Team:Bielefeld-CeBiTec/Toxicity Theory

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Toxicity

Gold, silver, copper and iron ions are of interest due to their chemical properties. On the other hand some of the ions possess toxic properties for the cell (Ochoa-Herrera et al., 2011; Shareena et al., 2015; Zhao & Stevens, 2009). Therefore the toxicity of the different ions of the metals needs to be included into consideration when planning the uptake and processing of the ions as a substrate for nanoparticles. Not only is the toxicity of the dissolved ions of interest but also the potential toxic effect of nanoparticles on the cell.

Gold

Gold nanoparticles (AuNPs) are popular in many scientific applications, e.g. the transfection of human cells (Chang et al., 2008). However, there are several reports regarding its toxicity whose results differ greatly from each other (Brust et al., 1995; Caruntu et al., 2002; Zhang et al., 2015). AuNPs in the form of nanorods could be identified as non-toxic, solely the coating agent was found to be toxic (Alkilany et al., 2009). AuNPs in general do not possess toxic properties. Reported toxic effects of AuNPs result from poor purification of the AuNPs from Au(III) (Shareena Dasari, 2015). Gold ions, such as Au(I) and Au(III), have toxic properties. Shareena Dasari et al. proved in 2015 that exposure to Au(I) and Au(III) inhibits the growth of nonpathogenic Escherichia coli in every examined buffer as seen in figure 1. Furthermore they determined the half maximal inhibitory concentrations (IC₅₀) for both ions in the examined buffers as seen in table 1, clearly indicating that gold ions possess toxic properties to E. coli. The toxic effect of gold ions is due to its ability to oxidative cleavage of peptide and protein disulfide bonds (Witkiewicz & Shaw, 1981). Since gold ions are toxic to the NPs producing cell, the reduction to AuNPs is desirable, however the stress to the cell and its inhibitory effect have to be investigated.

Silver

Silver nanoparticles (AgNPs) are known to possess toxic properties. The toxicity of AgNPs varies in response to the shape and size of the AgNPs. The toxicity increases significantly when the AgNPs are smaller than 10 nm (Ivask et al., 2014). It has been demonstrated that AgNPs exhibit toxic effects in bacteria at environmentally relevant concentrations (Colman et al., 2013). The growth inhibition is dependent on the concentration of the AgNPs. The minimal inhibitory concentration (MIC) for AgNPs in E. coli is considered to be between 3.3 and 6.6 nM (Kim et al., 2007). The exposure to AgNPs results in an apoptosis-like response of the cell. To begin with, the membrane is depolarized by AgNPs, generating reactive oxygen species (ROS), such as hydroxyl peroxide, hydroxyl radicals and superoxide anions.These ROS cause oxidative stress and lead to the fragmentation of DNA. Simultaneously calcium accumulates in the cytoplasm of the cell. An increased concentration of calcium results in the inversion of phosphatidylserine in the membrane. All of these processes ultimately lead to the activation of bacterial caspase-like proteins and RecA (Bortner & Cidlowski, 2007; Yun & Lee, 2017). (Figure 2 einfügen) However there are considerations whether the AgNPs are toxic or whether the toxic effect is due to ions dissolving from the nanoparticles (Hwang et al., 2008). The toxic effects of silver salts have been known since antiquity. Even Hippocrates recognized its antimicrobial properties in water (Magner, 1992). The toxic effect of silver ions relies on the same chemical features as those of the AgNPs. When being exposed to silver ions, the bacterium experiences several forms of oxidative stress, mainly ROS which arise from Fenton chemistry. Ag(I) disrupts metabolic pathways that drive Fenton chemistry and lead to the overproduction of hydroxyl radicals and cell death (Morones-Ramirez et al., 2013). At a concentration of 18.9 µM, all bacterial growth comes to an end (Zhao & Stevens, 1998). Silver is toxic in both of its forms: as a nanoparticle and as dissolved ions. Therefore an approach to decrease the toxic effect on the cell is needed.

Copper

Copper is known for its toxic and bactericidal properties and is often used as an antimicrobial agent in form of copper nanoparticles (CuNPs) (Cioffi et al., 2005). Recent studies revealed that the inactivation and bactericidal activity works in a size-dependent manner. The smaller a CuNP is, the higher is its inhibitory potential to bacteria. Furthermore, the toxicity is probably elicited in a strain-specific manner in E. coli obtained from different sources (Alum et al., 2018). CuNPs’ toxic properties appear to result from oxidative stress and protein damage, DNA damage and membrane damage. The generation of hydroxyl peroxide by CuNPs is assumed to be the reason for the toxicity of CuNPs. Li et al. could observe 2013 the release of copper and the production of Cu(I) ions. Copper is considered to be essential in small amounts to both human and bacteria (Burgess et al., 1999). It plays an important role in electron-transfer reactions (Kaplan & Lutsenko, 2009). Yet copper ions can induce cell death and exhibit toxic effects. This is due to copper ions interfering with the cell proteins or enzymes by chelating sulfhydryl groups and peroxidizing the lipids of the cell membrane (Yeager, 1991). A broad variety of microorganisms, such as E. coli, could be proven to be inhibited in growth or killed by the exposure to Cu(II) (Ochoa-Herrera et al., 2011). Furthermore, copper ions can interact with oxygen by catalyzing Haber-Weiss and/or Fenton reactions. This results in the generation of reactive oxygen species which can ultimately damage biomolecules (Halliwell, 2007; Halliwell & Gutteridge, 2015). Copper is toxic in both of its forms: as a nanoparticle and as dissolved ions. Therefore an approach to decrease the toxic effect on the cell is needed.

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