Epigenetic toxicity of PFOA and GenX in HepG2 cells and their role in lipid metabolism

Wen, Yi; Mirji, Niharika; Irudayaraj, Joseph

doi:10.1016/j.tiv.2020.104797

Cited by 72 publications

(43 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In recent in vitro studies, GenX exposure produced toxic effects on rat thyroid cells ( Coperchini et al. 2020 ) and human liver carcinoma cells ( Wen et al. 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Measurement of Novel, Drinking Water-Associated PFAS in Blood from Adults and Children in Wilmington, North Carolina

Kotlarz

McCord

Collier

et al. 2020

Environ Health Perspect

144

110

View full text Add to dashboard Cite

Background: From 1980 to 2017, a fluorochemical manufacturing facility discharged wastewater containing poorly understood per- and polyfluoroalkyl substances (PFAS) to the Cape Fear River, the primary drinking water source for Wilmington, North Carolina, residents. Those PFAS included several fluoroethers including HFPO-DA also known as GenX. Little is known about the bioaccumulation potential of these fluoroethers. Objective: We determined levels of fluoroethers and legacy PFAS in serum samples from Wilmington residents. Methods: In November 2017 and May 2018, we enrolled 344 Wilmington residents of age into the GenX Exposure Study and collected blood samples. Repeated blood samples were collected from 44 participants 6 months after enrollment. We analyzed serum for 10 fluoroethers and 10 legacy PFAS using liquid chromatography–high-resolution mass spectrometry. Results: Participants’ ages ranged from 6 to 86 y, and they lived in the lower Cape Fear Region for 20 y on average (standard deviation: 16 y). Six fluoroethers were detected in serum; Nafion by-product 2, PFO4DA, and PFO5DoA were detected in of participants. PFO3OA and NVHOS were infrequently detected. Hydro-EVE was present in a subset of samples, but we could not quantify it. GenX was not detected above our analytical method reporting limit ( ). In participants with repeated samples, the median decrease in fluoroether levels ranged from 28% for PFO5DoA to 65% for PFO4DA in 6 months due to wastewater discharge control. Four legacy PFAS (PFHxS, PFOA, PFOS, PFNA) were detected in most ( ) participants; these levels were higher than U.S. national levels for the 2015–2016 National Health and Nutrition Examination Survey. The sum concentration of fluoroethers contributed 24% to participants’ total serum PFAS (median: ). Conclusion: Poorly understood fluoroethers released into the Cape Fear River by a fluorochemical manufacturing facility were detected in blood samples from Wilmington, North Carolina, residents. Health implications of exposure to these novel PFAS have not been well characterized. https://doi.org/10.1289/EHP6837

show abstract

“…In recent in vitro studies, GenX exposure produced toxic effects on rat thyroid cells ( Coperchini et al. 2020 ) and human liver carcinoma cells ( Wen et al. 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Measurement of Novel, Drinking Water-Associated PFAS in Blood from Adults and Children in Wilmington, North Carolina

Kotlarz

McCord

Collier

et al. 2020

Environ Health Perspect

144

110

View full text Add to dashboard Cite

show abstract

“…One of these studies has revealed the hypomethylation of glutathione-S-transferase Pi in liver cells [70]. The previous studies from our group have also reported significant alterations in DNA methylation in vitro in HepG2 cells [24] and in vivo in mice kidney and liver tissues [23,26]. However, the effect of PFOA on the epigenetic alterations of intestinal tissues has not been studied to date.…”

Section: Pfoa Alters Expression Of Dna Methylation Genes In the Intestinementioning

confidence: 96%

“…This may also suggest the possibility of a PFOA role in several human pathologies such as liver diseases, cardiovascular diseases, chronic renal disease, and abnormal fetal development. Animal studies have revealed accumulation and distribution of PFOA in tissues leading to several toxicities including neurotoxicity, genotoxicity, nephrotoxicity, epigenetic toxicity, immunotoxicity, reproductive and developmental toxicity, and hepatotoxicity [ 21 , 22 , 23 , 24 , 25 , 26 ]. Studies have shown that PFOA can alter the activities of liver enzymes [ 27 ], cause anti-inflammatory effects by modulating the levels of proinflammatory cytokines [ 28 ], and exert cytotoxic effects on liver and thyroid cells [ 29 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

“…An increase in kidney and testicular cancers was also observed among people living close to chemical plants [ 32 ]. Several studies have demonstrated the alterations in metabolic pathways as a result of PFOA exposure, such as increased oxidative stress and fibrotic markers [ 26 , 33 ], peroxisome proliferator-activated receptor (PPARs) activation [ 34 ], initiation of P450 [ 35 ], altered expression of lipid metabolism and cell cycle genes [ 24 ], and disruption of efflux transporters—for example, Bcrp, which has an important role in the elimination of drugs and environmental chemicals from kidney and liver [ 36 ].…”

Section: Introductionmentioning

confidence: 99%

“…Despite these studies, there is still limited evidence on the toxicity of PFOA on intestinal epigenetics and tight junction (TJ) genes. From our previous studies, we observed significant alterations in mRNA expression of epigenetic genes in liver (HepG2) cells and mice kidney tissues due to acute PFOA exposure which promoted early indicators of fibroblast activation in mice kidney tissues [ 23 , 24 , 25 , 26 ]. The changes in the DNA methylation patterns were also found to be linked with alteration of disease-related genes in inflammatory bowel disease (IBD) and inhibition of various tumor suppressor genes in cancers [ 45 ].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Effect of Perfluorooctanoic Acid on the Epigenetic and Tight Junction Genes of the Mouse Intestine

Rashid

Ahmad

Irudayaraj

2020

Toxics

View full text Add to dashboard Cite

Perfluorooctanoic acid (PFOA) has been implicated in various toxicities including neurotoxicity, genotoxicity, nephrotoxicity, epigenetic toxicity, immunotoxicity, reproductive toxicity, and hepatotoxicity. However, information on the accumulation of PFOA in the intestine and its toxic effects on intestinal epigenetics and tight junction (TJ) genes is sparse. CD1 mice were dosed with PFOA (1, 5, 10, or 20 mg/kg/day) for 10 days, and its accumulation and induced alterations in the expression of epigenetic and tight junction genes in the small intestine and colon were evaluated using LC–MS and qPCR techniques. PFOA reduced the expression levels of DNA methyltransferases (Dnmt1, Dnmt3a, Dnmt3b) primarily in the small intestine whereas, in the colon, a decrease was observed only at high concentrations. Moreover, ten-eleven translocation genes (Tet2 and Tet3) expression was dysregulated in the small intestine, whereas in the colon Tets remained unaffected. The tight junction genes Claudins (Cldn), Occludin (Ocln), and Tight Junction Protein (Tjp) were also heavily altered in the small intestine. TJs responded differently across the gut, in proportion to PFOA dosing. Our study reveals that PFOA triggers DNA methylation changes and alters the expression of genes essential for maintaining the physical barrier of intestine, with more profound effects in the small intestine compared to the colon.

show abstract

Short‐Chain Per/Polyfluoroalkyl Acids (C7 and Below)

Lasee,

Dourson,

Onyema

2024

Patty's Toxicology

View full text Add to dashboard Cite

This chapter is about a series of short‐chain per‐ and polyfluoroalkyl substances (PFAS). In the past, PFAS were described as fluorinated fatty acids or sulfonates. The overall structure of PFAS is a carbon chain with fluorine atoms substituting for hydrogen atoms. The resulting chemicals are chemically stable, water and oil resistant, and useful for many industrial applications, such as in the formation of polymers. The most notorious in this group are the fluorinated fatty acids (carboxylates) or sulfonates. In biological systems, these chemicals are generally well‐absorbed by the oral route and resistant to metabolism but also have the unusual property of having drastically different elimination kinetics between mammalian species. The available literature on this group of PFAS (C7 and below) is modest. This chapter will not attempt to review all this literature. Rather, human studies will be emphasized. Since human studies often suggest associations between PFAS exposure and health outcomes, these studies will be followed by definitive experimental animal studies that give insights into the human evidence. Afterward, a summary of attempts to estimate potential human risk by various international agencies will be described. What will become obvious, however, is that the overall uncertainty in the database of some of these chemicals has led to widely divergent risk assessment positions that need to be resolved. Risk management decisions on specific members of this class of chemistries are seen to be premature without such scientific resolution.

show abstract

Epigenetic toxicity of PFOA and GenX in HepG2 cells and their role in lipid metabolism

Cited by 72 publications

References 56 publications

Measurement of Novel, Drinking Water-Associated PFAS in Blood from Adults and Children in Wilmington, North Carolina

Measurement of Novel, Drinking Water-Associated PFAS in Blood from Adults and Children in Wilmington, North Carolina

Effect of Perfluorooctanoic Acid on the Epigenetic and Tight Junction Genes of the Mouse Intestine

Short‐Chain Per/Polyfluoroalkyl Acids (C7 and Below)

Contact Info

Product

Resources

About