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Research Group - Chemicals and female fertility

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

We are interested in chemical exposures that damage ovaries or disrupt the endocrine system because the fertility of a woman is dependent on healthy ovaries that are controlled by timely and appropriate action of hormones. For example, the development of ovarian follicles that contain the 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 possible pregnancy. Disruption of these signaling events by chemicals could lead to difficulties in becoming pregnant. Furthermore, certain exposures such as alkylating chemotherapy agents can directly damage the oocytes, putting the patient undergoing cancer treatments into a high risk of infertility as a side effect of the treatments.

Infertility is a common problem. Approximately 10-15 % of all couples suffer from involuntarily 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 in vitro fertilization (IVF) techniques, about one third remain childless.

It is important to study how chemical exposures contribute to infertility since better understanding of the effects can help in designing more precise therapies for patients, and better assays for chemical health risk assessment. In the long run, this can lead to changes in chemical legislation and restrictions in the use of chemicals.

Our work revolves around three main aims: i) identification of chemicals that associate to adverse reproductive outcomes in women living in Sweden, ii) analysis of human ovarian tissue on molecular and cellular level, iii) delineation of mechanisms through which chemical exposures disrupt ovarian and endometrial function.

Projects

Chemical exposures and fertility in women living in Sweden

Aim

To identify chemical exposures that associate with reduced fertility in women living in Sweden.

Methods

We use data from the Swedish pregnancy cohort SELMA to analyze associations between maternal exposure to chemicals and time-to-pregnancy. We also analyze whether chemicals present in ovaries of fertility treatment patients affect the success rate of the treatments. In addition, we investigate associations between chemicals and the size of ovarian reserve using cohorts of caesarean section patients and 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.

Collaborations: These studies are based on collaborations with Prof Bornehag (Karlstad University), Dr Holte (Carl von Linnékliniken in Uppsala), Assc Prof Ylva Sjunnesson and Dr Sara Persson (Swedish University of Agricultural Sciences, Uppsala), Prof Kirsi Jahnukainen (University of Helsinki, Finland), Prof Claus Yding Andersen (University of Copenhagen, Denmark), and Prof Kristina Gemzell-Danielsson, Dr Marie-Therese Vinnars, Dr Nikos Papadogiannakis and Dr Karin Pettersson (Karolinska Institutet and University Hospital). Chemical analyses are carried out in collaboration with Prof Kivimäki (National Institute for Health and Welfare, Finland) and Assc Prof Lindh (University of Lund).

Publications

“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

”Persistent Environmental Endocrine-Disrupting Chemicals in Ovarian Follicular Fluid and in vitro Fertilization Treatment Outcome in Women” Björvang & Damdimopoulou 2020 Ups J Med Sci

”Impact of First-Line Cancer Treatment on the Follicle Quality in Cryopreserved Ovarian Samples From Girls and Young Women” Pampanini, Wagner 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 through development in order to evaluate mechanisms of chemical toxicity and to build models that mimic human ovaries in vitro

Methods

We carry out a molecular and cellular characterization of human ovarian tissue on a single cell level to map different cell populations and signaling networks within the normal adult ovaries. In addition, we study child ovaries. We have initiated a national fertility preservation study for girls and young women, entitled Sveafertil, that gives patients in 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 deconstruction 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 (University of Helsinki, Finland), Assc Prof Lanner and Prof Kere (Karolinska Institutet), Dr Pettersson and Dr Palm (Karolinska University Hospital), Prof Yding Andersen (Rigshospitalet, Copenhagen, Denmark), and Prof Salumets (Tartu University, Estonia), as well as all pediatric oncology and hematology units in Sweden.

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 want to thank all the tissue donors, midwives, and doctors that make our studies possible. All our studies are covered by ethical approvals from the Stockholm Region Ethical Review Board.

Publications

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

Mechanisms and models for chemical disruption of fertility in women

Aim

To identify mechanisms and biomarkers of adverse effects of chemical exposure in human ovaries

Methods

We use human ovary tissue culture and primary cell cultures combined to transcriptomics technologies in order to delineate mechanisms underpinning chemical toxicity in ovaries and endometrium. The findings are constructed to AOP-like networks and evaluated for possibilities to be included in guideline assays for reproductive toxicity.

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 Julie Boberg and Dr Terje Svingen (Technical University of Denmark), Dr Holte and Prof Olovsson (University of Uppsala), Prof Salumets (Tartu University, Estonia), Prof Flaws (University of Illinois, USA), Assc Prof Öberg (Karolinska Institutet), and Prof van Duursen (Vrije  Universiteit Amsterdam, the Netherlands).

Publications

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

Current research funding

  • Swedish Research Council FORMAS Future research leader (2016-2019)
  • Swedish Research Council VR (2018-2019)
  • Swedish Research Council FORMAS EDC2020 (2014-2020)
  • Jane & Aatos Erkko foundation (2016-2020)
  • Childhood Cancer Foundation (2018-2020)
  • Swedish Research Council FORMAS Combination Effects Pandora (2019-2022)
  • EU Horizon2020 FREIA (2019-2023)
  • EU Horixon2020 ERIN (2020-2023)
  • Rydbeck foundation (2020)
  • Karolinska Institutet KID funding

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