Open this publication in new window or tab >>Karolinska Inst, Dept Biosci & Nutr, Bioinformat & Express Anal Core Facil, Stockholm, Sweden..
Tallinn Univ Technol, Dept Chem & Biotechnol, Tallinn, Estonia.;Nova Vita Clin, Tallinn, Estonia..
Karolinska Inst, Dept Clin Sci, Div Obstet & Gynecol, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Gynecol & Reprod Med, Stockholm, Sweden..
Univ Illinois, Dept Comparat Biosci, Champaign, IL USA..
Univ Illinois, Roy J Carver Biotechnol Ctr, Champaign, IL USA..
Competence Ctr Hlth Technol, Tartu, Estonia.;Univ Tartu, Inst Chem, Tartu, Estonia..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Reproductive biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Reproductive Health.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Reproductive Health Research.
Karolinska Inst, Dept Clin Sci, Div Obstet & Gynecol, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Gynecol & Reprod Med, Stockholm, Sweden..
Karolinska Inst, Dept Clin Sci, Div Obstet & Gynecol, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Gynecol & Reprod Med, Stockholm, Sweden.;Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden..
Karolinska Univ Hosp, Dept Gynecol & Reprod Med, Stockholm, Sweden.;Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden..
Karolinska Inst, Inst Environm Med, Unit Integrat Toxicol, Stockholm, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Reproductive biology.
Karolinska Inst, Dept Clin Sci, Div Obstet & Gynecol, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden.;Competence Ctr Hlth Technol, Tartu, Estonia.;Karolinska Univ Hosp, Dept Gynecol & Reprod Med, Stockholm, Sweden.;Univ Tartu, Inst Clin Med, Dept Obstet & Gynecol, Tartu, Estonia..
Tallinn Univ Technol, Dept Chem & Biotechnol, Tallinn, Estonia..
Karolinska Univ Hosp, Stockholm, Sweden.;Univ Illinois, Dept Comparat Biosci, Champaign, IL USA..
Karolinska Inst, Dept Clin Sci, Div Obstet & Gynecol, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Gynecol & Reprod Med, Stockholm, Sweden..
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2023 (English)In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 119, article id 108393Article in journal (Refereed) Published
Abstract [en]
Chemical health risk assessment is based on single chemicals, but humans and wildlife are exposed to extensive mixtures of industrial substances and pharmaceuticals. Such exposures are life-long and correlate with multiple morbidities, including infertility. How combinatorial effects of chemicals should be handled in hazard charac-terization and risk assessment are open questions. Further, test systems are missing for several relevant health outcomes including reproductive health and fertility in women. Here, our aim was to screen multiple ovarian cell models for phthalate induced effects to identify biomarkers of exposure. We used an epidemiological cohort study to define different phthalate mixtures for in vitro testing. The mixtures were then tested in five cell models representing ovarian granulosa or stromal cells, namely COV434, KGN, primary human granulosa cells, primary mouse granulosa cells, and primary human ovarian stromal cells. Exposures at epidemiologically relevant levels did not markedly elicit cytotoxicity or affect steroidogenesis in short 24-hour exposure. However, significant effects on gene expression were identified by RNA-sequencing. Altogether, the exposures changed the expression of 124 genes on the average (9-479 genes per exposure) in human cell models, without obvious concentration or mixture-dependent effects on gene numbers. The mixtures stimulated distinct changes in different cell models. Despite differences, our analyses suggest commonalities in responses towards phthalates, which forms a starting point for follow-up studies on identification and validation of candidate biomarkers that could be developed to novel assays for regulatory testing or even into clinical tests.
Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Phthalates, Endocrine disrupting chemicals, Chemical mixtures, Reproduction, Ovaries, Female fertility, Risk assessment, In vitro models
National Category
Obstetrics, Gynecology and Reproductive Medicine Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-507546 (URN)10.1016/j.reprotox.2023.108393 (DOI)001001785800001 ()37160244 (PubMedID)
Funder
Swedish Research Council Formas, 2018-02280EU, Horizon 2020, EU952516
2023-07-072023-07-072023-07-07Bibliographically approved