title: Delayed myelosuppression with acute exposure to hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and environmental degradation product hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX) in rats.
abstract: Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), a widely used munitions compound, and hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX), its N-nitroso product of anaerobic microbial nitroreduction, are contaminants of military sites. Previous studies have shown MNX to be the most acutely toxic among the nitroreduced degradation products of RDX and to cause mild anemia at high dose. The present study compares hematotoxicity with acute oral exposure to MNX with parent RDX. Both RDX and MNX caused a modest decrease in blood hemoglobin and ~50% loss of granulocytes (NOAELs=47 mg/kg) in female Sprague-Dawley rats observed 14 days post-exposure. We explored the possibility that blood cell loss observed after 14 days was delayed in onset because of toxicity to bone marrow (BM) progenitors. RDX and MNX decreased granulocyte/macrophage-colony forming cells (GM-CFCs) at 14, but not 7, days (NOAELs=24 mg/kg). The earliest observed time at which MNX decreased GM-CFCs was 10 days post-exposure. RDX and MNX likewise decreased BM burst-forming units-erythroid (BFU-Es) at 14, but not 7, days. Granulocyte-erythrocyte-monocyte-megakaryocyte (GEMM)-CFCs were unaffected by RDX and MNX at 7 days suggesting precursor depletion did not account for GM-CFC and BFU-E loss. MNX added to the culture media was without effect on GM-CFC formation indicating no direct inhibition. Flow cytometry showed no differential loss of BM multilineage progenitors (Thy1.1(+)) or erythroid (CD71(+)) precursors with MNX suggesting myeloid and erythroid lineages were comparably affected. Collectively, these data indicate that acute exposure to both RDX and MNX caused delayed suppression of myelo- and erythropoiesis with subsequent decrease of peripheral granulocytes and erythrocytes.
authors.affiliation: Department of Toxicology, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209, USA.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Jaligama
authors.forename: Vijay M
authors.initials: VM
authors.lastname: Kale
authors.forename: Mitchell S
authors.initials: MS
authors.lastname: Wilbanks
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Perkins
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Meyer
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015672:Erythroid Precursor Cells / Q000187:drug effects / Q000378:metabolism; D053834:Explosive Agents / Q000633:toxicity*; D005260:Female; D005434:Flow Cytometry; D055014:Granulocyte-Macrophage Progenitor Cells / Q000187:drug effects / Q000378:metabolism; D006400:Hematocrit; D006454:Hemoglobins / Q000378:metabolism; D023461:Myeloid Progenitor Cells / Q000187:drug effects / Q000378:metabolism; D038042:Myelopoiesis / Q000187:drug effects*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D014227:Triazines / Q000633:toxicity*
chemical_list: D053834:Explosive Agents; D006454:Hemoglobins; D014227:Triazines; C508167:hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine; C009160:cyclonite