Toxicity of inorganic arsenic and its metabolites on haematopoietic progenitors "in vitro": comparison between species and sexes.
Inorganic arsenic (iAs) and its metabolites are transferred to the foetus through the placental barrier and this exposure can compromise the normal development of the unborn. For this reason, we assessed the toxicity of sodium arsenite (iAs(III)) and its metabolites dimethylarsinic acid (DMA(V)), monomethylarsonic acid (MMA(V)) and monomethylarsonous acid (MMA(III)) on human haematopoietic cord blood cells and murine bone marrow progenitors in vitro, looking at the effects induced at different concentrations in the two genders. The expression of two enzymes responsible for arsenic biotransformation arsenic methyltranferase (AS3MT) and glutathione S-transferase omega 1 (GSTO1) was evaluated in human cord blood cells. Cord blood and bone marrow cells were exposed in vitro to iAs(III) at a wide range of concentrations: from 0.0001 microM to 10 microM. The methylated arsenic metabolites were tested only on human cord blood cells at concentrations ranging from 0.00064 microM to 50 microM. The results showed that iAs(III) was toxic on male and female colony forming units to about the same extent both in human and in mouse. Surprisingly, very low concentrations of iAs(III) increased the proliferation rate of both human and murine female cells, while male cells showed no significant modulation. MMA(V) and DMA(V) did not exert detectable toxicity on the cord blood cells, while MMA(III) had a marked toxic effect both in male and female human progenitors. AS3MT mRNA expression was not induced in human cord blood cells after iAs(III) exposure. GSTO1 expression decreased after MMA(III) treatment. This study provides evidence that exposure to iAs(III) and MMA(III) at muM concentrations is associated with immunosuppression in vitro.
ECVAM, IHCP, Institute for the Health and Consumer Protection, JRC, Ispra, Italy. daniele.ferrario@jrc.it
Daniele
D
Ferrario
Cristina
C
Croera
Roberta
R
Brustio
Angelo
A
Collotta
Gerard
G
Bowe
Marie
M
Vahter
Laura
L
Gribaldo
D000818:Animals; D020261:Arsenic Poisoning / Q000473:pathology*; D001152:Arsenicals; D001854:Bone Marrow Cells / Q000187:drug effects; D003114:Colony-Forming Units Assay; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D005260:Female; D005312:Fetal Blood / Q000166:cytology; D005982:Glutathione Transferase / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D008297:Male; D008780:Methyltransferases / Q000378:metabolism; D051379:Mice; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012727:Sex Characteristics; D013045:Species Specificity
D001152:Arsenicals; D012313:RNA; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D008780:Methyltransferases; C505756:AS3MT protein, human; C490476:GSTO1 protein, human; D005982:Glutathione Transferase