Replacement per- and polyfluoroalkyl substances (PFAS) are potent modulators of lipogenic and drug metabolizing gene expression signatures in primary human hepatocytes

Marques, Emily; Pfohl, Marisa; Wei, Wei; Tarantola, Giuseppe; Ford, Lucie; Amaeze, Ogochukwu; Alesio, Jessica; Ryu, Sangwoo; Jia, Xuelian; Zhu, Hao; Bothun, Geoffrey D.; Slitt, Angela L.

doi:10.1016/j.taap.2022.115991

Cited by 32 publications

(18 citation statements)

References 59 publications

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“…In human HepaRG cells, high concentrations of PFOA, PFOS, and PFNA increased triglyceride content [ 34 ]. By contrast, in primary human hepatocytes, PFOA and PFOS did not significantly alter triglyceride content [ 85 ]. Further study on the impact of PFAS on triglyceride content in the human liver is warranted, for example, in hepatocyte humanized mice [ 86 , 87 ].…”

Section: Discussionmentioning

confidence: 99%

Exposure to low-dose perfluorooctanoic acid promotes hepatic steatosis and disrupts the hepatic transcriptome in mice

Attema¹,

Janssen²,

Rijkers³

et al. 2022

Molecular Metabolism

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Section: Discussionmentioning

confidence: 99%

Exposure to low-dose perfluorooctanoic acid promotes hepatic steatosis and disrupts the hepatic transcriptome in mice

Attema¹,

Janssen²,

Rijkers³

et al. 2022

Molecular Metabolism

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“…A recent study on human hepatocytes found that 25 μM PFOS could induce at least 7 transcripts out of 35 related to lipid metabolism, lipid transport, and antioxidant response pathways. Moreover, PFOS induced the expression of genes related to xenobiotic metabolism, such as CYP2B6 and SULT2A1, but no lipid accumulation was observed in hepatocytes [ 59 ].…”

Section: Effects Of Pfos On the Liver And Related Mechanisms Of Toxicitymentioning

confidence: 99%

Adverse Effects of Perfluorooctane Sulfonate on the Liver and Relevant Mechanisms

Wang

Liu

Yan

et al. 2022

Toxics

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Perfluorooctane sulfonate (PFOS) is a persistent, widely present organic pollutant. PFOS can enter the human body through drinking water, ingestion of food, contact with utensils containing PFOS, and occupational exposure to PFOS, and can have adverse effects on human health. Increasing research shows that the liver is the major target of PFOS, and that PFOS can damage liver tissue and disrupt its function; however, the exact mechanisms remain unclear. In this study, we reviewed the adverse effects of PFOS on liver tissue and cells, as well as on liver function, to provide a reference for subsequent studies related to the toxicity of PFOS and liver injury caused by PFOS.

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“…4,5,7 It is important to accurately characterize the liver histopathology in HFPO-DA treated mice as claims of steatosis are already making their way into review articles, 2 risk assessments, 3 and discussion sections in primary research articles. 20 Consistent with PPARα activation, hepatocellular hypertrophy was evident in most of the studies (Table 1), and absolute and relative liver weights were increased 2-fold at 5 mg/kg/day (Supplemental Figure S2). This cellular hypertrophy leads to increased liver size and possibly focal necrosis due to compression against the capsule or adjacent organs that can cause focal hypoxia and cell death as the blood supply of the liver is limited just below the capsule.…”

Section: Discussionmentioning

confidence: 70%

Assessment of Mouse Liver Histopathology Following Exposure to HFPO-DA With Emphasis on Understanding Mechanisms of Hepatocellular Death

et al. 2023

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Ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate (HFPO-DA) is a short chain member of per- and polyfluoroalkyl substances (PFAS). To better understand the relevance of histopathological effects seen in livers of mice exposed to HFPO-DA for human health risk assessment, histopathological effects were summarized from hematoxylin and eosin (H&E)-stained sections in several repeat-dose toxicity studies in mice. Findings across studies revealed histopathological changes consistent with peroxisomal proliferation, whereas two reports of steatosis could not be confirmed in the published figures. In addition, mechanisms of hepatocellular death were assessed in H&E sections as well as with the apoptotic marker cleaved caspase-3 (CCasp3) in newly cut sections from archived liver blocks from select studies. A comparison of serially CCasp3 immunolabeled and H&E-stained sections revealed that mechanisms of hepatocellular death cannot be clearly discerned in H&E-stained liver sections alone as several examples of putatively necrotic cells were positive for CCasp3. Published whole genome transcriptomic data were also reevaluated for enrichment of various forms of hepatocellular death in response to HFPO-DA, which revealed enrichment of apoptosis and autophagy, but not ferroptosis, pyroptosis, or necroptosis. These morphological and molecular findings are consistent with transcriptomic evidence for peroxisome proliferator-activated receptor alpha (PPARα) signaling in HFPO-DA exposed mice.

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Replacement per- and polyfluoroalkyl substances (PFAS) are potent modulators of lipogenic and drug metabolizing gene expression signatures in primary human hepatocytes

Cited by 32 publications

References 59 publications

Exposure to low-dose perfluorooctanoic acid promotes hepatic steatosis and disrupts the hepatic transcriptome in mice

Exposure to low-dose perfluorooctanoic acid promotes hepatic steatosis and disrupts the hepatic transcriptome in mice

Adverse Effects of Perfluorooctane Sulfonate on the Liver and Relevant Mechanisms

Assessment of Mouse Liver Histopathology Following Exposure to HFPO-DA With Emphasis on Understanding Mechanisms of Hepatocellular Death

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