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Mechanistic Toxicology : Molecular interactions and underlying mechanisms of dendritic cell activation in skin sensitization

Lindberg, Tim LU (2019)
Abstract
Allergic skin diseases caused by low molecular weight chemical compounds are a major health concern among the general population, especially in certain occupational groups. To limit exposure to such compounds, it is important that thorough risk assessments are performed before products reach the consumer market. Traditionally, such risk assessments have been based on animal tests, but due to several factors, including legislations and ethical concerns, the use of animal testing has become increasingly unjustifiable. In this context, one focus in predictive toxicology has been the development of alternative methods to replace animal experiments. Although several alternative methods have been validated for regulatory decision making, they... (More)
Allergic skin diseases caused by low molecular weight chemical compounds are a major health concern among the general population, especially in certain occupational groups. To limit exposure to such compounds, it is important that thorough risk assessments are performed before products reach the consumer market. Traditionally, such risk assessments have been based on animal tests, but due to several factors, including legislations and ethical concerns, the use of animal testing has become increasingly unjustifiable. In this context, one focus in predictive toxicology has been the development of alternative methods to replace animal experiments. Although several alternative methods have been validated for regulatory decision making, they lack certain endpoints for complete risk assessments, and molecular mechanisms underlying skin sensitization are still not entirely understood. The work described in this thesis aims at increasing our knowledge about the mechanisms in dendritic cell activation in response to skin sensitizers and to further develop a dendritic cell-based in vitro assay.

In Paper I, we investigated the microRNA regulation in response to stimulation of a DC model with structurally similar rubber sensitizers. The changes triggered by the rubber sensitizers in both mRNA and microRNA expression suggest a chemical-specific regulation, despite the structural similarity of the rubber sensitizers. In Paper II, the skin sensitizing properties of herbicidal formulations are investigated. Here, we predicted the herbicide glyphosate as a non-sensitizer, while the co-formulant polyethylated tallow amine and two glyphosate-based formulations were predicted as sensitizers. Additionally, we also investigated the proteomic alterations in response to these chemicals and formulations, and identified cellular responses associated with the differentially expressed proteins. In the last two papers, Paper III and Paper IV, we present additional applications for the in vitro assay setup used in this thesis. In Paper III, we identified a biomarker signature for the prediction of skin sensitizer potency, demonstrating a balanced accuracy of 78% targeting three potency classes, i.e., 1A (strong sensitizers), 1B (weak sensitizers) and no cat (non-sensitizers). In Paper IV, we applied a statistical method, the conformal prediction framework, to investigate the predictive boundaries of the in vitro assay, and concluded, based on 70 chemicals, that the assay can be applied to a large chemical space.

In conclusion, the work presented here can contribute to a better understanding of the mechanisms underlying the immunological response to skin sensitizing chemicals, which together with state-of-the-art predictive assays could be used for improved risk assessment of chemical compounds and to develop tools for prevention and treatment of allergic skin diseases.
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author
supervisor
opponent
  • Professor Gibbs, Susan, VU University Medical Center, The Netherlands
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Skin Sensitization, Toxicology, Mechanisms, Dendritic Cells
pages
165 pages
publisher
Department of Immunotechnology, Lund University
defense location
Hörsalen, Medicon Village, Scheelevägen 2, Lund University, Faculty of Engineering LTH
defense date
2019-06-14 09:15
ISBN
978-91-7895-028-7
978-91-7895-029-4
language
English
LU publication?
yes
id
8c82dc70-52a6-434c-9c1e-bed2b01a7538
date added to LUP
2019-05-15 16:46:46
date last changed
2019-05-22 15:35:14
@phdthesis{8c82dc70-52a6-434c-9c1e-bed2b01a7538,
  abstract     = {Allergic skin diseases caused by low molecular weight chemical compounds are a major health concern among the general population, especially in certain occupational groups. To limit exposure to such compounds, it is important that thorough risk assessments are performed before products reach the consumer market. Traditionally, such risk assessments have been based on animal tests, but due to several factors, including legislations and ethical concerns, the use of animal testing has become increasingly unjustifiable. In this context, one focus in predictive toxicology has been the development of alternative methods to replace animal experiments. Although several alternative methods have been validated for regulatory decision making, they lack certain endpoints for complete risk assessments, and molecular mechanisms underlying skin sensitization are still not entirely understood. The work described in this thesis aims at increasing our knowledge about the mechanisms in dendritic cell activation in response to skin sensitizers and to further develop a dendritic cell-based in vitro assay.<br/><br/>In Paper I, we investigated the microRNA regulation in response to stimulation of a DC model with structurally similar rubber sensitizers. The changes triggered by the rubber sensitizers in both mRNA and microRNA expression suggest a chemical-specific regulation, despite the structural similarity of the rubber sensitizers. In Paper II, the skin sensitizing properties of herbicidal formulations are investigated. Here, we predicted the herbicide glyphosate as a non-sensitizer, while the co-formulant polyethylated tallow amine and two glyphosate-based formulations were predicted as sensitizers. Additionally, we also investigated the proteomic alterations in response to these chemicals and formulations, and identified cellular responses associated with the differentially expressed proteins. In the last two papers, Paper III and Paper IV, we present additional applications for the in vitro assay setup used in this thesis. In Paper III, we identified a biomarker signature for the prediction of skin sensitizer potency, demonstrating a balanced accuracy of 78% targeting three potency classes, i.e., 1A (strong sensitizers), 1B (weak sensitizers) and no cat (non-sensitizers). In Paper IV, we applied a statistical method, the conformal prediction framework, to investigate the predictive boundaries of the in vitro assay, and concluded, based on 70 chemicals, that the assay can be applied to a large chemical space.<br/><br/>In conclusion, the work presented here can contribute to a better understanding of the mechanisms underlying the immunological response to skin sensitizing chemicals, which together with state-of-the-art predictive assays could be used for improved risk assessment of chemical compounds and to develop tools for prevention and treatment of allergic skin diseases.<br/>},
  author       = {Lindberg, Tim},
  isbn         = {978-91-7895-028-7},
  keyword      = {Skin Sensitization,Toxicology,Mechanisms,Dendritic Cells},
  language     = {eng},
  month        = {05},
  pages        = {165},
  publisher    = {Department of Immunotechnology, Lund University},
  school       = {Lund University},
  title        = {Mechanistic Toxicology : Molecular interactions and underlying mechanisms of dendritic cell activation in skin sensitization},
  year         = {2019},
}