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

Highlights: • MMA⁺³ inhibits PARP-1 activity in mouse thymus cells. • UA, at high concentrations, increases PARP-1 activity in mouse thymus cells. • MMA⁺³ effects on PARP-1 were not substantially mediated by oxidative stress. • MMA⁺³ + UA exposures produced minimal interactive effects on PARP-1 activity. 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.