Modulation of PARP activity by Monomethylarsonous (MMA +3 ) acid and uranium in mouse thymus.

Arsenic exposure is well established to impair the function of zinc finger proteins, including PARP-1. Previous studies from our lab show that early developing T cells in the thymus are very sensitive to arsenite (As ⁺³ )-induced genotoxicity mediated through PARP-1 inhibition. Additionally, it has been shown that uranium (in the form of uranyl acetate, UA) also suppresses PARP-1 activity in HEK cells. However, very little is known about whether the As ⁺³ metabolite, monomethylarsonous acid (MMA ⁺³ ), also inhibits PARP-1 activity and if this is modified by combined exposures with other metals, such as uranium. In the present study, we found that MMA ⁺³ significantly suppressed PARP-1 function, whereas UA at high concentrations significantly increased PARP-1 activity. To evaluate whether the effects on PARP-1 activity were mediated through oxidative stress, we measured the induction of hemoxygenase-1 (Hmox-1) expression by qPCR. MMA ⁺³ , but not UA, significantly induced oxidative stress; however, the inhibition of PARP-1 produced by MMA ⁺³ was not reversed by the addition of the antioxidant, Tempol. Further evaluation revealed minimal interactive effects of MMA ⁺³ and UA on PARP-1 function. Collectively, our results show that contrary to As ⁺³ , the suppressive effects of MMA ⁺³ on PARP-1 were not substantially driven by oxidative stress ^. in mouse thymus cells. Results for this study provide important insights into the effects of MMA ⁺³ and uranium exposures on PARP-1 function, which is essential for future studies focused on understanding the effects of complex environmentally relevant metal mixtures.
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