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In this study, we explored such potential in porcine pre\u2010pubertal Sertoli cells (SCs).\u00a0Cd toxicity resulted in impaired SC viability and function, abnormal cellular H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> generation and efflux, and induction of reductive stress by the upregulation of Nrf2 expression and activity, cystine uptake and glutathione biosynthesis, glutathione\u2010S\u2010transferase P (GSTP) expression, and protein glutathionylation inhibition. Cd toxicity also stimulated the activity of cellular kinases (MAPK\u2010ERK1\/2 and Akt) and NFkB transcription factor, and cJun expression was increased. MLT produced a potent cytoprotective effect when co\u2010administered with Cd to SCs; its efficacy and the molecular mechanism behind its cytoprotective function varied according to Cd concentrations. However, a significant restoration of cell viability and function, and of H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> levels, was observed both at 5\u00a0and 10\u2009\u03bcM Cd. Mechanistically, these effects of MLT were associated with a significant reduction of the Cd\u2010induced activation of Nrf2 and GSTP expression at all Cd concentrations. CAT and MAPK\u2010ERK1\/2 activity upregulation was associated with these effects at 5\u2009\u03bcM Cd, whereas glutathione biosynthesis and efflux were involved at 10\u2009\u03bcM Cd together with an increased expression of the cystine transporter xCT, of cJun and Akt and NFkB activity.\u00a0MLT protects SCs from Cd toxicity reducing its H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> generation and reductive stress effects. A reduced activity of Nrf2 and the modulation of other molecular players of MLT signaling, provide a mechanistic rational for the cytoprotective effect of this molecule in SCs.<\/jats:p>","DOI":"10.1111\/jpi.12806","type":"journal-article","created":{"date-parts":[[2022,5,7]],"date-time":"2022-05-07T03:44:15Z","timestamp":1651895055000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Melatonin modulates Nrf2 activity to protect porcine pre\u2010pubertal Sertoli cells from the abnormal H<sub>2<\/sub>O<sub>2<\/sub> generation and reductive stress effects of cadmium"],"prefix":"10.1111","volume":"73","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3849-757X","authenticated-orcid":false,"given":"Desir\u00e9e","family":"Bartolini","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Perugia Perugia Italy"},{"name":"Department of Medicine and Surgery, Section of Human, Clinical and Forensic Anatomy University of Perugia Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iva","family":"Arato","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery University of Perugia Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Mancuso","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery University of Perugia Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Giustarini","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy University of Siena Siena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catia","family":"Bellucci","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery University of Perugia Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmine","family":"Vacca","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Biology and Biotechnology University of Perugia Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Chiara","family":"Aglietti","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery University of Perugia Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Maria","family":"Stabile","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Section of Human, Clinical and Forensic Anatomy University of Perugia Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranieri","family":"Rossi","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy University of Siena Siena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Cruciani","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Biology and Biotechnology University of Perugia Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Rende","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Section of Human, Clinical and Forensic Anatomy University of Perugia Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Calafiore","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery University of Perugia Perugia Italy"},{"name":"Department of Medicine and Surgery, International Biotechnological Center for Endocrine, Metabolic and Embryo\u2010Reproductive Translational Research (CIRTEMER) University of Perugia Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Luca","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery University of Perugia Perugia Italy"},{"name":"Division of Medical Andrology and Endocrinology of Reproduction Saint Mary Hospital Terni Italy"},{"name":"Department of Medicine and Surgery, International Biotechnological Center for Endocrine, Metabolic and Embryo\u2010Reproductive Translational Research (CIRTEMER) University of Perugia Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3626-051X","authenticated-orcid":false,"given":"Francesco","family":"Galli","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Perugia Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,5,24]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"WHO.Examination and Processing of Human Semen. 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