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Comparative Immunotoxicity and Transcriptomic Profiling of Seven PFAS in THP-1 Macrophages

ABSTRACT: Per- and polyfluoroalkyl substances (PFAS) are a large class of persistent synthetic chemicals widely used across industrial and consumer products. While legacy PFAS, such as perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), have been extensively studied and linked to immunotoxicity, far less is known about the immune-related hazards of newer-generation alternatives. In this study, we systematically evaluated the immunotoxic potential of seven PFAS, including three perfluoroalkyl acids (PFOA, PFOS, PFHpS) and four (poly-)ether PFAS (PFESA BP2, PFESA BP1, DOPFLCA, 8:2 Cl-PFESA) using a THP-1 macrophage model with dose-range exposures for up to 72 hours. Despite an equipotent dosing scheme, the molecular responses to different PFAS congeners were distinct. RNA sequencing revealed that PFOA and PFHpS, but not PFOS, elicited a larger number of differentially expressed genes than ether PFAS. We observed that the absolute PFAS concentration correlated more strongly with the number of DEGs than viability-based potency, suggesting differences in the underlying mechanisms of toxicity. The shared transcriptional signature highlighted PPAR signalling at the core of molecular responses to both legacy and newer-generation alternatives, while an adverse outcome pathway analysis revealed functional differences between the congeners. Together, these findings reveal compound-specific and structure-related differences in immunomodulatory potential among PFAS, with clear distinction by PFAS type. This study provides comprehensive comparative insights to inform hazard evaluation and support the development of safer PFAS alternatives.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313992 | GEO | 2026/08/03

REPOSITORIES: GEO

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Project description:The potential effects of poly- and perfluoroalkyl substances (PFAS) are a recent human and environmental health concern. There is a persistent link between PFAS exposure and cancer, but the mechanisms are poorly understood. Although epidemiological evidence supporting PFAS exposure and cancer in general is conflicting, there is a relatively strong evidence linking PFAS and testicular germ cell tumors (TGCTs). However, there have been no mechanistic studies to date cancerning PFAS and TGCTs. In this report, the effects of the legacy PFAS, perfluorooctanesulfonic acid (PFOS) and the newer "clean energy" PFAS, lithium bis(trifluoromethylsulfonyl)imide (LiTFSi and called HQ-115) on TGCT tumorigenicity, survival, metabolism, and gene regulation were investigated. In vitro, proliferation and survival of both chemo-sensitive and -resistant TGCT cells were minimally affected by a wide concentration range of PFOS and HQ-115. However, both chemicals promoted the growth of TGCT cells in mouse xenografts at doses consistenet with human exposure but had minimal acute toxicity, as assessed by total body, kidney, and testis weight. PFOS, but not HQ-115, increased liver weight. Transcriptiomic alterations of PFOS-exposed normal mouse testes were dominated by cancer-related pathways and gene expression altersations associated with the H3K27me3 polycomb pathway and DNA methylation, epigenetic pathways were previously shown to be critical for the survival of TGCT cells after cisplatin-based chemotherapy. Similar pattersn of PFOS-mediated gene expression occured in PFOS-exposed cells in vitro. Metabolomic studies revealed that PFOS also altered metabolites associiated with steroid biosynthesis and fatty acid metabolism in TGCT cells, consistent with the proposed ability of PFAS to mimic fatty acied based ligands controlling lipid metabolism and the proposed role of PFAS as endocrine disrupters. Our data, this first cell and animal based study on PFAS in TGCTs, support a pro-tumorigenic effect of PFAS on TGCT biology and suggests epigenetic, metabolic, and endocrine disruption as potential mechanisms of action that are consistent with the non-mutagenic nature of the PFAS class.

Project description:Background: Previous epidemiological studies have repeatedly found per- and polyfluoroalkyl substances (PFAS) exposure associated with higher circulating cholesterol, one of the greatest risk factors for development of coronary artery disease. The main route of cholesterol catabolism is through its conversion to bile acids, which circulate between the liver and ileum via enterohepatic circulation. Patients with coronary artery disease have decreased bile acid excretion, indicating that PFAS-induced changes of enterohepatic circulation may play a critical role in cardiovascular risk. Objectives: Using a mouse model with high LDL-VLDL cholesterol and aortic lesion development similar to humans, the current study investigates mechanisms linking exposure to a PFAS mixture with increased cholesterol. Methods: Male and female Ldlr-/- mice were fed an atherogenic diet (Clinton/Cybulsky low fat, 0.15% cholesterol) and exposed to a mixture of 5 PFAS representing legacy, replacement, and emerging subtypes (i.e., PFOA, PFOS, PFNA, PFHxS, GenX), each at a concentration of 2 mg/L, for 7 weeks. Blood was collected longitudinally for cholesterol measurements and mass spectrometry was used to measure circulating and fecal bile acids. Transcriptomic analysis of ileal samples was performed via RNA-sequencing. Results: After 7 weeks of PFAS exposure, average circulating PFAS levels were measured at 21.6, 20.1, 31.2, 23.5, and 1.5 µg/mL in PFAS-exposed females and 12.9, 9.7, 23, 14.3, and 1.7 µg/mL in PFAS-exposed males for PFOA, PFOS, PFHxS, PFNA, and GenX, respectively. PFAS exposure led to elevated circulating cholesterol levels after 7 weeks compared to vehicle mice, with females increasing 18% and males increasing 24%. Total circulating bile acid levels were elevated in PFAS-exposed mice by 230% in males and 290% in females compared to vehicle. PFAS decreased fecal bile acid levels by 62% in females and 59% in males. In the ileum, expression levels of the bile acid reuptake transporter ASBT were increased due to PFAS exposure. Discussion: Mice exposed to a PFAS mixture display increased circulating cholesterol and bile acids perhaps due to changes in enterohepatic circulation. This study implicates PFAS-mediated effects at the site of the ileum as a possible critical mediator of increased cardiovascular risk due to PFAS.

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Comparative Immunotoxicity and Transcriptomic Profiling of Seven PFAS in THP-1 Macrophages

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