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Elucidating the influence of environmentally relevant toxic metal mixture on molecular mechanisms involved in the development of neurodegenerative diseases: In silico toxicogenomic data-mining

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2021
Authors
Živančević, Katarina
Baralić, Katarina
Jorgovanović, Dragica
Buha-Đorđević, Aleksandra
Ćurčić, Marijana
Antonijević Miljaković, Evica
Antonijević, Biljana
Bulat, Zorica
Article (Published version)
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Abstract
This in silico toxicogenomic analysis aims to: (i) testify the hypothesis about the influence of the environmentally relevant toxic metals (lead, methylmercury (organic form of mercury), cadmium and arsenic) on molecular mechanisms involved in amyotrophic lateral sclerosis (ALS), Parkinson’s Disease (PD) and Alzheimer’s disease (AD) development; and (ii) demonstrate the capability of in silico toxicogenomic data-mining for distinguishing the probable mechanisms of mixture-induced toxic effects. The Comparative Toxicogenomics Database (CTD; http://ctd. mdibl.org) and Cytoscape software were used as the main data-mining tools in this analysis. The results have shown that there were 7, 13 and 14 common genes for all the metals present in the mixture for each of the selected neurodegenerative disease (ND), respectively: ALS, PD and AD. Physical interactions (68.18%) were the most prominent interactions between the genes extracted for ALS, co-expression (60.85%) for PD and interact...ions predicted by the server (44.30%) for AD. SOD2 gene was noted as the mutual gene for all the selected ND. Oxidative stress, folate metabolism, vitamin B12, AGE-RAGE, apoptosis were noted as the key disrupted molecular pathways that contribute to the neurodegenerative disease’s development. Gene ontology analysis revealed biological processes affected by the investigated mixture (glutathione metabolic process was listed as the most important for ALS, cellular response to toxic substance for PD, and neuron death for AD). Our results emphasize the role of oxidative stress, particularly SOD2, in neurodegeneration triggered by environmental toxic metal mixture and give a new insight into common molecular mechanisms involved in ALS, PD and AD pathology.

Keywords:
Neurodegeneration / Lead / Methylmercury / Cadmium / Arsenic / Toxicogenomic data-mining
Source:
Environmental Research, 2021, 194, 110727-
Publisher:
  • Elsevier
Projects:
  • Ministry of Education, Science and Technological Development, Republic of Serbia, Grant no. 451-03-68/2020-14/200161 (University of Belgrade, Faculty of Pharmacy) (RS-200161)

DOI: 10.1016/j.envres.2021.110727

ISSN: 0013-9351

Scopus: 2-s2.0-85100143212
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URI
https://farfar.pharmacy.bg.ac.rs/handle/123456789/3780
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  • Radovi istraživača / Researchers’ publications
Institution
Pharmacy

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