Why is elevation of serum cholesterol associated with exposure to perfluoroalkyl substances (PFAS) in humans? A workshop report on potential mechanisms

Andersen, Melvin E.; Hagenbuch, Bruno; Apte, Udayan; Corton, J. Christopher; Fletcher, Tony; Lau, Christopher; Roth, William L.; Staels, Bart; Vega, Gloria Lena; Clewell, Harvey J.; Longnecker, Matthew P.

doi:10.1016/j.tox.2021.152845

Cited by 58 publications

(41 citation statements)

References 127 publications

(162 reference statements)

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“…In our study, we have included a parameter “Free” to account for the plasma protein binding and the unbound fraction. This approach is also consistent with other PBPK and IVIVE studies. , Another approach to account for this is to use a conversion factor (i.e., 33.3 for PFOA when the plasma binding fraction is 3%) …”

Section: Discussionsupporting

confidence: 73%

“…44,45 Another approach to account for this is to use a conversion factor (i.e., 33.3 for PFOA when the plasma binding fraction is 3%). 61 Fourth, in the HED calculation with reverse dosimetry analysis, the calculation of the dosmetric adjustment factor (DAF) was based on a dose level of 1 mg/kg/day. This dose is higher than the actual human environmental exposure level (usually in the ng/kg/day range).…”

Section: Discussionmentioning

confidence: 99%

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Integration of Toxicogenomics and Physiologically Based Pharmacokinetic Modeling in Human Health Risk Assessment of Perfluorooctane Sulfonate

Chen

Chou

Lin

2022

Environ. Sci. Technol.

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Toxicogenomics and physiologically based pharmacokinetic (PBPK) models are useful approaches in chemical risk assessment, but the methodology to incorporate toxicogenomic data into a PBPK model to inform risk assessment remains to be developed. This study aimed to develop a probabilistic human health risk assessment approach by integrating toxicogenomic dose–response data and PBPK modeling using perfluorooctane sulfonate (PFOS) as a case study. Based on the available human in vitro and mouse in vivo toxicogenomic data, we identified the differentially expressed genes (DEGs) at each exposure paradigm/duration. Kyoto Encyclopedia of Genes and Genomes and disease ontology enrichment analyses were conducted on the DEGs to identify significantly enriched pathways and diseases. The dose–response data of DEGs were analyzed using the Bayesian benchmark dose (BMD) method. Using a previously published PBPK model, the gene BMDs were converted to human equivalent doses (HEDs), which were summarized to pathway and disease HEDs and then extrapolated to reference doses (RfDs) by considering an uncertainty factor of 30 for mouse in vivo data and 10 for human in vitro data. The results suggested that the median RfDs at different exposure paradigms were similar to the 2016 U.S. Environmental Protection Agency’s recommended RfD, while the RfDs for the most sensitive pathways and diseases were closer to the recent European Food Safety Authority’s guidance values. In conclusion, genomic dose–response data and PBPK modeling can be integrated to become a useful alternative approach in risk assessment of environmental chemicals. This approach considers multiple endpoints, provides toxicity mechanistic insights, and does not rely on apical toxicity endpoints.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Integration of Toxicogenomics and Physiologically Based Pharmacokinetic Modeling in Human Health Risk Assessment of Perfluorooctane Sulfonate

Chen

Chou

Lin

2022

Environ. Sci. Technol.

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“…A population study found that plasma PFOA and PFOS exposure were associated with altered transcription levels of genes involved in cholesterol transport or mobilization . Previous experimental studies have also shown that lipid metabolism-related genes may be affected by PFAS exposure, − which impaired bile acid metabolism/synthesis and strongly reduced CYP7A1 enzyme activity, playing a role in PFAS-induced dyslipidemia in humans. ,, Taken together, our study suggests that PFOA and PFOS exposure may cause disturbances in adult cholesterol levels through altered DNA methylation of genes regulating lipid metabolism.…”

Section: Discussionsupporting

confidence: 62%

Plasma PFOA and PFOS Levels, DNA Methylation, and Blood Lipid Levels: A Pilot Study

Cheng

Wei

Zhang

et al. 2022

Environ. Sci. Technol.

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Exposure to perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) is associated with blood lipids in adults, but the underlying mechanisms remain unclear. This pilot study aimed to investigate the associations between PFOA or PFOS and epigenome-wide DNA methylation and assess the mediating effect of DNA methylation on the PFOA/PFOS-blood lipid association. We measured plasma PFOA/PFOS and leukocyte DNA methylation in 98 patients enrolled from the hospital between October 2018 and August 2019. The median plasma PFOA/PFOS levels were 0.85 and 2.29 ng/mL. Plasma PFOA and PFOS levels were significantly associated with elevated total cholesterol (TC) and lowdensity lipoprotein cholesterol (LDL) levels. There were 63/87 CpG positions and 8/11 differentially methylated regions (DMRs) associated with plasma PFOA/PFOS levels, respectively. In addition, 5 CpG positions (annotated to AFF3, CREB5, NRG2, USF2, and intergenic region) and one DMR annotated to IRF6 may mediate the association between plasma PFOA/PFOS and LDL levels (mediated proportion from 7.29 to 46.77%); two CpG positions may mediate the association between plasma PFOA/PFOS and TC levels (annotated to CREB5 and USF2, mediated proportion is around 30%). The data suggest that PFOA/PFOS exposure alters DNA methylation. More importantly, the association of PFOA/ PFOS with lipid indicators was partly mediated by DNA methylation changes in lipid metabolism-related genes.

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“…In particular, PFOS leads to significant downregulation of the gene and protein levels of CYP7A1, the key enzyme that catalyzes the first and rate-limiting step in the synthesis of bile acids from cholesterol [ 107 ]. PFOS causes a decrease in HNF4α protein expression in human hepatocytes, a transcription factor that regulates CYP7A1, and a decrease in CYP7A1 leads to a decrease in bile acid production and an increase in cholesterol ( Figure 2 ) [ 89 , 108 ].…”

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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Why is elevation of serum cholesterol associated with exposure to perfluoroalkyl substances (PFAS) in humans? A workshop report on potential mechanisms

Cited by 58 publications

References 127 publications

Integration of Toxicogenomics and Physiologically Based Pharmacokinetic Modeling in Human Health Risk Assessment of Perfluorooctane Sulfonate

Integration of Toxicogenomics and Physiologically Based Pharmacokinetic Modeling in Human Health Risk Assessment of Perfluorooctane Sulfonate

Plasma PFOA and PFOS Levels, DNA Methylation, and Blood Lipid Levels: A Pilot Study

Adverse Effects of Perfluorooctane Sulfonate on the Liver and Relevant Mechanisms

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