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Updated: Feb 22, 2026
Author Spotlight: Investigating the Mechanisms and Inducing Models of Polycystic Ovary Syndrome
Published on: July 5, 2024
Multi-level evidence reveals KCTD15 and FAM19A2 as key targets in PFOA/PFOS-mediated PCOS pathogenesis
Yuxiao Jiang1, Liying Ge2, Shanshan Zhang3
1Department of Physiology, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou, Jiangsu, China; School of Life Sciences, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou, Jiangsu, China.
Background:
Polycystic ovary syndrome (PCOS), a common endocrine disorder, has been linked to environmental factors such as exposure to per- and polyfluoroalkyl substances (PFAS), which may induce disruptions in ovarian function. However, the molecular mechanisms underlying PFAS-PCOS interactions remain poorly understood.
Methods:
We performed absorption, metabolism, distribution, excretion (ADME) profiling analysis of PFOA/PFOS using SwissADME. Target genes were retrieved from multiple databases and intersected with PCOS-associated genes from Gene Expression Omnibus (GEO) datasets, followed by GO and KEGG enrichment analyses. Weighted Gene Co-expression Network Analysis (WGCNA) identified PCOS -related modules, and hub genes were selected via LASSO regression. Immune infiltration was evaluated using single-sample Gene Set Enrichment Analysis (ssGSEA). Molecular docking and dynamics simulations validated interactions with SwissDock, PyMOL, and associated tools. Causal genetic relationships were assessed through Mendelian Randomization (MR) analyses. The impacts of PFOA/PFOS on ovarian granulosa cells (GCs) and hub gene expression were examined in vitro.
Results:
In silico ADME predictions using SwissADME indicated low gastrointestinal (GI) absorption for PFOA/PFOS, based on their physicochemical properties. Shared targets between PFOA/PFOS and PCOS were enriched in endocrine resistance and PI3K-Akt signaling pathways. Integration of computational toxicology and machine learning identified two hub genes, KCTD15 and FAM19A2. ssGSEA indicated altered immune profiles, with hub genes correlated to T-cell infiltration. MR analyses confirmed causal links between KCTD15/FAM19A2 and PCOS. Molecular dynamics simulations (MDS) showed stable binding of PFOA/PFOS to KCTD15/FAM19A2 proteins. In vitro experiments demonstrated that PFOA/PFOS exposure reduced GC viability and upregulated KCTD15/FAM19A2 expression.
Conclusions:
This study identifies KCTD15/FAM19A2 as potential hub genes linked to PFOA/PFOS exposure in PCOS, providing preliminary evidence for a causal association. These findings may inform future research into targeted interventions within environmental reproductive toxicology.
Insights
This study links per- and polyfluoroalkyl substances (PFAS) exposure to polycystic ovary syndrome (PCOS) by identifying KCTD15 and FAM19A2 as key genes. Findings suggest a causal association and inform environmental reproductive toxicology research.
Area of Science:
- Environmental Reproductive Toxicology
- Endocrinology
- Computational Biology
Background:
- Polycystic Ovary Syndrome (PCOS) is a common endocrine disorder linked to environmental factors like per- and polyfluoroalkyl substances (PFAS).
- The molecular mechanisms of PFAS-PCOS interactions and their impact on ovarian function are not well understood.
Purpose of the Study:
- To investigate the molecular mechanisms underlying the association between PFAS exposure and PCOS.
- To identify potential molecular targets and causal links between PFAS and PCOS.
Main Methods:
- Utilized in silico absorption, metabolism, distribution, excretion (ADME) profiling and bioinformatics analyses (GEO, GO, KEGG, WGCNA, LASSO).
- Employed Mendelian Randomization (MR) and molecular dynamics simulations (MDS) to assess causality and protein interactions.
- Conducted in vitro experiments on ovarian granulosa cells (GCs) to evaluate the impact of PFAS exposure.
Main Results:
- Identified KCTD15 and FAM19A2 as hub genes associated with PCOS and PFAS exposure.
- Confirmed causal relationships between KCTD15/FAM19A2 and PCOS using MR analyses.
- Demonstrated that PFAS exposure reduces GC viability and alters KCTD15/FAM19A2 expression in vitro, with stable protein binding observed via MDS.
Conclusions:
- KCTD15 and FAM19A2 are identified as potential key genes mediating the effects of PFAS exposure in PCOS.
- Provides preliminary evidence for a causal link between PFAS exposure and PCOS, highlighting potential targets for environmental reproductive toxicology.
