Title: Modulation of PARP activity by Monomethylarsonous (MMA+3) acid and uranium in mouse thymus.
Authors: Medina, Sebastian; Zhou, Xixi; Lauer, Fredine T; Zhang, Haikun; Liu, Ke Jian; Lewis, Johnnye; Burchiel, Scott W
Published In Toxicol Appl Pharmacol, (2021 01 15)
Abstract: 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.
PubMed ID: 33279514
MeSH Terms: Animals; Cells, Cultured; Dose-Response Relationship, Drug; Heme Oxygenase-1/genetics; Heme Oxygenase-1/metabolism; Male; Membrane Proteins/genetics; Membrane Proteins/metabolism; Mice, Inbred C57BL; Organometallic Compounds/toxicity*; Oxidative Stress/drug effects; Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors*; Poly (ADP-Ribose) Polymerase-1/metabolism; Poly(ADP-ribose) Polymerase Inhibitors/toxicity*; Thymus Gland/drug effects*; Thymus Gland/enzymology