title: Flavocoxid Protects Against Cadmium-Induced Disruption of the Blood–Testis Barrier and Improves Testicular Damage and Germ Cell Impairment in Mice [corrected].
abstract: Cadmium (Cd) causes male infertility. There is the need to identify safe treatments counteracting this toxicity. Flavocoxid is a flavonoid that induces a balanced inhibition of cyclooxygenase (COX)-1 and COX-2 peroxidase moieties and of 5-lipoxygenase (LOX) and has efficacy in the male genitourinary system. We investigated flavocoxid effects on Cd-induced testicular toxicity in mice. Swiss mice were divided into 4 groups: 2 control groups received 0.9% NaCl (vehicle; 1 ml/kg/day) or flavocoxid (20 mg/kg/day ip); 2 groups were challenged with cadmium chloride (CdCl2; 2 mg/kg/day ip) and administered with vehicle or flavocoxid. The treatment lasted for 1 or 2 weeks. The testes were processed for biochemical and morphological studies. CdCl2 increased phosphorylated extracellular signal-regulated kinase (p-ERK) 1/2, tumor necrosis factor (TNF)-α, COX-2, 5-LOX, malondialdehyde (MDA), B-cell-lymphoma (Bcl)-2-associated X protein (Bax), follicle-stimulating hormone (FSH), luteinizing hormone (LH), transforming growth factor (TGF) -β3, decreased Bcl-2, testosterone, inhibin-B, occludin, N-Cadherin, induced structural damages in the testis and disrupted the blood-testis barrier. Many TUNEL-positive germ cells and changes in claudin-11, occludin, and N-cadherin localization were present. Flavocoxid administration reduced, in a time-dependent way, p-ERK 1/2, TNF-α, COX-2, 5-LOX, MDA, Bax, FSH, LH, TGF-β3, augmented Bcl-2, testosterone, inhibin B, occludin, N-Cadherin, and improved the structural organization of the testis and the blood-testis barrier. Few TUNEL-positive germ cells were present and a morphological retrieval of the intercellular junctions was observed. In conclusion, flavocoxid has a protective anti-inflammatory, antioxidant, and antiapoptotic function against Cd-induced toxicity in mice testis. We suggest that flavocoxid may play a relevant positive role against environmental levels of Cd, otherwise deleterious to gametogenesis and tubular integrity.
authors.affiliation: *Department of Clinical and Experimental Medicine.
authors.forename: Letteria
authors.initials: L
authors.lastname: Minutoli
authors.affiliation: Department of Biomedical Sciences and Morphological and Functional Images.
authors.forename: Antonio
authors.initials: A
authors.lastname: Micali
authors.affiliation: Department of Biomedical Sciences and Morphological and Functional Images.
authors.forename: Antonina
authors.initials: A
authors.lastname: Pisani
authors.affiliation: Department of Biomedical Sciences and Morphological and Functional Images.
authors.forename: Domenico
authors.initials: D
authors.lastname: Puzzolo
authors.affiliation: *Department of Clinical and Experimental Medicine.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bitto
authors.affiliation: *Department of Clinical and Experimental Medicine.
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Rinaldi
authors.affiliation: *Department of Clinical and Experimental Medicine.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pizzino
authors.affiliation: *Department of Clinical and Experimental Medicine.
authors.forename: Natasha
authors.initials: N
authors.lastname: Irrera
authors.affiliation: *Department of Clinical and Experimental Medicine.
authors.forename: Federica
authors.initials: F
authors.lastname: Galfo
authors.affiliation: Department of Paediatric, Gynaecological Microbiological and Biomedical Sciences.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Arena
authors.affiliation: *Department of Clinical and Experimental Medicine.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pallio
authors.affiliation: *Department of Clinical and Experimental Medicine.
authors.forename: Anna
authors.initials: A
authors.lastname: Mecchio
authors.affiliation: Department of Veterinary Sciences.
authors.forename: Antonino
authors.initials: A
authors.lastname: Germanà
authors.affiliation: Department of Biomedical Sciences and Morphological and Functional Images.
authors.forename: Daniele
authors.initials: D
authors.lastname: Bruschetta
authors.affiliation: Department of Biological and Environmental Sciences and.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Laurà
authors.affiliation: Department of Human Pathology, University of Messina, Messina, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Magno
authors.affiliation: *Department of Clinical and Experimental Medicine.
authors.forename: Herbert
authors.initials: H
authors.lastname: Marini
authors.affiliation: *Department of Clinical and Experimental Medicine, fsquadrito@unime.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Squadrito
authors.affiliation: Department of Paediatric, Gynaecological Microbiological and Biomedical Sciences.
authors.forename: Domenica
authors.initials: D
authors.lastname: Altavilla
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D000975:Antioxidants / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D001814:Blood-Testis Barrier / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D015820:Cadherins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D002105:Cadmium Poisoning / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D002392:Catechin / Q000627:therapeutic use*; D004338:Drug Combinations; D007248:Infertility, Male / Q000209:etiology / Q000517:prevention & control*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D062793:Occludin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012671:Seminiferous Tubules / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D013091:Spermatogenesis / Q000187:drug effects*; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D015415:Biomarkers; D015820:Cadherins; C489083:Cdh2 protein, mouse; D004338:Drug Combinations; D062793:Occludin; C568986:Ocln protein, mouse; C544478:flavocoxid; D002392:Catechin
keywords: TNF-α; flavocoxid; germ cells; light microscopy; p-ERK 1/2; seminiferous tubules