Molecular mechanisms of Mn induced neurotoxicity: <scp>RONS</scp> generation, genotoxicity, and <scp>DNA</scp>‐damage response

Bornhorst, Julia; Meyer, Sören; Weber, Till; Böker, Carolina; Marschall, Talke Anu; Mangerich, Aswin; Beneke, Sascha; Bürkle, Alexander; Schwerdtle, Tanja

doi:10.1002/mnfr.201200758

Cited by 36 publications

(28 citation statements)

References 98 publications

(137 reference statements)

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“…66 The genomic instability caused by Mn might also be due to an inhibitory effect on an essential signaling reaction related to the response to DNA damage, as indicated in vitro by strongly inhibited DNA damage-stimulated poly(ADP-ribosyl)ation following Mn exposure. 22,67 Poly(ADP-ribosyl)ation is a post-translational modification which is catalyzed by the poly(ADP-ribose) polymerase (PARP) family of proteins. In response to DNA strand breaks, two members of the PARP superfamily, PARP-1 and PARP-2, are rapidly activated and transfer ADP-ribosyl units from NAD 1 onto themselves and other target proteins, thus producing protein-coupled ADP-ribose polymers of up to 200 units.…”

Section: Mutations Induced By Manganesementioning

confidence: 99%

DNA Damage Induced by Manganese

Bornhorst¹,

Schwerdtle²

2014

Manganese in Health and Disease

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This chapter summarizes the current studies on the genotoxic potential of manganese (Mn) and is thereby points out that the knowledge gained up to now is quite equivocal. Besides reviewing the current literature on Mn-induced DNA damage on a chromosomal as well as a DNA level, possible underlying mechanisms, including disturbances of DNA replication/DNA polymerases as well as DNA damage response pathways, are discussed. Finally, this chapter gives a brief overview of the possible consequences of DNA damage induced by manganese.

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Section: Mutations Induced By Manganesementioning

confidence: 99%

DNA Damage Induced by Manganese

Bornhorst¹,

Schwerdtle²

2014

Manganese in Health and Disease

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“…As detailed earlier, in vivo and in vitro exposure to Mn is associated with oxidative stress, [107][108][109][110][111][112] leading to behavioral impairments and neuroinflammation. 35,107,113 Consequently, the use of antioxidants has been investigated as a potential pharmacological approach to treat the toxicity of Mn.…”

Section: Antioxidant Approach Against Manganismmentioning

confidence: 96%

Manganese and Oxidative Stress

Ávila¹,

Farina²,

Rocha³

et al. 2014

Manganese in Health and Disease

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Although reactive oxygen species (ROS) are known to play crucial roles in maintaining cellular homeostasis, either an excessive increase in their production or a decrease of their detoxification causes oxidative stress, which is characterized as a disturbance in the pro-oxidant/antioxidant balance in favor of the former, leading to cellular damage. This chapter delves into the relationship between manganese (Mn) toxicity and oxidative stress. Although Mn has central physiological roles as cofactor of several enzymes, including antioxidant enzymes (i.e. Mn-superoxide dismutase), this chapter focuses on the pro-oxidative properties of Mn, presenting and discussing literature data concerning its effects on mitochondrial functioning, dopamine oxidation, and antioxidant defenses. The potential use of antioxidant approaches to mitigate Mn-induced toxicity is also presented.

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“…To determine whether thio-DMA V alters the activity of recombinant PARP-1 a non-radioactive immuno-slot-blot assay was applied [29]. Preincubation of recombinant PARP-1 for 2 min with thio-DMA V in concentrations up to 250 M did not diminish the PARP-1 Table 3 Effect of the arsenicals on Caspase-2 and GADD45A gene expression.…”

Section: Impact On the Activity Of Recombinant Parp-1mentioning

confidence: 99%

“…Activity of recombinant PARP-1 (expressed in a baculovirus system [31]) was quantified by a further established immuno-slotblot technique [29] based on a test system published recently [32]. Briefly, after 2 min preincubation of PARP-1 (0.69 ng/L (61 nM)) with the respective arsenic species in preincubation buffer at room temperature, the PARP-1 reaction was carried out for 5 min at 37 • C in reaction buffer.…”

Section: Activity Of Recombinant Parp-1mentioning

confidence: 99%

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Toxicological properties of the thiolated inorganic arsenic and arsenosugar metabolite thio-dimethylarsinic acid in human bladder cells

Ebert

Leffers

Weber

et al. 2014

Journal of Trace Elements in Medicine and Biology

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Thio-dimethylarsinic acid (thio-DMA(V)) has recently been identified as human metabolite after exposure toward both the human carcinogen inorganic arsenic and arsenosugars, which are the major arsenical constituents of marine algae. This study aims to get further insight in the toxic modes of action of thio-DMA(V) in cultured human urothelial cells. Among others effects of thio-DMA(V) on eight cell death related endpoints, cell cycle distribution, genotoxicity, cellular bioavailability as well as for the first time its impact on DNA damage induced poly(ADP-ribosyl)ation were investigated and compared to effects induced by arsenite. The data indicate that thio-DMA(V) exerts its cellular toxicity in a similar or even lower concentration range, however most likely via different mechanisms, than arsenite. Most interestingly, thio-DMA(V) decreased damage-induced cellular poly(ADP-ribosyl)ation by 35,000-fold lower concentrations than arsenite. The inhibition of this essential DNA-damage induced and DNA-repair related signaling reaction might contribute to inorganic arsenic induced toxicity, at least in the bladder. Therefore, and also because thio-DMA(V) is to date by far the most toxic human metabolite identified after arsenosugar intake, thio-DMA(V) should contemporary be fully (also in vivo) toxicologically characterized, to assess risks to human health related to inorganic arsenic but especially arsenosugar dietary intake.

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Molecular mechanisms of Mn induced neurotoxicity: RONS generation, genotoxicity, and DNA‐damage response

Abstract: The observed inhibition of DNA-damage-induced poly(ADP-ribosyl)ation in human astrocytes by exposure-relevant Mn concentrations indicate that in terms of Mn the existing guidelines for infant formula but also drinking water should be critically reconsidered.

Cited by 36 publications

References 98 publications

DNA Damage Induced by Manganese

DNA Damage Induced by Manganese

Manganese and Oxidative Stress

Toxicological properties of the thiolated inorganic arsenic and arsenosugar metabolite thio-dimethylarsinic acid in human bladder cells

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