
authors.initials: V
authors.lastname: Cellini
authors.forename: Rita
authors.initials: R
authors.lastname: Canipari
authors.forename: Sandra
authors.initials: S
authors.lastname: Cecconi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005659:Fungicides, Industrial / Q000633:toxicity*; D006107:Granulosa Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D008344:Maneb / Q000633:toxicity*; D051379:Mice; D018613:Microscopy, Confocal; D006080:Ovarian Follicle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015038:Zineb / Q000633:toxicity*
chemical_list: D005659:Fungicides, Industrial; D016159:Tumor Suppressor Protein p53; D008344:Maneb; C013099:mancozeb; D015038:Zineb