Single-cell study of human ovarian response to phthalate exposure reveals glial cell susceptibility and disruption of adhesion and mitochondrial pathways.
8 affiliations
- 1Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Department of Gynecology and Reproductive Medicine, Karolinska University Hospital, Stockholm, Sweden.
- 2Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Department of Gynecology and Reproductive Medicine, Karolinska University Hospital, Stockholm, Sweden; Department of Immunology, Genetics and Pathology, Cancer Precision Medicine, Uppsala University, Uppsala, Sweden.
- 3Department of Gynecology and Reproductive Medicine, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
- 4Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
- 5Department of Pregnancy and Delivery, Karolinska University Hospital, Stockholm, Sweden.
- 6Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
- 7Department of Immunology, Genetics and Pathology, Cancer Precision Medicine, Uppsala University, Uppsala, Sweden.
- 8Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Department of Gynecology and Reproductive Medicine, Karolinska University Hospital, Stockholm, Sweden. Electronic address: [email protected].
Abstract
Background
Phthalates are known male endocrine disruptors and reproductive toxicants. Despite growing evidence of female effects, mechanistic knowledge in key reproductive organs remains limited, hindering regulations. Here, we conducted an experimental study to map the impact of mono(2-ethylhexyl) phthalate (MEHP), the primary metabolite of di(2-ethylhexyl) phthalate (DEHP), on adult human ovarian tissue at single-cell resolution.Methods
Ovarian tissue explants from seven donors (five gender-affirming surgery, two caesarean-section) were exposed to two MEHP concentrations: an epidemiologically relevant 20.51 nM and a 1000-fold higher 20.51 μM. After six days, single-cell RNA sequencing (one donor) and immunostainings (six donors) were used to characterise gene expression changes across cell types. Primary ovarian cells derived from three gender-affirming surgery patients and stem cell-derived Schwann cells were used for validation.Findings
Explants retained all major ovarian cell types, including rare glial cells and oocytes. MEHP altered transcriptomes across all cell types, disrupting pathways related to actin cytoskeleton, cell adhesion, and oxidative phosphorylation (OXPHOS). Protein analyses confirmed altered EIF5A, MT-ND3, MT-ND4L, and VCL expression, genes linked to mitochondrial translation, OXPHOS, adhesion, and cytoskeleton. MEHP also reduced cell-cell communication, particularly glial-stromal interactions. Mitochondrial stress assay in primary cells indicated increased proton leakage, and Schwann cell responses mirrored the scRNA-seq findings.Interpretation
Ovarian toxicity studies traditionally focus on follicles, but this study reveals the susceptibility of non-follicular cells. Importantly, the sensitivity of ovarian nervous system cells to MEHP offers new mechanistic insights into reported links between phthalates, altered ovarian sensitivity index, and polyendocrine metabolic ovarian syndrome. Our findings highlight the need for a holistic assessment of ovarian toxicity that considers all ovarian cell types, not only follicles.Funding
Swedish Research Council for Sustainable Development and the European Union.
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BibTeX
@article{panagiotou2026singlecell,
title = {{Single-cell study of human ovarian response to phthalate exposure reveals glial cell susceptibility and disruption of adhesion and mitochondrial pathways.}},
author = {Eleftheria Maria Panagiotou and Loren Méar and Ilmatar Rooda and Alesandro Haxhiu and Elisabeth Moussaud-Lamodière and Karolina Wasilewska and Tianyi Li and Catarina Arnelo and Karin Pettersson and Kiriaki Papaikonomou and Cecilia Lindskog and Pauliina Damdimopoulou},
journal = {EBioMedicine},
year = {2026},
month = oct,
doi = {10.1016/j.ebiom.2026.106487},
url = {https://europepmc.org/article/MED/42838884},
note = {CC BY},
}
RIS
TY - JOUR
TI - Single-cell study of human ovarian response to phthalate exposure reveals glial cell susceptibility and disruption of adhesion and mitochondrial pathways.
AU - Eleftheria Maria Panagiotou
AU - Loren Méar
AU - Ilmatar Rooda
AU - Alesandro Haxhiu
AU - Elisabeth Moussaud-Lamodière
AU - Karolina Wasilewska
AU - Tianyi Li
AU - Catarina Arnelo
AU - Karin Pettersson
AU - Kiriaki Papaikonomou
AU - Cecilia Lindskog
AU - Pauliina Damdimopoulou
PY - 2026
DA - 2026/10/01
JO - EBioMedicine
DO - 10.1016/j.ebiom.2026.106487
UR - https://europepmc.org/article/MED/42838884
AB - Background Phthalates are known male endocrine disruptors and reproductive toxicants. Despite growing evidence of female effects, mechanistic knowledge in key reproductive organs remains limited, hindering regulations. Here, we conducted an experimental study to map the impact of mono(2-ethylhexyl) phthalate (MEHP), the primary metabolite of di(2-ethylhexyl) phthalate (DEHP), on adult human ovarian tissue at single-cell resolution.Methods Ovarian tissue explants from seven donors (five gender-affirming surgery, two caesarean-section) were exposed to two MEHP concentrations: an epidemiologically relevant 20.51 nM and a 1000-fold higher 20.51 μM. After six days, single-cell RNA sequencing (one donor) and immunostainings (six donors) were used to characterise gene expression changes across cell types. Primary ovarian cells derived from three gender-affirming surgery patients and stem cell-derived Schwann cells were used for validation.Findings Explants retained all major ovarian cell types, including rare glial cells and oocytes. MEHP altered transcriptomes across all cell types, disrupting pathways related to actin cytoskeleton, cell adhesion, and oxidative phosphorylation (OXPHOS). Protein analyses confirmed altered EIF5A, MT-ND3, MT-ND4L, and VCL expression, genes linked to mitochondrial translation, OXPHOS, adhesion, and cytoskeleton. MEHP also reduced cell-cell communication, particularly glial-stromal interactions. Mitochondrial stress assay in primary cells indicated increased proton leakage, and Schwann cell responses mirrored the scRNA-seq findings.Interpretation Ovarian toxicity studies traditionally focus on follicles, but this study reveals the susceptibility of non-follicular cells. Importantly, the sensitivity of ovarian nervous system cells to MEHP offers new mechanistic insights into reported links between phthalates, altered ovarian sensitivity index, and polyendocrine metabolic ovarian syndrome. Our findings highlight the need for a holistic assessment of ovarian toxicity that considers all ovarian cell types, not only follicles.Funding Swedish Research Council for Sustainable Development and the European Union.
SN - 2352-3964
ER -