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Investigating the Mechanism of Neurotoxic Effects of PFAS in Differentiated Neuronal Cells through Transcriptomics and Lipidomics Analysis

ABSTRACT: Per- and polyfluorinated alkyl substances (PFAS) are pervasive environmental contaminants that bioaccumulate in tissues and pose risks to human health. Increasing evidence links PFAS to neurodegenerative and behavioral disorders, yet the underlying mechanisms of their effects on neuronal function remain largely unexplored. In this study, we utilized SH-SY5Y neuroblastoma cells, differentiated into neuronal-like cells, to investigate the impact of six PFAS compounds perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorodecanoic acid (PFDA), perfluorodecanesulfonic acid (PFDS), 8:2 fluorotelomer sulfonate (8:2 FTS), and 8:2 fluorotelomer alcohol (8:2 FTOH) neuronal health. Following a 30 μM exposure for 24 h, PFAS accumulation ranged from 40−6500 ng/mg of protein. Transcriptomic analysis revealed 721 differentially expressed genes (DEGs) across treatments (padj < 0.05), with 11 DEGs shared among all PFAS exposures, indicating potential biomarkers for neuronal PFAS toxicity. PFOA-treated cells showed downregulation of genes involved in synaptic growth and neural function, while PFOS, PFDS, 8:2 FTS, and 8:2 FTOH exposures resulted in the upregulation of genes related to hypoxia response and amino acid metabolism. Lipidomic profiling further demonstrated significant increases in fatty acid levels with PFDA, PFDS, and 8:2 FTS and depletion of triacylglycerols with 8:2 FTOH treatments. These findings suggest that the neurotoxic effects of PFAS are structurally dependent, offering insights into the molecular processes that may drive PFAS-induced neuronal dysfunction.

ORGANISM(S): Homo sapiens

PROVIDER: GSE254408 | GEO | 2024/12/02

REPOSITORIES: GEO

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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.

Project description:Per- and polyfluoroalkyl substances (PFAS) are some of the most prominent organic contaminants in human blood that have the potential to disrupt biological processes and pathways in the liver. Although the toxicological implications from human exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are well established, data on other, lesser-understood PFAS are limited. A challenge for regulatory authorities is to determine acceptable levels of human exposure to large, diverse classes of environmental contaminants. New approach methodologies (NAMs) that apply bioinformatics tools to interpret biological data are being increasingly considered to inform risk assessment when traditional toxicology methodologies are not amenable. The aim of the current investigation was to identify the biological responses relevant to PFAS mode of action as the concentration (benchmark dose) that these effects take place in order to utililze this information to inform/facilitate read-across for risk assessment of data-poor PFAS. A TempO-Seq platform (BioSpyder) measured gene expression changes in human liver microtissues (i.e., spheroids) after 1-day and 10-day exposures to increasing concentrations of PFAS. A bioinformatics framework was applied to 23 PFAS sub-classed into carboxylates (PFCAs), sulfonates (PFSAs), or PFAS precursors that were analyzed for the total altered transcripts, the concentration where effects take place, and identifying target genes of interest. Both PFCAs and PFSAs exhibited a trend toward increased transcriptional changes with carbon chain-length. Specifically, longer-chain compounds (7 to 10 carbons) were more likely to surpass liver-toxic transcriptomic thresholds established from previous studies than shorter chain PFAS. Longer-chain PFAS were also more potent, inducing transcriptional effects at lower concentrations. However, PFOS was the most potent PFAS and of all precursors, only PFOSA (a PFOS precursor) induced a response. The combined high-throughput transcriptomic and bioinformatics analyses revealed the capability of NAMs to assess the effects of PFAS in liver microtissues; such data improves our understanding of PFAS-related effects in humans and facilitates the use of read-across in human health risk assessment for other data-poor chemicals.

Project description:Per- and polyfluoroalkyl substances (PFAS) are chemicals that are relatively resistant to degradation. While such features are desirable in a variety of consumer and industry products, such as firefighting foams and non-stick cookware coating, some PFAS, including perfluorooctanoic acid (PFOA), are toxic and bioaccumulate. Hexafluoropropylene oxide dimer acid (HFPO-DA) is an emerging PFAS developed to replace PFOA and has not been extensively studied. To evaluate the potential toxicity of HFPO-DA with a cost- and time-efficient approach, we exposed C. elegans larvae to 4×10-9–4 g/L HFPO-DA in liquid media and performed assays measuring developmental, behavioral, locomotor, and transcriptional effects at various exposure levels. After 48 hours of 1.5–4 g/L HFPO-DA exposure, acute developmental toxicity was observed as developmental delay; statistically significantly delayed (p < 0.05) progeny production was observed in worms exposed to 2–4 g/L HFPO-DA. After 48 hours of 4×10-9–0.4 g/L exposure, no significant behavioral or locomotor effect was observed relative to the 0 g/L control group. Statistically significant differential gene expression was identified with over 99% confidence via the R-package NOISeq in all fourteen 48-hour 1.25×10¬-5–4 g/L HFPO-DA exposure groups, except for 6.25×10¬-5 g/L. Among 10298 genes analyzed, 2624 differentially expressed genes (DEGs) were identified in the developmentally delayed 4 g/L group only, and 78 genes were differentially expressed in at least one of the thirteen exposure groups testing 1.25×10¬-5–2 g/L HFPO-DA exposures. Genes encoding for detoxification proteins such as cytochrome P450 enzymes and UDP glucuronosyltransferases are upregulated in 0.25–4 g/L acute exposure groups. In the lower exposure concentration groups, statistically significant gene expression changes were also observed, though these DEGs did not share any biological functions, except for six ribosomal protein-coding genes. While our transcriptional data is insufficient for conclusive mechanistic explanation, the statistically significant gene expression differences detected at 1.25×10¬-5 g/L, the lowest concentration tested for transcriptional changes, is concerning and calls for further targeted analyses that focus on low-dose HFPO-DA exposure effects.

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Investigating the Mechanism of Neurotoxic Effects of PFAS in Differentiated Neuronal Cells through Transcriptomics and Lipidomics Analysis

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