Genotoxicity induced by monomethylarsonous acid (MMA+3) in mouse thymic developing T cells

摘要

Drinking water exposure to arsenic is known to cause immunotoxicity. Our previous studies demonstrated that monomethylarsonous acid (MMA⁺³) was the major arsenical species presented in mouse thymus cells after a 30 d drinking water exposure to arsenite (As⁺³). MMA⁺³ was also showed to be ten times more toxic than As⁺³ on the suppression of IL-7/STAT5 signaling in the double negative (DN) thymic T cells. In order to examine the genotoxicity induced by low to moderate doses of MMA⁺³, isolated mouse thymus cells were treated with 5, 50 and 500 nM MMA⁺³ for 18 h in vitro. MMA⁺³ suppressed the proliferation of thymus cells in a dose dependent manner. MMA⁺³ at 5 nM induced DNA damage in DN not double positive (DP) cells. Differential sensitivity to double strand breaks and reactive oxygen species generation was noticed between DN and DP cells at 50 nM, but the effects were not seen at the high dose (500 nM). A stronger apoptotic effect induced by MMA⁺³ was noticed in DN cells than DP cells at low doses (5 and 50 nM), which was negated by the strong apoptosis induction at the high dose (500 nM). Analysis of intracellular MMA⁺³ concentrations in DN and DP cells, revealed that more MMA⁺³ accumulated in the DN cells after the in vitro treatment. Collectively, these results suggested that MMA⁺³ could directly induce strong genotoxicity in the early developing T cells in the thymus. The DN cells were much more sensitive to MMA⁺³ induced genotoxicity and apoptosis than DP cells, probably due to the higher intracellular levels of MMA⁺³.