Myelotoxicity of trichothecenes and apoptosis: an in vitro study on human cord blood CD34+ hematopoietic progenitor.
Previous studies have revealed that hematological disorders associated with trichothecenes intoxication in humans could result from hematopoiesis inhibition. The most frequent and potent trichothecene mycotoxins are T-2 toxin and deoxynivalenol (DON), respectively. Apoptosis induction by these two toxins was investigated in vitro on human hematopoietic progenitors (CD34+ cells). Hoechst coloration, DNA fragmentation and annexin-V/PI labeling in flow cytometry showed that T-2 toxin, in contrast to DON, induced apoptosis in CD34+ cells. T-2 toxin effect was dose- and time-dependent with a significant increase of apoptotic cells as early as 3h after incubation at 10(-7) M and a maximum reached at 12 h. This observation evidenced the high sensitivity of hematopoietic progenitors to T-2 toxin. The inhibition of T-2 toxin-induced apoptosis by a pan-caspase inhibitor (Z-VAD-fmk) suggested the involvement of caspases. The proportional increase of caspase-3 specific activity (DEVDase) with T-2 toxin concentration confirmed its role in the process. After incubation of CD34+ cells with T-2 toxin, in conditions that induced apoptosis, clonal expansion of granulo-monocytes, erythrocytes and megakaryocytes precursors was dose-dependently inhibited. The hematological effects observed in T-2 toxin mycotoxicosis could then be assigned to hematopoiesis inhibition by apoptosis. Different mechanisms that need to be further elucidated are involved in DON myelotoxicity.
Le Dréan
G
G
Laboratoire de Toxicologie Alimentaire, EA 3880, Université de Bretagne Occidentale, Technopôle Brest-Iroise, 29280 Plouzané, France. gwenola.ledrean@univ-brest.fr
Auffret
M
M
Batina
P
P
Arnold
F
F
Sibiril
Y
Y
Arzur
D
D
Parent-Massin
D
D
D018952:Antigens, CD34; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D053938:DNA Fragmentation; D005312:Fetal Blood; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D013605:T-2 Toxin / Q000633:toxicity*; D014255:Trichothecenes / Q000633:toxicity*
D018952:Antigens, CD34; D014255:Trichothecenes; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D013605:T-2 Toxin; C007262:deoxynivalenol