Effects of Manganese on Genomic Integrity in the Multicellular Model Organism Caenorhabditis elegans

International Journal of Molecular Sciences

Michael Aschner¹  Merle M. Nicolai²  Anna Gremme²  Ann-Kathrin Weishaupt²  Julia Bornhorst²  Vanessa Brinkmann³  Gerhard Fritz³  Anna Wellenberg³  Jessica Baesler⁴  Tanja Schwerdtle⁴  Nicola Winkelbeiner⁴ 

[1] Albert Einstein College of Medicine, Department of Molecular Pharmacology, Neuroscience and Pediatrics, Bronx, NY 10032, USA;Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Gaußstraße 20, 42119 Wuppertal, Germany;Institute of Toxicology, Medical Faculty, Heinrich Heine University Düsseldorf, Moorenstr.5, 40225 Düsseldorf, Germany;TraceAge—DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly (FOR 2558), Berlin-Potsdam-Jena-Wuppertal, 14558 Nuthetal, Germany;

关键词: manganese;    oxidative stress;    DNA repair;    DNA damage response;    Caenorhabditis elegans;   

DOI  :  10.3390/ijms222010905

来源: DOAJ

【 摘 要 】

Although manganese (Mn) is an essential trace element, overexposure is associated with Mn-induced toxicity and neurological dysfunction. Even though Mn-induced oxidative stress is discussed extensively, neither the underlying mechanisms of the potential consequences of Mn-induced oxidative stress on DNA damage and DNA repair, nor the possibly resulting toxicity are characterized yet. In this study, we use the model organism Caenorhabditis elegans to investigate the mode of action of Mn toxicity, focusing on genomic integrity by means of DNA damage and DNA damage response. Experiments were conducted to analyze Mn bioavailability, lethality, and induction of DNA damage. Different deletion mutant strains were then used to investigate the role of base excision repair (BER) and dePARylation (DNA damage response) proteins in Mn-induced toxicity. The results indicate a dose- and time-dependent uptake of Mn, resulting in increased lethality. Excessive exposure to Mn decreases genomic integrity and activates BER. Altogether, this study characterizes the consequences of Mn exposure on genomic integrity and therefore broadens the molecular understanding of pathways underlying Mn-induced toxicity. Additionally, studying the basal poly(ADP-ribosylation) (PARylation) of worms lacking poly(ADP-ribose) glycohydrolase (PARG) parg-1 or parg-2 (two orthologue of PARG), indicates that parg-1 accounts for most of the glycohydrolase activity in worms.

【 授权许可】

Unknown