A. Rasim Barutcu, Michael B. Black, Melvin E. Andersen
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引用次数: 0
Abstract
To identify pathway perturbations and examine biological modes of action (MOAs) for various perfluoroalkyl substances, we re-analyzed published in vitro gene expression studies from human primary liver spheroids. With treatment times ranging from 10 to 14 days, shorter-chain PFAS (those with 6 or fewer fluorinated carbon atoms in the alkyl chain) showed enrichment for pathways of fatty acid metabolism and fatty acid beta-oxidation with upregulated genes. Longer-chain PFAS compounds, specifically PFOS (perfluorooctane sulfonate), PFDS (perfluorodecane sulfonate), and higher doses of PFOA (perfluorooctanoic acid), had enrichment for pathways involved in steroid metabolism, fatty acid metabolism, and biological oxidation for downregulated genes. Although PFNA (perfluorononanoic acid), PFDA (perfluorodecanoic acid), and PFUnDA (perfluoroundecanoic acid) were more toxic and could only be examined after a 1-day treatment, all three had enrichment patterns similar to those observed with PFOS. With PFOA there were dose-dependent changes in pathway enrichment, shifting from upregulation of fatty acid metabolism and downregulation of steroid metabolism to downregulation of both at higher doses. The response to PFHpS (perfluoroheptanesulfonic acid) was similar to the PFOA pattern at the lower treatment dose. Based on results of transcription factor binding sites analyses, we propose that downregulation of pathways of lipid metabolism by longer chain PFAS may be due to inhibitory interactions of PPARD on genes controlled by PPARA and PPARG. In conclusion, our transcriptomic analysis indicates that the biological MOAs of PFAS compounds differ according to chain length and dose, and that risk assessments for PFAS should consider these differences in biological MOAs when evaluating mixtures of these compounds.
期刊介绍:
Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products.
Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged.
Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.