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Mechanistic studies on the adverse effects of manganese overexposure in differentiated LUHMES cells
Merle M Nicolai1, Barbara Witt2, Sharleen Friese3
1Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Wuppertal, Germany.
Abstract:
Manganese (Mn) is an essential trace element, but overexposure is associated with toxicity and neurological dysfunction. Accumulation of Mn can be observed in dopamine-rich regions of the brain in vivo and Mn-induced oxidative stress has been discussed extensively. Nevertheless, Mn-induced DNA damage, adverse effects of DNA repair, and possible resulting consequences for the neurite network are not yet characterized. For this, LUHMES cells were used, as they differentiate into dopaminergic-like neurons and form extensive neurite networks. Experiments were conducted to analyze Mn bioavailability and cytotoxicity of MnCl2, indicating a dose-dependent uptake and substantial cytotoxic effects. DNA damage, analyzed by means of 8-oxo-7,8-dihydro-2'-guanine (8oxodG) and single DNA strand break formation, showed significant dose- and time-dependent increase of DNA damage upon 48 h Mn exposure. Furthermore, the DNA damage response was increased which was assessed by analytical quantification of poly(ADP-ribosyl)ation (PARylation). Gene expression of the respective DNA repair genes was not significantly affected. Degradation of the neuronal network is significantly altered by 48 h Mn exposure. Altogether, this study contributes to the characterization of Mn-induced neurotoxicity, by analyzing the adverse effects of Mn on genome integrity in dopaminergic-like neurons and respective outcomes.
Insights
Manganese (Mn) overexposure causes DNA damage and neurotoxicity in dopaminergic neurons. This study reveals Mn
Area of Science:
- Neuroscience
- Toxicology
- Genetics
Background:
- Manganese (Mn) is essential but toxic at high levels, linked to neurological issues.
- Mn accumulates in dopamine-rich brain areas, causing oxidative stress.
- Mn's effects on DNA integrity and neuronal networks are poorly understood.
Purpose of the Study:
- To investigate Mn-induced DNA damage and its impact on neuronal networks.
- To characterize Mn's effects on genome integrity in dopaminergic-like neurons.
Main Methods:
- Used LUHMES cells, which differentiate into dopaminergic-like neurons.
- Analyzed Mn bioavailability, cytotoxicity, DNA damage (8oxodG, strand breaks), and DNA repair response (PARylation).
Main Results:
- MnCl2 exhibited dose-dependent uptake and cytotoxicity.
- Significant dose- and time-dependent DNA damage and repair response increase observed.
- Neuronal network degradation was significantly altered by Mn exposure.
- DNA repair gene expression remained unaffected.
Conclusions:
- Mn exposure induces significant DNA damage and alters neuronal network integrity.
- This study characterizes Mn-induced neurotoxicity by examining genome integrity in dopaminergic neurons.
