TY - JOUR
T1 - Differential protein expression of hippocampal cells associated with heavy metals (Pb, As, and MeHg) neurotoxicity:
T2 - Deepening into the molecular mechanism of neurodegenerative diseases
AU - Karri, Venkatanaidu
AU - Ramos, David
AU - Bauza Martinez, Julia
AU - Odena, Antonia
AU - Oliveira, Eliandre
AU - Coort, Susan L.
AU - Evelo, Chris T.
AU - Mariman, Edwin C. M.
AU - Schuhmacher, Marta
AU - Kumar, Vikas
PY - 2018/9/15
Y1 - 2018/9/15
N2 - Chronic exposure to heavy metals such as Pb, As, and MeHg can be associated with an increased risk of developing neurodegenerative diseases. Our in vitro bioassays results showed the potency of heavy metals in the order of Pb <As <MeHg on hippocampal cells. The main objective of this study was combining in vitro label free proteomics and systems biology approach for elucidating patterns of biological response, discovering underlying mechanisms of Pb, As, and MeHg toxicity in hippocampal cells. The omics data was refined by using different filters and normalization and multilevel analysis tools were employed to explore the data visualization. The functional and pathway visualization was performed by using Gene ontology and PathVisio tools. Using these all integrated approaches, we identified significant proteins across treatments within the mitochondrial dysfunction, oxidative stress, ubiquitin proteome dysfunction, and mRNA splicing related to neurodegenerative diseases. The systems biology analysis revealed significant alterations in proteins implicated in Parkinson's disease (PD) and Alzheimer's disease (AD). The current proteomics analysis of three metals support the insight into the proteins involved in neurodegeneration and the altered proteins can be useful for metal-specific biomarkers of exposure and its adverse effects.Significance: The proteomics techniques have been claimed to be more sensitive than the conventional toxicological assays, facilitating the measurement of responses to heavy metals (Pb, As, and MeHg) exposure before obvious harm has occurred demonstrating their predictive value. Also, proteomics allows for the comparison of responses between Pb, As, and MeHg metals, permitting the evaluation of potency differences hippocampal cells of the brain. Hereby, the molecular information provided by pathway and gene functional analysis can be used to develop a more thorough understanding of each metal mechanism at the protein level for different neurological adverse outcomes (e.g. Parkinson's disease, Alzheimer's diseases). Efforts are put into developing proteomics based toxicity testing methods using in vitro models for improving human risk assessment. Some of the key proteins identified can also potentially be used as biomarkers in epidemiologic studies. These heavy metal response patterns shed new light on the mechanisms of mRNA splicing, ubiquitin pathway role in neurodegeneration, and can be useful for the development of molecular biomarkers of heavy metals exposure.
AB - Chronic exposure to heavy metals such as Pb, As, and MeHg can be associated with an increased risk of developing neurodegenerative diseases. Our in vitro bioassays results showed the potency of heavy metals in the order of Pb <As <MeHg on hippocampal cells. The main objective of this study was combining in vitro label free proteomics and systems biology approach for elucidating patterns of biological response, discovering underlying mechanisms of Pb, As, and MeHg toxicity in hippocampal cells. The omics data was refined by using different filters and normalization and multilevel analysis tools were employed to explore the data visualization. The functional and pathway visualization was performed by using Gene ontology and PathVisio tools. Using these all integrated approaches, we identified significant proteins across treatments within the mitochondrial dysfunction, oxidative stress, ubiquitin proteome dysfunction, and mRNA splicing related to neurodegenerative diseases. The systems biology analysis revealed significant alterations in proteins implicated in Parkinson's disease (PD) and Alzheimer's disease (AD). The current proteomics analysis of three metals support the insight into the proteins involved in neurodegeneration and the altered proteins can be useful for metal-specific biomarkers of exposure and its adverse effects.Significance: The proteomics techniques have been claimed to be more sensitive than the conventional toxicological assays, facilitating the measurement of responses to heavy metals (Pb, As, and MeHg) exposure before obvious harm has occurred demonstrating their predictive value. Also, proteomics allows for the comparison of responses between Pb, As, and MeHg metals, permitting the evaluation of potency differences hippocampal cells of the brain. Hereby, the molecular information provided by pathway and gene functional analysis can be used to develop a more thorough understanding of each metal mechanism at the protein level for different neurological adverse outcomes (e.g. Parkinson's disease, Alzheimer's diseases). Efforts are put into developing proteomics based toxicity testing methods using in vitro models for improving human risk assessment. Some of the key proteins identified can also potentially be used as biomarkers in epidemiologic studies. These heavy metal response patterns shed new light on the mechanisms of mRNA splicing, ubiquitin pathway role in neurodegeneration, and can be useful for the development of molecular biomarkers of heavy metals exposure.
KW - Metal exposure
KW - Proteomics
KW - Pathway visualization
KW - Neurodegenerative diseases
KW - UBIQUITIN-PROTEASOME SYSTEM
KW - METHYLMERCURY-INDUCED NEUROTOXICITY
KW - ALZHEIMERS-DISEASE
KW - PARKINSONS-DISEASE
KW - OXIDATIVE STRESS
KW - MITOCHONDRIAL DYSFUNCTION
KW - A-BETA
KW - ARSENIC EXPOSURE
KW - ALPHA-SYNUCLEIN
KW - LEAD-EXPOSURE
U2 - 10.1016/j.jprot.2018.06.020
DO - 10.1016/j.jprot.2018.06.020
M3 - Article
C2 - 30017948
SN - 1874-3919
VL - 187
SP - 106
EP - 125
JO - Journal of Proteomics
JF - Journal of Proteomics
ER -