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

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 sh...

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Published in:	Reproductive toxicology (Elmsford, N.Y.) Vol. 119; p. 108393
Main Authors:	Tarvainen, Ilari, Soto, Delia A., Laws, Mary J., Björvang, Richelle D., Damdimopoulos, Anastasios, Roos, Kristine, Li, Tianyi, Kramer, Stav, Li, Zhong, Lavogina, Darja, Visser, Nadja, Kallak, Theodora K., Lager, Susanne, Gidlöf, Sebastian, Edlund, Erik, Papaikonomou, Kiriaki, Öberg, Mattias, Olovsson, Matts, Salumets, Andres, Velthut-Meikas, Agne, Flaws, Jodi A., Damdimopoulou, Pauliina
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-08-2023
Subjects:	Chemical mixtures Endocrine disrupting chemicals Female fertility In vitro models Medicin och hälsovetenskap Ovaries Phthalates Reproduction Risk assessment RT In vitro models MEHP DMSO EDC IFI6 PFAS MBzP Endocrine disrupting chemicals MWHS Reproduction FDR Hs-GC DEHP FBS Risk assessment Chemical mixtures FSH MBP CCDC163 SPRY4-AS1 BMI LC-MS-MS EQUI LOD UMAP MEOHP MEHHP DCAKD Mm-GC Female fertility DEG DMEM/F12 GO EPIDEM WQS-m POI Ovaries MiBP Phthalates MCPP MECPP IVF WQS MEP ELISA
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Summary:	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 characterization 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. •Three phthalate mixtures were defined based on an epidemiological cohort study.•Phthalate mixtures were tested in five cell models representing ovaries in vitro.•Phthalate mixtures regulated multiple genes and pathways in ovarian cells.•Genes regulated by phthalate mixtures differed between exposures and cell models.•Commonalities within and between cell models suggest “a phthalate signature”.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0890-6238 1873-1708 1873-1708
DOI:	10.1016/j.reprotox.2023.108393