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

Merle M Nicolai,Michael Aschner,Anna Gremme,Vanessa Brinkmann,Julia Bornhorst,Jessica Baesler,Ann-Kathrin Weishaupt,Nicola Winkelbeiner,Gerhard Fritz,Anna Wellenberg,Tanja Schwerdtle

doi:10.3390/ijms222010905

Abstract

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.

Highlights

Licensee MDPI, Basel, Switzerland.Exposure to the transition metal and essential trace element manganese (Mn) occurs both naturally and anthropogenically
All further experiments were conducted with nematodes exposed to MnCl2 at sub-toxic to toxic concentrations (in detail: up to 250 mM MnCl2 for 1 h; up to 60 mM MnCl2 for 4 h), as genotoxic chemicals are expected to induce decreased genomic integrity at doses that do not trigger extensive cell death and might follow a non-linear dose–response relationship in genotoxicity testing [31,32]
As our studies show that the bioavailability at LD50 values for 1 h and 4 h was proportional to time and concentration (Figure 1), we decided to focus on the investigation of DNA damage after 1 h MnCl2 exposure

Summary

Introduction

Exposure to the transition metal and essential trace element manganese (Mn) occurs both naturally and anthropogenically. Natural sources of Mn are diverse and ubiquitous with Mn being the 12th most abundant element in the Earth’s crust. Mn does not usually exist in its elemental form, but is found as silicates, carbonates, and oxides [1]. The element can exist in several oxidative states, with Mn(II) and Mn(III) being the most common forms in biological systems [2]. Due to the rich natural occurrence of Mn in vegetables, cereal

Methods

Results

Conclusion