Pharmacokinetics and Pharmacodynamics of Perfluorooctane Sulfonate (PFOS) and Its Role in the Development and Progression of Prostate, Ovarian and Breast Cancers

Abstract

Environmental pollution, driven by industrialization, urbanization, and agricultural practices, has intensified global ecological degradation. Among the most concerning pollutants is PFOS, a synthetic compound known for its chemical stability, environmental persistence, and bioaccumulative potential. Widely utilised in industrial and consumer products, PFOS infiltrates ecosystems and food chains, posing substantial risks to human and animal health. Upon exposure, PFOS disrupts lipid metabolism, damages cellular membranes, and alters signaling pathways through partial metabolism by cytochrome P450 enzymes. Accumulating evidence links PFOS to oxidative stress, mitochondrial dysfunction, endocrine disruption, neurotoxicity, and immunotoxicity. Critically, PFOS contributes to the development and progression of prostate, breast, and ovarian cancers via mechanisms such as hormonal interference, chronic inflammation, and epigenetic modifications. Epidemiological studies further associate elevated PFOS serum levels with increased cancer risk, particularly in occupationally and environmentally exposed populations. This review brings together the latest knowledge on PFOS emissions, mechanistic toxicity, and cancer-causing potential, highlighting the urgent need for focused research and improved regulatory measures to safeguard public health.

Keywords: breast cancer; carcinogenesis; ovarian cancer; perfluorooctane sulfonate; persistent organic pollutants; prostate cancer; toxicodynamics; toxicokinetic.

Figure 1

Primary exposure routes of PFOS. PFOS enters the environment through industrial activities, consumer products, aqueous fire-fighting foams, and waste infrastructure. Contaminated water and ecosystems serve as major pathways for human exposure, including maternal transfer via breast milk and cord blood. Arrows indicate the directional flow of PFOS from sources to exposure endpoints. Source: Generated with https://app.diagrams.net/, accessed on 23 April 2025.

Figure 2

PFOS-mediated induction and progression of PCa. PFOS mediates the transition from normal prostate epithelium to clinical adenocarcinoma. A: The mechanisms of tumor initiation by PFOS involve oxidative stress, DNA damage, inflammation, and telomere shortening, leading to prostatic intraepithelial neoplasia (PIN). B: The formation of PIN can be driven by the activation of other signaling nodes, such as PI3K/Akt/NF-κB. C: Progression is driven by activation of oncogenes such as c-MYC and the repression of PTEN by PFOS. D: PFOS-mediated increase in the expression of IL-8, MMP-2, MMP-9, and VEGF then mediates the transformation of occult adenocarcinoma to clinical adenocarcinoma. E: Other signaling pathways, such as WNT/β-catenin, N-Cadherin and vimentin further facilitate the metastasis of PCa to distant organs Generated with BioRender (https://app.biorender.com, accessed on 28 October 2025).

Figure 3

PFOS-mediated induction and progression of BCa. PFOS drives the sequential transformation of normal breast epithelial cells into metastatic carcinoma. A: The initiation step involves DNA damage, inflammation, and telomere shortening. B: These processes can deregulate the expression of certain genes, such as PTEN, c-MYC, PI3K/Akt, and MAPK, leading to the formation of atypical ductal hyperplasia. C: The mechanisms of progression are marked by elevated expression of VEGF, MMP-2/9, and IL-8 levels, which promote tumor growth and angiogenesis, leading to the formation of carcinoma in situ. D: PFOS can further trigger the transformation of carcinoma in situ into invasive carcinoma. This process is facilitated by WNT/β-catenin signaling and epithelial–mesenchymal transition markers, enabling dissemination to distant organs such as the lungs, liver, bones, and brain. Generated with BioRender (https://app.biorender.com, accessed on 28 October 2025).

Figure 4

PFOS-mediated induction and progression of OC. Exposure to PFOS mediates the transformation of normal ovarian tissues into metastatic ovarian carcinoma. A: The Initiation step involves oxidative stress, DNA damage, inflammation, and genomic instability. B: These biological processes can induce dysregulation in the expression of some genes, including PTEN, KRAS and BRAS, thus leading to epithelial dysplasia (precursor lesions). C: The progression step is driven by the accumulations of several mutations, including PTEN, BRCA 1/2, TP53, KRAS, and BRAS, ultimately resulting in the formation of carcinoma in situ (otherwise known as serous tubal intraepithelial carcinoma (STIC)). D: PFOS further drives the activation of several genes, including VEGF, MMP-9/MMP-2, and IL-8. This process is necessary for tumor angiogenesis and invasion, leading to the formation of invasive ovarian carcinoma. E: The metastatic step is facilitated by WNT/β-catenin signaling, vimentin upregulation, and GSK3β inhibition, enabling epithelial–mesenchymal transition and cellular migration. Generated with BioRender (https://app.biorender.com, accessed on 28 October 2025).

Figure 5

Emission and distribution pathways of PFOS. Point sources include industrial discharge, aqueous fire-fighting foams, suppression systems, landfills, and wastewater treatment facilities. Non-point sources encompass atmospheric deposition, consumer and household products, agricultural runoff, urban runoff, and roadway runoff. Arrows indicate the flow of PFOS from emission sources into the environment. Generated with https://app.diagrams.net/, accessed on 28 April 2025.

Figure 6

PFOS-mediated disruption of lipid metabolism in the liver. PFOS activates peroxisome proliferator-activated receptor alpha (PPARα), leading to lipid accumulation in hepatic cells. This dysregulation progresses from hepatic steatosis (fatty liver) to inflammation (hepatitis), fibrosis, and ultimately hepatocellular carcinoma. Generated with BioRender (https://app.biorender.com, accessed on 28 April 2025).

Figure 7

PFOS-mediated induction of oxidative stress. (A): PFOS disrupts the Keap1–Nrf2 signaling axis, promoting the nuclear translocation of Nrf2 and its binding to antioxidant response elements (AREs), which activates transcription of cytoprotective genes. (B): PFOS enhances mitochondrial production of reactive oxygen species (ROS), including superoxide anions (O₂⁻), hydrogen peroxide (H₂O₂), and hydroxyl radicals (OH•), leading to oxidative damage of lipids, proteins, and DNA. These events contribute to cellular dysfunction and apoptosis. Generated with BioRender (https://app.biorender.com, accessed on 4 May 2025).

Figure 8

PFOS-mediated epigenetic modifications. (A): PFOS disrupts DNA methylation dynamics by inhibiting DNA methyltransferases (DNMTs) and promoting demethylation, leading to the transition from transcriptionally repressive heterochromatin to active euchromatin and aberrant gene expression. (B): PFOS alters histone methylation through the upregulation of histone demethylases, affecting chromatin structure and transcriptional activity. These changes contribute to the activation of oncogenes and suppression of tumor suppressor genes. Generated with BioRender (https://app.biorender.com, accessed on 4 May 2025).

Figure 9

PFOS-mediated endocrine function disruption. PFOS inhibits iodine uptake, suppresses thyroid peroxidase activity, and disrupts the conversion of thyroxine (T4) to triiodothyronine (T3) by deiodinases. These disruptions lead to reduced levels of T4 and T3, impairing key physiological processes including neurogenesis, brain development, heart rate regulation, and glucose metabolism. Generated with BioRender (https://app.biorender.com, accessed on 15 May 2025).

Figure 10

PFOS-mediated disruptions of B-cell and T-cell function. PFOS impairs adaptive immune responses by targeting key cellular processes. In B-cells, PFOS depletes naïve B-cell populations, reduces plasma cell differentiation, and suppresses antibody production. In T-cells, PFOS inhibits activation markers (CD3, CD4/CD8, MHC-TCR) and cytokine signaling (e.g., IL-2, IFN-γ), leading to diminished T-cell activation and proliferation. These disruptions collectively contribute to immunosuppression. Generated with BioRender (https://app.biorender.com, accessed on 15 May 2025).

Figure 11

Structure of the androgen receptor (AR) gene. The AR gene is located on the X chromosome and comprises eight exons. The encoded protein includes three major functional domains: the N-terminal domain (NTD; residues 1–555), DNA-binding domain (DBD; residues 556–623), and ligand-binding domain (LBD; residues 666–919). These domains are essential for AR-mediated transcriptional regulation and play critical roles in PCa development and progression. Generated with BioRender (https://app.biorender.com, accessed on 10 June 2025).

Figure 12

AR signaling pathway in PCa. The diagram illustrates the molecular cascade beginning with cholesterol conversion to testosterone via CYP17 lyase. Testosterone is further metabolized to dihydrotestosterone (DHT) by 5α-reductase, which binds to cytosolic AR, triggering dissociation from heat shock proteins (HSPs) and enabling nuclear translocation. Inside the nucleus, the AR-DHT complex binds to androgen response elements (AREs) on DNA, initiating transcription of genes that drive PCa progression. Points of therapeutic inhibition are highlighted: (a) CYP17 lyase inhibitors (e.g., abiraterone) block androgen biosynthesis. (b) Androgen deprivation therapy reduces circulating testosterone. (c) 5α-reductase inhibitors (e.g., finasteride, dutasteride) prevent DHT formation. (d) AR inhibition or degradation targets the androgen receptor directly, either by blocking ligand binding, preventing nuclear translocation, or promoting proteasomal degradation. Degraders such as PROTAC act at this level. (e) AR antagonists (e.g., enzalutamide) inhibit receptor activation or promote degradation. (f) Transcriptional inhibitors block AR-mediated gene expression. Generated with BioRender (https://app.biorender.com, accessed on 10 June 2025).

Figure 13

ER signaling pathway in BCa. The figure illustrates both genomic and non-genomic mechanisms of ER activation. In the genomic pathway, estrogen binds to nuclear ERs, leading to receptor dimerization and translocation into the nucleus, where it regulates gene transcription. In the non-genomic pathway, estrogen interacts with membrane-associated ERs, triggering rapid signaling cascades including Ras/Raf/MEK/ERK, PI3K/Akt, and Src-mediated pathways. These cascades promote cell proliferation, survival, inflammation, protein synthesis, and metastasis through downstream effectors such as JNK, p38 MAPKs, NF-κB, and CREB. Generated with BioRender (https://app.biorender.com, accessed on 22 June 2025).

Figure 14

Mechanism of PFOS-mediated epigenetic perturbation in BCa. The figure illustrates how PFOS exposure induces epigenetic reprogramming through alterations in DNA methylation (5mC) and histone modifications. These changes disrupt the expression of genes regulating cell adhesion molecules such as β-integrin, E-cadherin, and occludin, compromising extracellular matrix integrity. The resulting epigenetic dysregulation hijacks cell growth signaling pathways such as ERK, AP-1, Cylin D1, and CDK4, promoting uncontrolled proliferation and contributing to BCa progression. Generated with BioRender (https://app.biorender.com, accessed on 29 October 2025).

Figure 15

Histological subtypes of OC. Generated with BioRender (https://app.biorender.com, accessed on 29 October 2025).