Projects / Programmes
The effects of different types of nanoparticles on neural cell and macrophages – analysis of short-term and long-term effects on cell stress, differentiation and cell signalling
| Code |
Science |
Field |
Subfield |
| 4.06.00 |
Biotechnical sciences |
Biotechnology |
|
| Code |
Science |
Field |
| T490 |
Technological sciences |
Biotechnology |
| Code |
Science |
Field |
| 3.04 |
Medical and Health Sciences |
Medical biotechnology |
nanoparticles, neurotoxicology, neurodegeneration, cell signalling, carcirogenicity, differentiation
Researchers (1)
| no. |
Code |
Name and surname |
Research area |
Role |
Period |
No. of publicationsNo. of publications |
| 1. |
34385 |
PhD Jasna Lojk |
Metabolic and hormonal disorders |
Head |
2017 - 2019 |
68 |
Organisations (1)
Abstract
In recent years, the exposure to environmental and engineered nanoparticles (NPs) has increased through environmental pollution and increased use of different engineered NPs in consumer products. Such NPs can enter and accumulate in the body, where they can cause different health-related problems, as indicated by several in vivo and human epidemiological studies. Brain is a particularly problematic accumulation site due to its restricted immune responses, low regeneration abilities, high lipid content and high energy consumption, which make it highly vulnerable to oxidative stress. Despite that, there are still many unanswered questions concerning the mechanisms of NP neurotoxicity, especially regarding potential long-term effects that could affect cell differentiation and lead to neurodegeneration or carcinogenesis. Moreover, several recent studies have shown that NPs not only affect the cells through direct cell damage but also through more subtle influences such as changes in cell signalling. Unfortunately, research in the potential health risks of NP exposure lags behind the rapid industrial development and commercialization of nanotechnology.
Within this postdoctoral project we will analyse potential toxicity and related mechanisms of selected relevant engineered NP types (SiO2, P25 TiO2, food-grade TiO2, silver) in a human neural cell model in vitro. Besides the general toxicity mechanisms (cell viability, ROS, apoptosis, cell cycle analysis, changes in autophagy) and NP-cell interactions (internalization pathways, intracellular trafficking and intracellular fate), we will also analyse possible NP-induced changes in cell signalling. We will focus on signalling related to cell stress, immune responses (e.g. NF-κB, c-JUN, AP-1, Nrf-2, JNK) and cancer (HIF-1, mTOR, MAPK, PI3K, p53). Moreover, we will use an in vitro neural cell model of differentiating cells, which will enable us to analyse the consequences of prolonged NP exposure/retention time on cell differentiation, possible neurodegenerative changes through altered intracellular localization and solubility of proteins related to neurodegenerative diseases (e.g. tau, α-synuclein, FUS, TDP-43) and carcinogenic changes (micronuclei formation, altered cell signalling) in human neural cells in vitro. Already performed thorough NP characterization will enable us to analyse the observed responses of neural cells and NP toxicity mechanisms in relation to physico-chemical parameters of these NPs.
With this project we want to contribute to better understanding of the mechanisms of NP toxicity on neural cells both following short and long exposure times with the focus on cell differentiation, neurodegeneration and carcinogenesis. Our analysis of neurotoxicity of specific engineered NPs will also enable us to better understand the relations between NP properties, their toxicity mechanisms and possible changes in cell signalling pathways, which could have profound effects on cell and tissue functions, and thus help us identify potential hazards of the analysed NPs that are widely used in industrial and consumer products.
Significance for science
With aging population and increasing incidence of neurodegenerative and developmental diseased, the knowledge of nanoneurotoxicity and possible involvement of NPs in these pathological processes is both essential and lacking. Within this project we aim to assess potential toxicity of engineered NPs on neural cells, the involved toxicity mechanisms, signalling pathways and long-term effects on neurodegenerative and carcinogenic changes in vitro. The NPs used in this project (SiO2, TiO2, silver NPs) were selected as engineered NPs widely used in consumer products such as food, packing, cosmetics, clothes and antibacterial coatings.
So far, studies have shown that NPs can trigger several stress mechanisms in neural cell models in vitro and can induce pathological changes following NP accumulation in the brain in vivo. Recently, a study has been published confirming the presence of combustion derived NPs in the brain tissue of Alzheimer’s patients and epidemiological studies are emerging, indicating environmental NPs as one of the possible causes for initiation or potentiation of neurological disorders. However, the mechanisms involved in NP-induced neurodegenerative changes, especially following long-term exposure, are not well understood. Only a few long-term studies have been performed on neural cell models so far. In this study, we would use a long-term cell model able to differentiate, which will better resemble in vivo conditions, to observe the effects of prolonged NP exposure and intracellular accumulation on cell differentiation, carcinogenic changes and potential changes that could lead to neurodegeneration in vivo. Analysis of NP toxicity mechanisms in combination with thorough NP characterization could also indicate which NP properties are responsible for observed changes.
Moreover, in the last years, studies started to emerge indicating the ability of NPs to influence the signalling pathways in the cells, including important signalling pathways involved in cell stress and immune response as well as cancer related signalling pathways. Thorough examination of the activity of these signalling pathways performed in this study could improve our knowledge on the mechanisms through which the selected engineered NPs influence neural cells in vitro.
Executing this project will thus enable us to:
- - -Evaluate the mechanisms of toxicity of engineered NP types frequently used in food, cosmetics and other consumer products (TiO2, SiO2, silver) on neural cell models in connection with their physico-chemical characterization,
- - systematically analyse the effects of selected NP formulation on cell signalling involved with cell stress and immune responses and carcinogenesis in neural cell model in vitro
- - analysis of possible indirect toxicity through cell-to cell transfer of signalling factors,
- - determining the mechanisms of long-term toxicity of NPs with the focus on the ability of NPs to induce neurodegenerative and tumorigenic changes in neural cell model in vitro.
Significance for the country
We are constantly exposed to increasing number and concentrations of NPs either through environmental pollution or through engineered NPs in consumer product and biomedical applications. However, the information on the possible negative consequences of this exposure is still poor. It was shown that non-degradable NPs can enter the brain through three routes and can accumulate in neural tissues with little to no mechanisms of elimination, leading to prolonged exposure and cell burden, which is proposed to be one of the mechanisms for manifestation of pathological and neurodegenerative changes in the brain.
With this project we want to add to the knowledge on short- and long-term toxicity mechanisms of engineered NPs in neural cell models in vitro with the emphasis on possible NP-induced changes in cell signalling and the ability of NPs to induce neurodegenerative and carcinogenic changes in neural cell model following long-term exposure. This is knowledge is crucial, since it will help us better understand the dangers of the engineered NPs to which we are exposed on daily bases and take appropriate measures both in terms of prevention (more strict measures regarding NP usage and release into the environment, improved safety guidelines) and treatment (novel treatments based on better understanding of NP toxicity mechanisms). Additional knowledge might also help us better understand the possible connection between increased exposure to NPs and increased incidence of neurodegenerative disorders and cancer in recent decades.
The neural cell model and protocols for evaluation of long-term toxicity mechanisms of NPs could also represent additional methodology for assessment of potential neurotoxicity of novel NP formulations before their translation in vivo. The research work will be performed in a way to make the translation of the obtained knowledge from in vitro to in vivo as easy as possible.
Part of the project will be performed abroad in a laboratory specialized in neurobiology. The PI trained in biology and nanotoxicology will thus add to her experience and knowledge from a complementary medical field. This will also enable us to establish new collaborations with foreign research groups, which will allow us access to novel experimental techniques and exchange of ideas from different scientific backgrounds.
Most important scientific results
Interim report,
final report
Most important socioeconomically and culturally relevant results
Interim report,
final report
