title: Megakaryocyte expansion and macrophage infiltration in bone marrow of rats subchronically treated with MNX, N-nitroso environmental degradation product of munitions compound RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine).
abstract: Hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX), environmental degradation product of munitions hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), causes seizures in rats with acute oral exposure like parent RDX. Our previous studies have additionally reported hematotoxicity with acute MNX exposure manifested as myelosuppression, anemia and splenic hemosiderosis. This study explored whether MNX administered subchronically continued to target bone marrow to elicit peripheral blood cytopenia. Female Sprague-Dawley rats were gavaged daily for 4 or 6 weeks with 47 mg kg-1day-1MNX (¼ LD50) or vehicle (5% dimethyl sulfoxide in corn oil) and hematological and clinical chemistry parameters, spleen weights, spleen and bone marrow histopathology and immunohistochemistry with ED1 anti-CD68 macrophage marker were evaluated 24 h after the last dose. Unexpectedly, no decrease in blood erythroid parameters was seen with subchronic MNX and convulsions and tremors ceased after 2 weeks of treatment. Toxicological effects observed were MNX-induced increases in blood granulocyte and platelet counts and in bone marrow megakaryocyte and ED1+-macrophage density. MNX was without effect on bone marrow cellularity and picrosirius red stained/collagen fiber deposition. Spleen weight increased modestly with extramedullary hematopoiesis evident, but hemosiderin and relative red and white pulp areas were unaffected. Collectively, this study demonstrated that erythroid effects characteristic of acute MNX exposure were not evident with subchronic exposure. However, megakaryocyte proliferation in bone marrow coincident with thrombocytosis after subchronic MNX exposure suggested continued hematotoxicity, but with a qualitatively different outcome. Granulocytosis and increased bone marrow macrophages implicated an inflammatory component in MNX hematotoxicity. Copyright © 2017 John Wiley & Sons, Ltd.
authors.affiliation: Department of Toxicology, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USA.
authors.forename: Sindhura
authors.initials: S
authors.lastname: Ramasahayam
authors.affiliation: Department of Toxicology, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USA.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Jaligama
authors.affiliation: Department of Toxicology, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USA.
authors.forename: Sahar M
authors.initials: SM
authors.lastname: Atwa
authors.affiliation: Department of Toxicology, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USA.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Salley
authors.affiliation: Department of Toxicology, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USA.
authors.forename: Marissa
authors.initials: M
authors.lastname: Thongdy
authors.affiliation: Department of Toxicology, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USA.
authors.forename: Benny L
authors.initials: BL
authors.lastname: Blaylock
authors.affiliation: Department of Toxicology, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USA.
authors.forename: Sharon A
authors.identifier: 0000-0002-4720-5949
authors.initials: SA
authors.lastname: Meyer
mesh_terms: D000818:Animals; D001673:Biodegradation, Environmental; D001772:Blood Cell Count; D001853:Bone Marrow / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D053834:Explosive Agents / Q000633:toxicity*; D005260:Female; D006411:Hematopoiesis, Extramedullary / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D008533:Megakaryocytes / Q000166:cytology / Q000187:drug effects*; D009929:Organ Size / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D014227:Triazines / Q000633:toxicity*
chemical_list: D004785:Environmental Pollutants; D053834:Explosive Agents; D014227:Triazines; C508167:hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine; C009160:cyclonite
keywords: bone marrow inflammation; macrophages; megakaryocyte; military environmental contaminant; thrombocytosis