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Hepatic Transcriptome Comparative In Silico Analysis Reveals Similar Pathways and Targets Altered by Legacy and Alternative Per- and Polyfluoroalkyl Substances in Mice
Citation:
Robarts, D., J. Dai, C. Lau, U. Apte, AND Jon Corton. Hepatic Transcriptome Comparative In Silico Analysis Reveals Similar Pathways and Targets Altered by Legacy and Alternative Per- and Polyfluoroalkyl Substances in Mice. Toxics. MDPI, Basel, Switzerland, 11(12):963, (2023). https://doi.org/10.3390/toxics11120963
Impact/Purpose:
Compared to other PFAS, PFOS, PFOA, PFNA, and PFHxS are most frequently found in the environment and bioaccumulate in humans (CDC 2021; Rogers et al. 2021). In humans, PFAS have been associated with liver injury and toxicant-associated fatty liver disease (TAFLD), a pathology similar to non-alcoholic fatty liver disease (NAFLD) (Armstrong and Guo 2019; Bassler et al. 2019; Jin et al. 2020). In rodents, these compounds induce a number of effects in the liver, including lipid accumulation, increases in hepatocyte size, and liver weight (Andersen et al. 2021). Alternative PFAS, including ammonium perfluoro-2-methyl-3-oxahexanoate (HFPO-DA or GenX), perfluoro-(2,5,8-trimethyl-3,6,9-trioxadodecanoic)acid (HFPO4), perfluoro-2,5-dimethyl-3,6-dioxanonanoic acid (HFPO-TA), potassium 9-chlorohexadecafluoro-3-oxanonane-1-sulfonate (F-53B), 6:2 fluorotelomer sulfonic acid (6:2 FTSA), and 2-perfluorohexyl ethanoic acid (6:2 FTCA) and a by-product of PFAS production called perfluoro-2-([perfluoro-3-(perfluoroethoxy)-2-propanyl]oxy)ethanesulfonic acid (Nafion BP2), are compounds that are found in many cases to be accumulating in the environment and in the blood of people and animals (Conley et al. 2022; Guillette et al. 2020; Kotlarz et al. 2020; Sen et al. 2022; Sheng et al. 2017). A major issue regarding these emerging PFAS is that little is known about their adverse health effects, including their potential mechanisms of liver toxicity. Most PFAS studied thus far are activators of peroxisome proliferator-activated receptor α (PPARα), a nuclear receptor family member expressed in the livers of rodents and humans. Chronic PPARα activation can lead to a number of toxicities, the most notable of which are increases in hepatocellular adenomas and carcinomas in mice, and increases in tumors in the liver, testis, and pancreas (known as the tumor triad) in rats (Corton et al. 2018; Klaunig et al. 2003). Long(er)-term oral exposures to PFOA, PFOS, and HFPO-DA have been shown to cause increases in tumors of the liver, pancreas, and/or testis (Klaunig et al. 2012; Thompson et al. 2019). In addition to PPARα, the legacy PFAS induced the activation of other transcription factors, including CAR and PXR (Abe et al. 2017; Oshida et al. 2015a; Ren et al. 2009; Rooney et al. 2019b), the oxidant-induced Nrf2 (Alharthy and Hardej 2021; Pfohl et al. 2020; Rooney et al. 2019b), and the sterol responsive element binding protein (SREBP), which regulates triglyceride and cholesterol synthesis (Corton 2019; Rooney et al. 2019a; Yan et al. 2015). To date, no comprehensive analysis of the transcript profiles induced by a large number of legacy and alternative PFAS have been compared to identify overlapping and unique molecular targets. In the present study, the transcript profiles induced by 11 legacy and alternative PFAS were computationally compared to those transcript profiles of 5 known PPARα activators using pathway analysis and characterized gene expression biomarkers. The biomarkers included those that are highly predictive of the modulation of 6 transcription factors important in lipid, metabolic, and cell growth homeostasis in the liver.
Description:
Per- and poly-fluoroalkyl substances (PFAS) are a large class of fluorinated carbon chains that include legacy PFAS, such as perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorohexane sulfonate (PFHxS). These compounds induce adverse health effects, including hepatotoxicity. Potential alternatives to the legacy PFAS (HFPO-DA (GenX), HFPO4, HFPO-TA, F-53B, 6:2 FTSA, and 6:2 FTCA), as well as a byproduct of PFAS manufacturing (Nafion BP2), are increasingly being found in the environment. The potential hazards of these new alternatives are less well known. To better understand the diversity of molecular targets of the PFAS, we performed a comparative toxicogenomics analysis of the gene expression changes in the livers of mice exposed to these PFAS, and compared these to five activators of PPARα, a common target of many PFAS. Using hierarchical clustering, pathway analysis, and predictive biomarkers, we found that most of the alternative PFAS modulate molecular targets that overlap with legacy PFAS. Only three of the 11 PFAS tested did not appreciably activate PPARα (Nafion BP2, 6:2 FTSA, and 6:2 FTCA). Predictive biomarkers showed that most PFAS (PFHxS, PFOA, PFOS, PFNA, HFPO-TA, F-53B, HFPO4, Nafion BP2) activated CAR. PFNA, PFHxS, PFOA, PFOS, HFPO4, HFPO-TA, F-53B, Nafion BP2, and 6:2 FTSA suppressed STAT5b, activated NRF2, and activated SREBP. There was no apparent relationship between the length of the carbon chain, type of head group, or number of ether linkages and the transcriptomic changes. This work highlights the similarities in molecular targets between the legacy and alternative PFAS.
URLs/Downloads:
DOI: Hepatic Transcriptome Comparative In Silico Analysis Reveals Similar Pathways and Targets Altered by Legacy and Alternative Per- and Polyfluoroalkyl Substances in Mice
https://pubmed.ncbi.nlm.nih.gov/38133364/