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Identification of Biomarkers and Outcomes of Endocrine Disruption in Human Ovarian Cortex using In Vitro Models

ABSTRACT: Endocrine disrupting chemicals (EDCs) are raising concerns about adverse effects on fertility in women. However, there is a lack of information regarding mechanisms of action and effects in humans. Our study aims to identify molecular mechanisms of endocrine disruption using two EDCs, diethylstilbestrol (DES) and ketoconazole (KTZ). Human ovarian cortical tissue obtained from Caesarean section patients were exposed to 10-9 M - 10-5 M KTZ and 10-10 M - 10-6 M DES in vitro for 6 days. Follicle survival and growth were studied via histology analysis and liquid-chromatography-mass spectrometry-based steroid quantification. RNA-sequencing was performed on primary ovarian cells and granulosa cancer cell lines COV434 and KGN that were exposed for 24 hours to the same concentrations of DES and KTZ as in the tissue culture. Significantly lower unilaminar follicle densities were observed in DES 10-10 M group, whereas low KTZ exposure reduced secondary follicle density. KTZ 10-5 M reduced levels of pregnenolone and progesterone. RNA-sequencing showed that 445 and 233 differentially expressed genes (FDR < 0.1) altogether in DES and KTZ exposed group. Gene set variation analysis showed that both chemicals modulated signalings that are important for folliculogenesis and steroidogenesis. We selected stearoyl-CoA desaturase (SCD) for validation because it was indicated in the affected gene sets by both chemicals. Up-regulation was confirmed in response to KTZ by qPCR in cell lines, and by in situ RNA hybridization and immunofluorescence in exposed ovarian tissue. Conclusively, SCD may serve as a potential novel human-relevant biomarker of EDC exposure and effects in ovaries.

ORGANISM(S): Homo sapiens

PROVIDER: GSE207094 | GEO | 2023/01/11

REPOSITORIES: GEO

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Project description:Exposure to persistent organic pollutants (POPs), such as dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCBs), has historically been linked to population collapses in wildlife. Despite international regulations, these legacy chemicals are still currently detected in women of reproductive age, and their levels correlate with reduced ovarian reserve, longer time-to-pregnancy, and higher risk of infertility. However, the specific modes of action underlying these associations remain unclear. Here, we examined the effects of five commonly occurring POPs − hexachlorobenzene (HCB), p,p'-dichlorodiphenyldichloroethylene (DDE), 2,3,3′,4,4′,5-hexachlorobiphenyl (PCB156), 2,2′,3,4,4′,5,5′-heptachlorobiphenyl (PCB180), perfluorooctane sulfonate (PFOS) − and their mixture on human ovaries in vitro. We exposed human ovarian cancer cell lines COV434, KGN, and PA1 as well as primary ovarian cells for 24 h, and ovarian tissue containing unilaminar follicles for 6 days. RNA-sequencing of samples exposed to concentrations covering epidemiologically relevant levels revealed significant gene expression changes related to central energy metabolism in the exposed cells, indicating glycolysis, oxidative phosphorylation, fatty acid metabolism, and reactive oxygen species as potential shared targets of POP exposures in ovarian cells. Alpha-enolase (ENO1), lactate dehydrogenase A (LDHA), cytochrome C oxidase subunit 4I1 (COX4I1), ATP synthase F1 subunit alpha (ATP5A), and glutathione peroxidase 4 (GPX4) were validated as targets through qPCR in additional cell culture experiments in KGN. In ovarian tissue cultures, we observed significant effects of exposure on follicle growth and atresia as well as protein expression. All POP exposures, except PCB180, decreased unilaminar follicle proportion and increased follicle atresia. Immunostaining confirmed altered expression of LDHA, ATP5A, and GPX4 in the exposed tissues. Moreover, POP exposures modified ATP production in KGN and tissue culture. In conclusion, our results demonstrate the disruption of cellular energy metabolism as a novel mode of action underlying POP-mediated interference of follicle growth in human ovaries.

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Identification of Biomarkers and Outcomes of Endocrine Disruption in Human Ovarian Cortex using In Vitro Models

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