Chemicals and female fertility – Pauliina Damdimopoulou Research Group

Our goal is to identify links between chemicals and fertility in women. We have measured concentrations of approximately 50 different environmental chemicals in serum samples collected from pregnant women and women undergoing fertility treatment. Our statistical analyses have shown that higher levels of several chemicals are related to a longer "time-to-pregnancy," i.e., the time it takes to become pregnant from when one starts trying. Furthermore, we have identified relationships between exposure and the number of immature eggs remaining in the ovaries, as well as a number of other markers of ovarian health.

Selected publications

”Ambient black carbon particles in human ovarian tissue and follicular fluid.” Bongaerts E, et al. 2023 Environ Int. 

”Associations between lifestyle factors and levels of per- and polyfluoroalkyl substances (PFASs), phthalates and parabens in follicular fluid in women undergoing fertility treatment.” Hallberg I, et al. 2023 J Expo Sci Environ Epidemiol. 

”Association between chemical mixtures and female fertility in women undergoing assisted reproduction in Sweden and Estonia.” Bellavia A, et al. 2023 Environ Res. 

“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

Some medical treatments, such as chemotherapy, can save lives but at the same time damage the ovaries and fertility. To enable future opportunities to have children, egg cells or ovarian tissue can be frozen before treatment begins. For children who have not yet gone through puberty, freezing ovarian tissue is the only option. The method is well-proven for adult women but less studied in children. We have initiated a national study, Sveafertil, where girls and young women at very high risk of infertility as a result of their treatments can freeze a part of their ovary and donate a small part for our research. Our goal is to compare ovarian tissue from children with adult tissue in detail and to identify molecules and cells affected by chemotherapy, and with this knowledge, refine methods for the youngest patients. Read more about the project on Sveafertil Project: Impact of Medical Treatments on the Ovary project page.

Selected publications

Reference standards for follicular density in ovarian cortex from birth to sexual maturity.
Hassan J, Knuus K, Lahtinen A, Rooda I, Otala M, Tuuri T, Gidlöf S, Edlund E, Menezes J, Malmros J, Byström P, Sundin M, Langenskiöld C, Vogt H, Frisk P, Petersen C, Damdimopoulou P, Jahnukainen K
Reprod Biomed Online 2023 Oct;47(4):103287

Fertility Preservation for Prepubertal Patients at Risk of Infertility: Present Status and Future Perspectives.
Pampanini V, Hassan J, Oliver E, Stukenborg JB, Damdimopoulou P, Jahnukainen K
Horm Res Paediatr 2020 ;93(11-12):599-608

Impact of first-line cancer treatment on the follicle quality in cryopreserved ovarian samples from girls and young women.
Pampanini V, Wagner M, Asadi-Azarbaijani B, Oskam IC, Sheikhi M, Sjödin MOD, Lindberg J, Hovatta O, Sahlin L, Björvang RD, Otala M, Damdimopoulou P, Jahnukainen K
Hum Reprod 2019 Sep;34(9):1674-1685

To study how environmental exposures and medical treatments affect the ovary, we must understand its function at a cellular and molecular level. One of our research goals is therefore to identify different cell types within the ovary and study how these change throughout life. The ovary undergoes changes, for example, during puberty, but the impact on the smallest follicles, which contain immature eggs, is not well studied. We analyze ovarian samples from girls, young women, and adult women to create a comprehensive picture of the ovary's development and function from childhood, through puberty, to adulthood. This detailed information will give us better conditions to map the environmental impact on the ovary, develop better test methods for reproductive toxicity, and understand the factors that contribute to infertility.

Selected publications

”Transcriptomics and Spatial Proteomics for Discovery and Validation of Missing Proteins in the Human Ovary.” Méar L, et al. 2024 J Proteome Res. 

”Spatial Proteomics for Further Exploration of Missing Proteins: A Case Study of the Ovary” Mear et al. 2022 J Proteome Res

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

ONLINE RESURS E-ovary

To determine if environmental exposures directly affect the ovary, we conduct controlled exposure experiments in the laboratory. We expose ovarian tissue and cultured cells to chemicals that we have identified in our population studies on chemicals and female fertility. We investigate whether the exposed follicles grow normally and which genes are affected. Our results show how and through which molecular mechanisms ovarian function can be affected by environmental factors. This information can be used to better understand the relationship between exposure and reduced fertility in women, as well as to develop tests to evaluate the reproductive toxicity of chemicals.

Selected publications

”Identification of phthalate mixture exposure targets in the human and mouse ovary in vitro.” Tarvainen I, et al. 2023 Reprod Toxicol.

”Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models.” Li T, et al. 2023 Toxicology. 

“AOP key event relationship report: Linking decreased androgen receptor activation with decreased granulosa cell proliferation of gonadotropin-independent follicles” Panagiotou et al. 2022 Reprod Tox

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

We use ovarian tissue to develop in vitro models that mimic the ovary or can replicate its various functions. Such models are necessary to assess the toxicity of chemicals in the laboratory in a human-relevant way, without the use of experimental animals. Furthermore, models that mimic ovaries could in the future be used to mature egg cells in vitro.

Selected publications

“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

Our studies on ovarian function are inspired by Professor Emerita Outi Hovatta and her long career as well as groundbreaking research in ovarian biology.

The studies we conduct on human ovarian tissue are made possible thanks to patients undergoing various surgeries at Karolinska University Hospital who choose to participate in our research. Without these participants and our clinical collaborators, the research would be impossible to conduct. We would like to express our warm thanks to all the patients, midwives, and doctors who make our research possible!

All our studies are approved by the Ethical Review Authority, and tissue is only collected from patients who have been informed about our studies and have given their consent.

We are proud to be part of several extensive collaborations across Europe that are funded by the EU. Here you can read about MERLON (2024-2028), FREIA (2019-2024), and ERIN (2020-2023).

MERLON

Website: under construction

Description: "Enhanced identification of endocrine disruptors through integration of science-based regulatory practices and innovative methodologies: The MERLON Project" - Svingen et al., 2024, Open Research Europe

FREIA

Website, Freia 

"Safeguarding Female Reproductive Health Against Endocrine Disrupting Chemicals - The FREIA Project" - van Duursen et al., 2020, International Journal of Molecular Sciences

ERIN

Website, Erin

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)

The samples donated to our research are used in several different types of studies.

We investigate:

• which cell types are present in the ovary
• how ovarian cells interact and communicate with each other
• how eggs develop and mature
• how environmental factors, chemicals, and medical treatments can affect ovarian function and female fertility

The knowledge gained from these studies helps us develop better methods for assessing how chemicals and medicines may affect reproductive health.

All samples are coded before being used in research. The researchers who analyze the samples do not have access to participants' identities.

Thanks to donations from patients, we have been able to:

• study which environmental chemicals are present in women's blood and follicular fluid
• investigate whether exposure to different chemicals is associated with fertility
• map the different cell types found in the ovaries of children and adults
• describe how the ovary develops from childhood to adulthood
• investigate how environmental chemicals and cancer treatments affect ovarian tissue and ovarian cells

Our ongoing research builds on this knowledge to develop improved methods for evaluating how chemicals and medical treatments affect female fertility. Many of today's safety tests rely on animal experiments and cannot always accurately predict effects in the human reproductive system. We therefore work to develop new methods based on human cells and tissues. In the long term, these approaches may contribute to more accurate risk assessment and a reduced need for animal testing.

Research findings are continuously published in scientific journals and presented at national and international conferences.

A selection of publications is listed below.

Single-cell analysis of human ovarian cortex identifies distinct cell populations but no oogonial stem cells

Wagner M, Yoshihara M, Douagi I, Damdimopoulos A, Panula S, Petropoulos S, Lu H, Pettersson K, Palm K, Katayama S, Hovatta O, Kere J, Lanner F, Damdimopoulou P.
Nature Communications (2020)

In this study, we performed the first detailed single-cell map of the human ovary. The findings improved our understanding of the different cell types present in the ovary and demonstrated that adult ovaries do not contain stem cells capable of generating new eggs.

In-depth analysis of transcriptomes in ovarian cortical follicles from children and adults reveals interfollicular heterogeneity

Rooda I, Hassan J, Hao J, Wagner M, Moussaud-Lamodière E, Jääger K, Otala M, Knuus K, Lindskog C, Papaikonomou K, Gidlöf S, Langenskiöld C, Vogt H, Frisk P, Malmros J, Tuuri T, Salumets A, Jahnukainen K, Velthut-Meikas A, Damdimopoulou P.
Nature Communications (2024)

In this study, we compared immature eggs from children and adults. We found that immature eggs in children differ from comparable eggs in adult women. The results show that puberty influences even the earliest stages of egg development, despite these eggs having long been considered biologically dormant.

Persistent organic pollutants and the size of ovarian reserve in reproductive-aged women

Björvang RD, Hassan J, Stefopoulou M, Gemzell-Danielsson K, Pedrelli M, Kiviranta H, Rantakokko P, Ruokojärvi P, Lindh CH, Acharya G, Damdimopoulou P.
Environment International (2021)

In this study, we found that women with higher levels of persistent environmental pollutants in their blood had a smaller ovarian reserve, meaning fewer remaining immature eggs in their ovaries. The findings suggest that environmental chemicals may influence reproductive ageing.

Follicular fluid and blood levels of persistent organic pollutants and reproductive outcomes among women undergoing assisted reproductive technologies

Björvang RD, Hallberg I, Pikki A, Berglund L, Pedrelli M, Kiviranta H, Rantakokko P, Ruokojärvi P, Lindh CH, Olovsson M, Persson S, Holte J, Sjunnesson Y, Damdimopoulou P.
Environmental Research (2022)

We showed that levels of persistent environmental pollutants in follicular fluid largely reflect those found in blood samples from women undergoing fertility treatment. We also observed that higher PFAS levels were associated with a lower likelihood of obtaining high-quality embryos.

Association between chemical mixtures and female fertility in women undergoing assisted reproduction in Sweden and Estonia

Bellavia A, Zou R, Björvang RD, Roos K, Sjunnesson Y, Hallberg I, Holte J, Pikki A, Lenters V, Portengen L, Koekkoek J, Lamoree M, Van Duursen M, Vermeulen R, Salumets A, Velthut-Meikas A, Damdimopoulou P.
Environmental Research (2023)

This study was conducted as part of a larger European Union research project. We found that mixtures of environmental chemicals in follicular fluid may influence how the ovaries respond to hormone stimulation during IVF treatment. The results highlight the importance of studying combined chemical exposures rather than individual chemicals in isolation.

Reduced ovarian cholesterol and steroid biosynthesis along with increased inflammation are associated with high DEHP metabolite levels in human ovarian follicular fluids

Varik I, Zou R, Bellavia A, Rosenberg K, Sjunnesson Y, Hallberg I, Holte J, Lenters V, Van Duursen M, Pedersen M, Svingen T, Vermeulen R, Salumets A, Damdimopoulou P, Velthut-Meikas A.
Environment International (2024)

Also performed within a larger European research project, this study showed that higher levels of certain phthalates in follicular fluid were associated with reduced follicle maturation during IVF treatment, as well as increased inflammation and altered hormone production within the follicle. These findings suggest that such chemicals may affect the environment in which eggs develop.

Identification of phthalate mixture exposure targets in the human and mouse ovary in vitro

Tarvainen I, Soto DA, Laws MJ, Björvang RD, Damdimopoulos A, Roos K, Li T, Kramer S, Li Z, Lavogina D, Visser N, Kallak TK, Lager S, Gidlöf S, Edlund E, Papaikonomou K, Öberg M, Olovsson M, Salumets A, Velthut-Meikas A, Flaws JA, Damdimopoulou P.
Reproductive Toxicology (2023)

We mapped the biological processes affected when ovaries are exposed to mixtures of phthalates. Many of the observed changes involved cellular energy production and metabolism, suggesting that these processes are particularly sensitive to chemical exposure.

Associations between lifestyle factors and levels of per- and polyfluoroalkyl substances (PFASs), phthalates and parabens in follicular fluid in women undergoing fertility treatment

Hallberg I, Björvang RD, Hadziosmanovic N, Koekkoekk J, Pikki A, van Duursen M, Lenters V, Sjunnesson Y, Holte J, Berglund L, Persson S, Olovsson M, Damdimopoulou P.
Journal of Exposure Science & Environmental Epidemiology (2023)

In this study, we investigated whether lifestyle factors influence the levels of environmental chemicals in follicular fluid. We found associations between certain dietary habits, including fish and egg consumption, and PFAS levels, as well as between perfume use and phthalate levels.

Exposure to the phthalate metabolite MEHP impacts survival and growth of human ovarian follicles in vitro

Panagiotou EM, Damdimopoulos A, Li T, Moussaud-Lamodière E, Pedersen M, Lebre F, Pettersson K, Arnelo C, Papaikonomou K, Alfaro-Moreno E, Lindskog C, Svingen T, Damdimopoulou P.
Toxicology (2024)

We demonstrated that the phthalate metabolite MEHP can affect the survival and growth of immature eggs and follicles in human ovarian tissue. These effects were observed at exposure levels that occur in everyday life.

Persistent organic pollutants dysregulate energy homeostasis in human ovaries in vitro

Li T, Björvang RD, Hao J, Di Nisio V, Damdimopoulos A, Lindskog C, Papaikonomou K, Damdimopoulou P.
Environment International (2024)

In this study, we investigated how persistent environmental pollutants, including PCBs, affect human ovarian tissue in the laboratory. We found that exposure disrupted cellular energy balance and metabolism at levels comparable to those encountered by humans.