Damdimopoulou lab - Chemicals and female fertility

Our team studies ovarian biology and the effects of chemical exposures on fertility in women. We are located at Campus Flemingsberg of Karolinska Institutet.

We are interested in the structure and function of human ovaries, and how exposure to chemicals might disrupt their normal development and function leading to infertility.

Female fertility depends on healthy ovaries that are controlled by timely and appropriate action of hormones. For example, the maturation of ovarian follicles containing oocytes is controlled by pituitary hormones as well as local ovarian growth factors. The maturing follicle in turn produces hormones that prepare the uterus for a possible pregnancy. Disruption of these signaling events by chemicals could lead to difficulties in becoming pregnant. Furthermore, certain medical treatments like alkylating chemotherapy can directly damage oocytes, leaving the patient undergoing cancer treatments at high risk of infertility as a side effect of their life-saving therapy.

Infertility is common. Approximately 10-15 % of couples suffer from involuntary infertility. In Sweden, approximately 21 000 fertility treatments are carried out each year resulting in over 5 000 babies (4 % of all births). Although many couples can become parents with the help of assisted reproduction, about one third remain childless.

It is important to study normal ovarian function in detail to understand how different ovarian cell types and hormones contribute to fertility. Using that information, it is possible to study how chemical exposures can disrupt ovarian function. Further, it will be possible to design better assays for detecting chemicals that disrupt fertility in women. In the long run, we hope to apply the findings of our research to change chemical legislations and improve in the use of chemicals in our society.

Our work is organized around four main aims:

  1. identification of chemicals that associate with adverse reproductive outcomes in women;
  2. analysis of human ovarian tissue on molecular and cellular level from birth to menopause;
  3. delineation of mechanisms through which chemical exposures disrupt ovarian function;
  4. development of in vitro models that mimic ovaries
From left: Pauliina Damdimopoulou, Eleftheria Maria Panagiotou and Richelle Duque Björvang. Photo: Cecilia Hultqvist

Research team members

Group Leader Pauliina Damdimopoulou, PhD, Docent

Postdoc Ilmatar Rooda, PhD

Postdoc Ilari Tarvainen, PhD

Postdoc Jie Hao, MD, PhD

PhD student Jasmin Hassan, MSc

PhD student Tianyi Li, MSc

PhD student Eleftheria-Maria Panagiotou, MSc

Visiting student Ravindra Naraine

MSc student Nikki Hiltunen

Projects

Chemical exposures and fertility in women

Aim

To identify chemical exposures that associate with reduced fertility in women

Methods

We use data from various cohorts to analyze associations between exposure to chemicals and fertility in women. For example, we study whether chemicals present in patients undergoing fertility treatment associate to ovarian function and chances of live birth. We also investigate associations between chemicals and the size of ovarian reserve in a cohort of caesarean section patients. Furthermore, we study the impact of chemotherapy on ovarian health in patients exposed to chemotherapy. Since ovarian health is defined already during fetal development, a part of our studies focuses on analysis of human fetal exposure to chemicals.

These studies are based on collaborations with Prof Bornehag (Karlstad University), Dr Holte (Carl von Linnékliniken in Uppsala), Assc Prof Sjunnesson and Dr Persson (Swedish University of Agricultural Sciences, Uppsala), Prof Olovsson (Uppsala University), Prof Jahnukainen (University of Helsinki, Finland), Prof Yding Andersen (University of Copenhagen, Denmark), and Prof Acharya, Prof Gemzell-Danielsson, Dr Papadogiannakis and Dr Pettersson (Karolinska Institutet and Karolinska University Hospital). Chemical analyses are carried out in collaboration with Prof Kivimäki (National Institute for Health and Welfare, Finland), Assc Prof Lindh (University of Lund), and Prof van Duursen (Vrije Universiteit Amsterdam).

Selected publications

“Follicular fluid and blood levels of persistent organic pollutants and reproductive outcomes among women undergoing assisted reproductive technologies" Björvang et al. 2021 Environ Res

“Persistent organic pollutants and the size of ovarian reserve in reproductive-aged women” Björvang et al. 2021 Environ Int

“Persistent organic pollutants, pre-pregnancy used of combined oral contraceptives, age and time-to-pregnancy in the SELMA cohort” Björvang et al. accepted for publication in Environ Health

”Impact of First-Line Cancer Treatment on the Follicle Quality in Cryopreserved Ovarian Samples From Girls and Young Women” Pampanini et al. 2019 Hum Reprod

”Concentrations of Perfluoroalkyl Substances (PFASs) in Human Embryonic and Fetal Organs From First, Second, and Third Trimester Pregnancies” Mamsen et al. 2019 Environ Int

Molecular and cellular characterization of human ovaries

Aim

To map cellular composition of human ovaries from birth to menopause

Methods

We carry out a molecular and cellular characterization of human ovarian tissue on a single cell level to identify different cell populations in normal human ovaries from childhood through fertile years to menopause. We have initiated a national fertility preservation study for girls and young women, entitled Sveafertil, that gives patients at very high risk of treatment-induced infertility the chance for fertility preservation through cryopreservation of ovarian tissue. A small fragment of the tissue comes to our research. By detailed analysis of human ovaries, we aim to reconstruct ovaries in vitro. Models that mimic human ovaries and follicle growth would be urgently needed in chemical health risk assessment as well as in fertility preservation research.

These projects are based on a collaboration with Prof Jahnukainen, Dr Tuuri and Dr Otala (University of Helsinki, Finland), Dr Petersen (Sahlgrenska University Hospital), Prof Salumets, Prof Acharya, Dr Lanner and Prof Kere (Karolinska Institutet), Dr Pettersson, Dr Palm and Dr Papaikonomou (Karolinska University Hospital), Prof Yding Andersen (Rigshospitalet, Copenhagen, Denmark), Assc Prof Velthult-Meikas (Tallinn University of Technology, Estonia), and all pediatric oncology and hematology units in Sweden.

Selected publications

”Single-cell Analysis of Human Ovarian Cortex Identifies Distinct Cell Populations but No Oogonial Stem Cells” Wagner et al. 2020 Nat Commun

“Fertility Preservation for Prepubertal Patients at Risk of Infertility: Present Status and Future Perspectives” Pampanini et al. 2020 Horm Res Paediatr

ONLINE RESOURCE E-ovary

Mechanisms and models for chemical disruption of fertility in women

Aim

To identify mechanisms of chemical toxicity in ovaries and to develop in vitro models that mimic ovaries for chemical toxicity testing

Methods

We use human ovarian tissue culture and cell cultures to identify mechanisms underpinning chemical toxicity in ovaries. We study how the chemicals we have identified in our cohort studies impact ovarian follicle viability and growth using tissue culture and transcriptomics technologies. We develop “adverse outcome pathways (AOP)” following the OECD endorsed strategy for describing adverse health outcomes to increase the regulatory impact of our findings.

These studies are a part of larger collaborative networks where novel assays for reproductive toxicity in the female are developed: the EU-project FREIA and the Swedish Research Council FORMAS-funded project Pandora. Key collaborators are Dr Boberg and Dr Svingen (Technical University of Denmark), Dr Holte and Prof Olovsson (University of Uppsala), Prof Salumets (Karolinska Institutet), Dr Velthult-Meikas (Tallinn University of Technology), Prof Flaws (University of Illinois, USA), Dr Öberg (Karolinska Institutet), and Prof van Duursen (Vrije Universiteit Amsterdam, the Netherlands).

Selected publications

"A Pragmatic Approach to Adverse Outcome Pathway Development and Evaluation” Svingen et al. 2021 Toxicol Sci

”Culture of human ovarian tissue in xeno-free conditions using laminin components of the human ovarian extracellular matrix.” Hao et al. 2020 J Assist Reprod Genet

”Putative adverse outcome pathways for female reproductive disorders to improve testing and regulation of chemicals.” Johansson et al. 2020 Arch Toxicol

”Safeguarding Female Reproductive Health Against Endocrine Disrupting Chemicals-The FREIA Project” van Duursen et al. 2020 Int J Mol Sci

”Retinoic acid signaling in ovarian folliculogenesis and steroidogenesis.” Damdimopoulou et al. 2019 Reprod Toxicol

Acknowledgements

Our studies on human ovarian tissue are inspired by Prof Emerita Outi Hovatta. The work would not be possible without the precious tissue donations by patients attending Karolinska University Hospital, and the dedicated hospital personnel. We sincerely thank all patients giving tissues to our studies, and the clinicians that make our studies possible.

All our studies are covered by ethical approvals from the Swedish Ethical Review Authority.

Links

EU-project FREIA “Safeguarding female reproductive health against endocrine disruptive chemicals”

EU-project ERIN  “Ethically responsible innovations in reproductive medicine”

Fertility preservation study Sveafertil

Online resources E-ovary

Information for patients who participate in our studies

Current research funding

  • Swedish Research Council FORMAS Combination Effects Pandora (2019-2022)
  • EU Horizon2020 FREIA (2019-2023)
  • EU Horixon2020 ERIN (2020-2023)
  • Karolinska Institutet KID funding (2019-2023)
  • Swedish Research Council FORMAS (2021-2023)
  • Swedish Research Council (2021-2023)
  • Childhood Cancer Foundation (2021-2023)
  • SFO stem cells and regenerative medicine (2021-2023)

Our research in news

Research presentations online

Keynote Lecture on Chemicals and Fertility in Women at Helsinki One Health Symposium (2020)

Presentation on EDCs, Plastics and Human Health at UNDP global webinar series and Endocrine Society press release event (2021)