The role of reactive oxygen species (ROS) in the signaling of FSH and ovarian factors

• Applicants: Privatdozent Dr. Lars Kunz; Professor Dr. Artur Mayerhofer
• Subject Area: Reproductive Medicine, Urology ; Endocrinology, Diabetology, Metabolism
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 262625742

• Final Report Year: 2018

Final Report Abstract

1. We could not confirm initial pilot results, namely that FSH action in human granulosa cells (primary and KGN) involves elevations of ROS/H2O2 levels. This caused a reorientation of the project focusing more on H2O2 as signaling molecule. 2. We identified ROS/H2O2-generating enzymes, specifically NOX4, which produces H2O2. We partially identified and characterized the H2O2 system of the human follicle, including aquaporins as H2O2 transporters and linked H2O2 actions to beneficial consequences, mainly cell growth. 3. We explored GC-derived factors in the FF (PEDF, L-DOPA, DA). We described that PEDF has ROS-elevating actions, resulting in GC death. We identified antioxidant properties of L-DOPA, which contrast with ROS-­elevating actions of DA in human GCs. 4. Still ongoing studies will add to the mentioned antioxidant actions of L-DOPA in KGN and will furthermore delineate the consequences of FSH stimulation in primary GCs and KGN cells at the proteomic level. The data obtained during this project collectively highlight the importance of ROS and H2O2 in the human ovary and possibly GC tumors; results that may be of clinical relevance as well. The results also raised a series of new questions, which may in the near future result in a follow-up proposal.

Publications

• (2019) The NADPH oxidase 4 is a major source of hydrogen peroxide in human granulosa-lutein and granulosa tumor cells. Scientific reports 9 (1) 3585
  Buck, Theresa; Hack, Carsten Theo; Berg, Dieter; Berg, Ulrike; Kunz, Lars; Mayerhofer, Artur
  (See online at https://doi.org/10.1038/s41598-019-40329-8)
• Pigment-Epithelium Derived Factor (PEDF) and the human ovary: a role in the generation of ROS in granulosa cells. Life Sci. 2014;97(2):129-36
  Kampfer C, Saller S, Windschüttl S, Berg D, Berg U, Mayerhofer A
  (See online at https://doi.org/10.1016/j.lfs.2013.12.007)
• ROS-generating Nox enzymes in human ovary: The role of Nox4. DVR­Kongress, Hamburg, 2015
  T. Buck, K. Dietrich, J. Blohberger, C. Herrmann, D. Berg, U. Berg, A. Mayerhofer
  
• L-DOPA in the human ovarian follicular fluid acts as an antioxidant factor on granulosa cells. J Ovarian Res. 2016;9(1):62
  Blohberger J, Buck T, Berg D, Berg U, Kunz L, Mayerhofer A
  (See online at https://doi.org/10.1186/s13048-016-0269-0)
• ROS-generating Nox enzymes in human ovary: The role of Nox4; DACH­Meeting, München, 2016
  T. Buck, K. Dietrich, A. Tiefenbacher, J. Blohberger, C. Herrmann, D. Berg, U. Berg, A. Mayerhofer
  
• A NanoString analysis of human granulosa cells, granulosa cell tumours and KGN cells. DVR, München, 2017
  Bagnjuk K., Bartsch H., Straub T., Berg U., Berg D, Kunz L., Mayr D., Mayerhofer A
  
• NOX4 ­ a major source of H2O2 in the human ovary, SSR Meeting, Washington DC, USA, 2017
  Theresa Buck, Carola Herrmann, Dieter Berg, Ulrike Berg, Lars Kunz, Artur Mayerhofer
  
• The levels of L-DOPA in human follicular fluid are not correlated with total antioxidant capacity and IVF­outcome: a pilot study. DVR, München, 2017
  T. Hack, T. Buck, D. Berg, U. Berg, L. Kunz, A. Mayerhofer