RNA‐sequencing analysis reveals the hepatotoxic mechanism of perfluoroalkyl alternatives, HFPO2 and HFPO4, following exposure in mice
Abstract
The toxicological impact of traditional perfluoroalkyl chemicals has led to the elimination and restriction of these substances. However, many novel perfluoroalkyl alternatives remain unregulated and little is known about their potential effects on environmental and human health. Daily administration of two alternative perfluoroalkyl substances, HFPO2 and HFPO4 (1 mg kg -1 body weight), for 28 days resulted in hepatomegaly and hepatic histopathological injury in mice, particularly in the HFPO4 group. We generated and compared high-throughput RNA-sequencing data from hepatic tissues in control and treatment group mice to clarify the mechanism of HFPO2 and HFPO4 hepatotoxicity. We identified 146 (101 upregulated, 45 downregulated) and 1295 (716 upregulated, 579 downregulated) hepatic transcripts that exhibited statistically significant changes (fold change ≥2 or ≤0.5, false discovery rate < 0.05) after HFPO2 and HFPO4 treatment, respectively. Among them, 111 (82 upregulated, 29 downregulated) transcripts were changed in both groups, and lipid metabolism associated genes were dominant. Thus, similar to their popular predecessors, HFPO2 and HFPO4 exposure exerted hepatic effects, including hepatomegaly and injury, and altered lipid metabolism gene levels in the liver, though HFPO4 exerted greater hepatotoxicity than HFPO2. The unregulated use of these emerging perfluoroalkyl alternatives may affect environmental and human health, and their biological effects need further explorat…
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The PPARα mechanism does not sufficiently explain all toxicities of all PFAAs, as not all PFAAs produce robust PPARα-mediated responses across species or even among strains of the same species.
“However, this mechanism does not sufficiently explain all toxicities of all PFAAs, as not all PFAAs produce robust PPARα-mediated responses across species or even among strains of the same species.28,29”
From A Never-Ending Story of Per- and Polyfluoroalkyl Substances (PFASs)? (2017) · cites this paper as [28]
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- Authors
- Wang, J., Wang, X., Sheng, N., Zhou, X., Cui, R., Zhang, H., & Dai, J.
- Affiliations
- Chinese Academy of Sciences (CN)
- Corresponding author
- Dai, Jiayin
- Venue
- Journal of Applied Toxicology
- Publisher
- Wiley
- Published
- 2016-08-24
- Volume
- 37
- Issue
- 4
- Pages
- 436-444
- ISSN
- 0260-437X (ISSN-L)
- 1099-1263
- OpenAlex
- W2512976965
- Cited by
- 73
- References
- 8
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 5 · 2023: 14 · 2022: 9 · 2021: 9 · 2020: 7 · 2019: 10 · 2018: 4 · 2017: 3 · 2016: 1
- FWCI
- 3.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Applied Toxicology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Chinese Academy of Sciences
- Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
- National Key Research and Development Program of China
- Topics
- Physical Sciences › Environmental Science › Environmental Chemistry › Per- and polyfluoroalkyl substances research
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
- Keywords
- perfluorohexanoic acid, hepatotoxicity, hepatic lipid metabolism, liver transcriptome, hepatomegaly, liver histopathology, gene expression changes, emerging PFAS
- MeSH terms
- Acetates, Animals, Cytochrome P-450 Enzyme System, Fluorocarbons, Liver, Liver Function Tests, Organ Size, Propionates, RNA, Transcriptional Activation, Sequence Analysis, RNA, PPAR gamma, Mice, Chemical and Drug Induced Liver Injury, High-Throughput Nucleotide Sequencing, Transcriptome
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