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

Andrea Bellavia; Runyu Zou; Richelle D. Björvang; Kristine Roos; Ylva Sjunnesson; Ida Hallberg; Jan Holte; Anne Pikki; Virissa Lenters; Lützen Portengen; Jacco Koekkoek; Marja Lamoree; Majorie Van Duursen; Roel Vermeulen; Andres Salumets; Agne Velthut-Meikas; Pauliina Damdimopoulou

doi:10.1016/j.envres.2022.114447

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

Andrea Bellavia, Runyu Zou, Richelle D. Björvang, Kristine Roos, Ylva Sjunnesson, Ida Hallberg, Jan Holte, Anne Pikki, Virissa Lenters, Lützen Portengen, Jacco Koekkoek, Marja Lamoree, Majorie Van Duursen, Roel Vermeulen, Andres Salumets, Agne Velthut-Meikas^*, Pauliina Damdimopoulou

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Objective: Women of reproductive age are exposed to ubiquitous chemicals such as phthalates, parabens, and per- and polyfluoroalkyl substances (PFAS), which have potential endocrine disrupting properties and might affect fertility. Our objective was to investigate associations between potential endocrine-disrupting chemicals (EDCs) and female fertility in two cohorts of women attending fertility clinics. Methods: In a total population of 333 women in Sweden and Estonia, we studied the associations between chemicals and female fertility, evaluating ovarian sensitivity index (OSI) as an indicator of ovarian response, as well as clinical pregnancy and live birth from fresh and frozen embryo transfers. We measured 59 chemicals in follicular fluid samples and detected 3 phthalate metabolites, di-2-ethylhexyl phthalate (DEHP) metabolites, 1 paraben, and 6 PFAS in >90% of the women. Associations were evaluated using multivariable-adjusted linear or logistic regression, categorizing EDCs into quartiles of their distributions, as well as with Bayesian Kernel Machine Regression. Results: We observed statistically significant lower OSI at higher concentrations of the sum of DEHP metabolites in the Swedish cohort (Q4 vs Q1, β = -0.21, 95% CI: −0.38, −0.05) and methylparaben in the Estonian cohort (Q3 vs Q1, β = -0.22, 95% CI: −0.44, −0.01). Signals of potential associations were also observed at higher concentrations of PFUnDA in both the combined population (Q2 vs. Q1, β = −0.16, 95% CI -0.31, −0.02) and the Estonian population (Q2 vs. Q1, β = −0.27, 95% CI -0.45, −0.08), and for PFOA in the Estonian population (Q4 vs. Q1, β = −0.31, 95% CI -0.61, −0.01). Associations of chemicals with clinical pregnancy and live birth presented wide confidence intervals. Conclusions: Within a large chemical mixture, we observed significant inverse associations levels of DEHP metabolites and methylparaben, and possibly PFUnDA and PFOA, with OSI, suggesting that these chemicals may contribute to altered ovarian function and infertility in women.

Original language	English
Article number	114447
Pages (from-to)	1-14
Number of pages	14
Journal	Environmental Research
Volume	216
DOIs	https://doi.org/10.1016/j.envres.2022.114447
Publication status	Published - 1 Jan 2023

Bibliographical note

Funding Information:
This project was funded by the European Union's Horizon 2020 research and innovation program (FREIA, grant no. 825100 ), the Estonian Research Council (grant PRG1076 and PSG608 ), Horizon 2020 innovation grant (ERIN, grant no. EU952516 ), and the Enterprise Estonia (grant no. EU48695 ). The project also received funding from Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS) (Grants No. 942-2015-476; 2015–00623 and 2013–01966 ) and the Dutch Research Council ( NWO ) (EXPOSOME-NL project number 024.004.017 ).

Funding Information:
This project was funded by the European Union's Horizon 2020 research and innovation program (FREIA, grant no. 825100), the Estonian Research Council (grant PRG1076 and PSG608), Horizon 2020 innovation grant (ERIN, grant no. EU952516), and the Enterprise Estonia (grant no. EU48695). The project also received funding from Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS) (Grants No. 942-2015-476; 2015–00623 and 2013–01966) and the Dutch Research Council (NWO) (EXPOSOME-NL project number 024.004.017). We thank Dr. Christian Lindh, from Lund University, for sharing the PFAS measurement data from the Swedish cohort. We are grateful to all study participants for donating their samples for research.

Publisher Copyright:
© 2022 The Authors

Funding

This project was funded by the European Union's Horizon 2020 research and innovation program (FREIA, grant no. 825100 ), the Estonian Research Council (grant PRG1076 and PSG608 ), Horizon 2020 innovation grant (ERIN, grant no. EU952516 ), and the Enterprise Estonia (grant no. EU48695 ). The project also received funding from Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS) (Grants No. 942-2015-476; 2015–00623 and 2013–01966 ) and the Dutch Research Council ( NWO ) (EXPOSOME-NL project number 024.004.017 ). This project was funded by the European Union's Horizon 2020 research and innovation program (FREIA, grant no. 825100), the Estonian Research Council (grant PRG1076 and PSG608), Horizon 2020 innovation grant (ERIN, grant no. EU952516), and the Enterprise Estonia (grant no. EU48695). The project also received funding from Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS) (Grants No. 942-2015-476; 2015–00623 and 2013–01966) and the Dutch Research Council (NWO) (EXPOSOME-NL project number 024.004.017). We thank Dr. Christian Lindh, from Lund University, for sharing the PFAS measurement data from the Swedish cohort. We are grateful to all study participants for donating their samples for research.

Funders	Funder number
Horizon 2020 innovation	EU952516, EU48695
Svenska Forskningsrådet Formas	2013–01966, 942-2015-476, 2015–00623
Svenska Forskningsrådet Formas
Eesti Teadusagentuur	PRG1076, PSG608
Eesti Teadusagentuur
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	024.004.017
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Lunds Universitet
Horizon 2020	825100
Horizon 2020

Keywords

Endocrine disruptors
environmental mixtures
female fertility
ovarian sensitivity index
parabens
phthalates

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10.1016/j.envres.2022.114447

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Bellavia, A., Zou, R., Björvang, R. D., 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. (2023). Association between chemical mixtures and female fertility in women undergoing assisted reproduction in Sweden and Estonia. Environmental Research, 216, 1-14. Article 114447. https://doi.org/10.1016/j.envres.2022.114447

@article{bf75bce1179a41e68473057f725b44e3,

title = "Association between chemical mixtures and female fertility in women undergoing assisted reproduction in Sweden and Estonia",

abstract = "Objective: Women of reproductive age are exposed to ubiquitous chemicals such as phthalates, parabens, and per- and polyfluoroalkyl substances (PFAS), which have potential endocrine disrupting properties and might affect fertility. Our objective was to investigate associations between potential endocrine-disrupting chemicals (EDCs) and female fertility in two cohorts of women attending fertility clinics. Methods: In a total population of 333 women in Sweden and Estonia, we studied the associations between chemicals and female fertility, evaluating ovarian sensitivity index (OSI) as an indicator of ovarian response, as well as clinical pregnancy and live birth from fresh and frozen embryo transfers. We measured 59 chemicals in follicular fluid samples and detected 3 phthalate metabolites, di-2-ethylhexyl phthalate (DEHP) metabolites, 1 paraben, and 6 PFAS in >90% of the women. Associations were evaluated using multivariable-adjusted linear or logistic regression, categorizing EDCs into quartiles of their distributions, as well as with Bayesian Kernel Machine Regression. Results: We observed statistically significant lower OSI at higher concentrations of the sum of DEHP metabolites in the Swedish cohort (Q4 vs Q1, β = -0.21, 95% CI: −0.38, −0.05) and methylparaben in the Estonian cohort (Q3 vs Q1, β = -0.22, 95% CI: −0.44, −0.01). Signals of potential associations were also observed at higher concentrations of PFUnDA in both the combined population (Q2 vs. Q1, β = −0.16, 95% CI -0.31, −0.02) and the Estonian population (Q2 vs. Q1, β = −0.27, 95% CI -0.45, −0.08), and for PFOA in the Estonian population (Q4 vs. Q1, β = −0.31, 95% CI -0.61, −0.01). Associations of chemicals with clinical pregnancy and live birth presented wide confidence intervals. Conclusions: Within a large chemical mixture, we observed significant inverse associations levels of DEHP metabolites and methylparaben, and possibly PFUnDA and PFOA, with OSI, suggesting that these chemicals may contribute to altered ovarian function and infertility in women.",

keywords = "Endocrine disruptors, environmental mixtures, female fertility, ovarian sensitivity index, parabens, phthalates",

author = "Andrea Bellavia and Runyu Zou and Bj{\"o}rvang, {Richelle D.} and Kristine Roos and Ylva Sjunnesson and Ida Hallberg and Jan Holte and Anne Pikki and Virissa Lenters and L{\"u}tzen Portengen and Jacco Koekkoek and Marja Lamoree and {Van Duursen}, Majorie and Roel Vermeulen and Andres Salumets and Agne Velthut-Meikas and Pauliina Damdimopoulou",

note = "Funding Information: This project was funded by the European Union's Horizon 2020 research and innovation program (FREIA, grant no. 825100 ), the Estonian Research Council (grant PRG1076 and PSG608 ), Horizon 2020 innovation grant (ERIN, grant no. EU952516 ), and the Enterprise Estonia (grant no. EU48695 ). The project also received funding from Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS) (Grants No. 942-2015-476; 2015–00623 and 2013–01966 ) and the Dutch Research Council ( NWO ) (EXPOSOME-NL project number 024.004.017 ). Funding Information: This project was funded by the European Union's Horizon 2020 research and innovation program (FREIA, grant no. 825100), the Estonian Research Council (grant PRG1076 and PSG608), Horizon 2020 innovation grant (ERIN, grant no. EU952516), and the Enterprise Estonia (grant no. EU48695). The project also received funding from Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS) (Grants No. 942-2015-476; 2015–00623 and 2013–01966) and the Dutch Research Council (NWO) (EXPOSOME-NL project number 024.004.017). We thank Dr. Christian Lindh, from Lund University, for sharing the PFAS measurement data from the Swedish cohort. We are grateful to all study participants for donating their samples for research. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2023",

month = jan,

day = "1",

doi = "10.1016/j.envres.2022.114447",

language = "English",

volume = "216",

pages = "1--14",

journal = "Environmental Research",

issn = "0013-9351",

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}

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 2023, 'Association between chemical mixtures and female fertility in women undergoing assisted reproduction in Sweden and Estonia', Environmental Research, vol. 216, 114447, pp. 1-14. https://doi.org/10.1016/j.envres.2022.114447

TY - JOUR

T1 - Association between chemical mixtures and female fertility in women undergoing assisted reproduction in Sweden and Estonia

AU - Bellavia, Andrea

AU - Zou, Runyu

AU - Björvang, Richelle D.

AU - Roos, Kristine

AU - Sjunnesson, Ylva

AU - Hallberg, Ida

AU - Holte, Jan

AU - Pikki, Anne

AU - Lenters, Virissa

AU - Portengen, Lützen

AU - Koekkoek, Jacco

AU - Lamoree, Marja

AU - Van Duursen, Majorie

AU - Vermeulen, Roel

AU - Salumets, Andres

AU - Velthut-Meikas, Agne

AU - Damdimopoulou, Pauliina

N1 - Funding Information: This project was funded by the European Union's Horizon 2020 research and innovation program (FREIA, grant no. 825100 ), the Estonian Research Council (grant PRG1076 and PSG608 ), Horizon 2020 innovation grant (ERIN, grant no. EU952516 ), and the Enterprise Estonia (grant no. EU48695 ). The project also received funding from Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS) (Grants No. 942-2015-476; 2015–00623 and 2013–01966 ) and the Dutch Research Council ( NWO ) (EXPOSOME-NL project number 024.004.017 ). Funding Information: This project was funded by the European Union's Horizon 2020 research and innovation program (FREIA, grant no. 825100), the Estonian Research Council (grant PRG1076 and PSG608), Horizon 2020 innovation grant (ERIN, grant no. EU952516), and the Enterprise Estonia (grant no. EU48695). The project also received funding from Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS) (Grants No. 942-2015-476; 2015–00623 and 2013–01966) and the Dutch Research Council (NWO) (EXPOSOME-NL project number 024.004.017). We thank Dr. Christian Lindh, from Lund University, for sharing the PFAS measurement data from the Swedish cohort. We are grateful to all study participants for donating their samples for research. Publisher Copyright: © 2022 The Authors

PY - 2023/1/1

Y1 - 2023/1/1

N2 - Objective: Women of reproductive age are exposed to ubiquitous chemicals such as phthalates, parabens, and per- and polyfluoroalkyl substances (PFAS), which have potential endocrine disrupting properties and might affect fertility. Our objective was to investigate associations between potential endocrine-disrupting chemicals (EDCs) and female fertility in two cohorts of women attending fertility clinics. Methods: In a total population of 333 women in Sweden and Estonia, we studied the associations between chemicals and female fertility, evaluating ovarian sensitivity index (OSI) as an indicator of ovarian response, as well as clinical pregnancy and live birth from fresh and frozen embryo transfers. We measured 59 chemicals in follicular fluid samples and detected 3 phthalate metabolites, di-2-ethylhexyl phthalate (DEHP) metabolites, 1 paraben, and 6 PFAS in >90% of the women. Associations were evaluated using multivariable-adjusted linear or logistic regression, categorizing EDCs into quartiles of their distributions, as well as with Bayesian Kernel Machine Regression. Results: We observed statistically significant lower OSI at higher concentrations of the sum of DEHP metabolites in the Swedish cohort (Q4 vs Q1, β = -0.21, 95% CI: −0.38, −0.05) and methylparaben in the Estonian cohort (Q3 vs Q1, β = -0.22, 95% CI: −0.44, −0.01). Signals of potential associations were also observed at higher concentrations of PFUnDA in both the combined population (Q2 vs. Q1, β = −0.16, 95% CI -0.31, −0.02) and the Estonian population (Q2 vs. Q1, β = −0.27, 95% CI -0.45, −0.08), and for PFOA in the Estonian population (Q4 vs. Q1, β = −0.31, 95% CI -0.61, −0.01). Associations of chemicals with clinical pregnancy and live birth presented wide confidence intervals. Conclusions: Within a large chemical mixture, we observed significant inverse associations levels of DEHP metabolites and methylparaben, and possibly PFUnDA and PFOA, with OSI, suggesting that these chemicals may contribute to altered ovarian function and infertility in women.

AB - Objective: Women of reproductive age are exposed to ubiquitous chemicals such as phthalates, parabens, and per- and polyfluoroalkyl substances (PFAS), which have potential endocrine disrupting properties and might affect fertility. Our objective was to investigate associations between potential endocrine-disrupting chemicals (EDCs) and female fertility in two cohorts of women attending fertility clinics. Methods: In a total population of 333 women in Sweden and Estonia, we studied the associations between chemicals and female fertility, evaluating ovarian sensitivity index (OSI) as an indicator of ovarian response, as well as clinical pregnancy and live birth from fresh and frozen embryo transfers. We measured 59 chemicals in follicular fluid samples and detected 3 phthalate metabolites, di-2-ethylhexyl phthalate (DEHP) metabolites, 1 paraben, and 6 PFAS in >90% of the women. Associations were evaluated using multivariable-adjusted linear or logistic regression, categorizing EDCs into quartiles of their distributions, as well as with Bayesian Kernel Machine Regression. Results: We observed statistically significant lower OSI at higher concentrations of the sum of DEHP metabolites in the Swedish cohort (Q4 vs Q1, β = -0.21, 95% CI: −0.38, −0.05) and methylparaben in the Estonian cohort (Q3 vs Q1, β = -0.22, 95% CI: −0.44, −0.01). Signals of potential associations were also observed at higher concentrations of PFUnDA in both the combined population (Q2 vs. Q1, β = −0.16, 95% CI -0.31, −0.02) and the Estonian population (Q2 vs. Q1, β = −0.27, 95% CI -0.45, −0.08), and for PFOA in the Estonian population (Q4 vs. Q1, β = −0.31, 95% CI -0.61, −0.01). Associations of chemicals with clinical pregnancy and live birth presented wide confidence intervals. Conclusions: Within a large chemical mixture, we observed significant inverse associations levels of DEHP metabolites and methylparaben, and possibly PFUnDA and PFOA, with OSI, suggesting that these chemicals may contribute to altered ovarian function and infertility in women.

KW - Endocrine disruptors

KW - environmental mixtures

KW - female fertility

KW - ovarian sensitivity index

KW - parabens

KW - phthalates

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

Abstract

Bibliographical note

Funding

Keywords

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