Dynamics and regulation of the oxidative stress response upon chemical exposure

Bischoff, L.J.M. (2022)

Doctoral Thesis

The focus of the described research in this thesis is on the oxidative stress response (Nrf2 pathway). The aim of the research presented in this thesis is to obtain more information concerning microRNAs which are involved in the Nrf2 pathway, to determine and evaluate the application of microRNAs for the construction of novel mechanistic biomarkers. Furthermore, we aimed to obtain a better understanding
with respect to the dynamics of the Nrf2 pathway to repeated xenobiotic exposure.
To investigate the effect of overexpression of microRNAs on the Nrf2 pathway response in general and in combination with chemical exposure, a microRNA mimic screen was performed. In this screen overexpression of microRNAs was induced by using synthetic microRNA mimics. Since repeated exposure may drive adaptation programs and may lead to different responses between single and repeated exposures. The effect of a second exposure on the dynamics of the Nrf2 pathway activation was conducted. Final, results of a study are shown where a panel of structurally different phenolic compounds were used to demonstrate the proof-of-concept that Nrf2 pathway reporters can successfully be applied as biomarkers to characterize the specific pro-oxidant responses of chemicals.

• Nrf2
• Srxn1
• MicroRNA
• Repeated exposure
• Biomarker
• Phenolic compounds
• HepG2

• All authors: Bischoff, L.J.M.
• Supervisor: Water, B. van de
• Co-supervisor: Noort, D.; Langenberg, J.P.
• Committee: Irth, H.; Bouwstra, J.A.; Jennings, P.; Lange, E.C.M. de; Vrieling, H.
• Qualification: Doctor (dr.)
• Awarding Institution: Leiden Academic Centre for Drug Research (LACDR), Faculty of Science, Leiden University
• Date: 2022-01-12
• ISBN (print): 9789464215908
• Sponsorship: This work was supported by the Ministry of Defence of the Netherlands and the European Commission Horizon2020 EU-ToxRisk project (grant nr 681002).