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Transcriptome and behavioral assessment in larval zebrafish (Danio rerio) following exposure to perfluorononanoic acid (PFNA)

ABSTRACT: Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent chemicals widely detected in aquatic systems and drinking water. Perfluorononanoic acid (PFNA), a long-chain PFAS, has been reported globally in environmental matrices and fish tis-sues. Although PFNA has been linked to developmental, metabolic, and neurological toxicity, its effects on lipid-related pathways and neurotoxicity remain poorly charac-terized. This study evaluated the developmental and neurotoxic effects of PFNA ex-posure in zebrafish embryos and larvae following a 7-day exposure to environmentally relevant PFNA concentrations. PFNA exposure did not significantly affect survival or deformity rates. Apoptosis was significantly increased in larvae exposed to 1 µg/L PFNA compared to controls, whereas reactive oxygen species were unaffected. Each tested concentration (0.1 µg/L and 10 µg/L) showed a different effect on the zebrafish transcriptome. Low-dose PFNA exposure primarily affected lipid transport, choles-terol metabolism, sphingolipid signaling, and neurodegeneration-related pathways, while high-dose PFNA altered synaptic signaling, axon guidance, and thyroid hormone synthesis. Hypoactivity was observed in the movement of larval zebrafish based on a visual motor response test. Taken together, PFNA exposure leads to molecular changes related to neurotoxicity and lipid metabolism in zebrafish, which may con-tribute to adverse neurodevelopmental outcomes.

ORGANISM(S): Danio rerio

PROVIDER: GSE324353 | GEO | 2026/05/05

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:Background and Purpose: Perfluoronanoic acid (PFNA) is a synthetic long chain (C  8) homologue of per and polyfluoroalkyl substances (PFAS) which is frequently detected in environment as an emerging contaminant with potential threats to living organisms. It has broad applications in industrial and consumer products including adhesives, water and paint repellent surfaces, non-sticky coatings and lubricants. PFNA is very stable and persistent in the environment due to high energy carbon-fluorine bonds and anti-degradation (photo and microbial) properties. Studies show that PFNA caused immune, cardiac, endocrine, reproductive and developmental toxicity. This study investigates the developmental toxicity of PFNA using behavioral assay especially focus on organ specific toxicity via transcriptomic analysis. Methods: Tropical 5D zebrafish embryos were exposed to different concentrations of PFNA (0, 0.031, 0.31, 3.12, 6.25 and 12.5 M) from 2-hour post fertilization (hpf) to 120 hpf under light/dark (14hr light/10 hr dark) or dark (24 hr dark) conditions in temperature-controlled incubator at 28 C. Larval photomotor response (LPR) was conducted to assess change in behavioral patterns. For organic specific toxicity, embryos were exposed to 0 and 12.5 M of PFNA for120 hpf. Brain and eyes were dissected and extracted RNA was sent to Novogene for sequencing. Gene Ontology (GO) and Kyoto Encyclopedia Genes and Genomes (KEGG) analysis were performed using SR plots. For statistical analysis, Kruskal-Wallis test followed by Dunn’s test was opted for behavior data using GraphPad Prism While R software was used for differential expression analysis. Results: PFNA exposure led to significant behavioral alterations in zebrafish larvae at 6.25 and 12.5 M characterized by hyperactivity during light phases and distinct “O-bend” responses in the LPR assay. This hyperactivity indicates neurotoxic and visual impairments which forced us to focus on transcriptomic analysis of brain and eye. RNA sequencing showed 287 differentially expressed genes (DEGs) in brain while that of 683 in eye. GO and KEGG pathways analysis revealed that the common affected pathways in both organs were circadian rhythms, steroid biosynthesis, fatty acid metabolism and PPAR signaling. Additionally, in brain we noticed disruptions in insulin and notch signaling while in eye P53 signaling and phototransduction were affected. Finally, these results suggest that PFNA affects circadian rhythms/biological clocks and vision by influencing various metabolic and signaling pathways potentially contributing to hyperactivity. Conclusion: This study demonstrates that PFNA exposure disrupts neurodevelopmental processes in zebrafish embryos by impairing circadian rhythm and vision. The findings underscore the neurotoxic potential of PFNA and its ability to interfere with both behavioral and molecular pathways. Collectively, this research highlights the need for environmental and regulatory evaluations of PFNA and other PFAS, focusing on their long-term impacts on neurodevelopment and circadian rhythm and potential health risks in contaminated ecosystems and populations.

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Transcriptome and behavioral assessment in larval zebrafish (Danio rerio) following exposure to perfluorononanoic acid (PFNA)

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