title: Endoplasmic Reticulum Stress and Apoptosis Triggered by Sub-Chronic Lead Exposure in Mice Spleen: a Histopathological Study.
abstract: Lead (Pb) is an environmental oncogenic metal that induces immunotoxicity and anaemia. Emerging evidence has linked Pb toxicity with endoplasmic reticulum-driven apoptosis and autophagy. Glucose-regulated protein of 78 kDa (Grp78 or binding immunoglobulin protein (BiP)), a master endoplasmic reticulum chaperone, drives macrophage activation and regulates protein folding and calcium flux in response to heavy metals. The spleen may be involved in Pb poisoning due to its crucial role in erythrocatheresis and immune response, although there are no data to support this theory. Here, we found haematic and histopathological changes in the spleen of mice exposed to medium doses of Pb acetate (200 ppm-1 mM) in drinking water for 45 days. Pb deposition was also detected in organs such as the liver, kidney, brain, bone, blood and faeces, indicating an accumulation of this metal despite relatively short exposure time. Blood Pb content (BBL) reached 21.6 μg/dL; echinocytes and poikilocytes were found in Pb smears of treated group. Inside the spleen, higher Fe(II) and Fe(III) deposits inside macrophages were observed. Grp78 immunostaining, weakly expressed in spleen cells of control mice, after Pb exposure was specifically restricted to macrophages and megakaryocytes of the marginal zone of red pulp. Furthermore, Pb exposure induced superoxide dismutase 1 (SOD1) expression, cleaved caspase-3 and p62/SQSTM1, consistent with oxidative stress, apoptosis and dysregulated autophagy in spleen compartments. We suggest that even at a middle dose, oral Pb intake induces oxidant iron deposition in the spleen and that this may trigger sustained Grp78 redistribution to cells, thus leading to oxidative and autophagy dysfunction as early local reactions to this dangerous metal.
authors.affiliation: Department of Clinical and Experimental Sciences, Division of Anatomy and Physiopathology, University of Brescia, Viale Europa 11, 25123, Brescia, Italy. giovanni.corsetti@unibs.it.
authors.forename: Giovanni
authors.identifier: http://orcid.org/0000-0003-0326-0644
authors.initials: G
authors.lastname: Corsetti
authors.affiliation: Department of Clinical and Experimental Sciences, Division of Anatomy and Physiopathology, University of Brescia, Viale Europa 11, 25123, Brescia, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Romano
authors.affiliation: Department of Clinical and Experimental Sciences, Division of Anatomy and Physiopathology, University of Brescia, Viale Europa 11, 25123, Brescia, Italy. alessandra.stacchiotti@unibs.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Stacchiotti
authors.affiliation: "S. Maugeri Foundation", IRCCS, Cardiology Division, Lumezzane Medical Centre, Brescia, Italy.
authors.forename: Evasio
authors.initials: E
authors.lastname: Pasini
authors.affiliation: Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
authors.forename: Francesco S
authors.initials: FS
authors.lastname: Dioguardi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D007854:Lead / Q000633:toxicity*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D008533:Megakaryocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D000071456:Sequestosome-1 Protein / Q000378:metabolism; D013154:Spleen / Q000378:metabolism* / Q000473:pathology; D000072105:Superoxide Dismutase-1 / Q000378:metabolism
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D007854:Lead; D007501:Iron; C000606291:Sod1 protein, mouse; D000072105:Superoxide Dismutase-1; C505409:Casp3 protein, mouse; D053148:Caspase 3
keywords: Apoptosis; Autophagy; Grp78; Lead; Oxidative stress; Spleen