Environmental perfluoroalkyl acid exposures are associated with liver disease characterized by apoptosis and altered serum adipocytokines

Bassler, John; Ducatman, Alan; Elliott, Meenal; Wen, Sijin; Wahlang, Banrida; Barnett, John B.; Cave, Matthew C.

doi:10.1016/j.envpol.2019.01.064

Cited by 151 publications

(88 citation statements)

References 57 publications

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“…(Mora et al 2018) In studies examining other markers of liver injury, positive associations were reported between PFAS (including PFOA and PFHxS) and cytokeratin 18, a marker for liver apoptosis, but inverse relationships were reported between PFAS and serum pro-inflammatory cytokines in adults. (Bassler et al 2019)…”

Section: Discussionmentioning

confidence: 99%

“…(Fromme et al 2009) Animal studies show that PFAS exposure to rodents causes liver enlargement, hepatocellular hypertrophy, elevated liver enzymes, and hepatic steatosis. (Das et al 2017; Martin et al 2007; Son et al 2008; Wan et al 2012; Wang, L. et al 2013; Wu et al 2017; Wu et al 2018) Recent cross-sectional studies in adults showed that elevated serum concentrations of PFOA were associated with increased levels of alanine aminotransferase (ALT), a surrogate marker for NAFLD (Gleason et al 2015; Lin et al 2010), and cytokeratin 18, a marker for liver apoptosis (Bassler et al 2019) Children are reported to have increased burden of PFAS exposure relative to body size (Morck et al 2015); however, there are few studies investigating PFAS hepatotoxicity in children. The only study published to date found negative associations of prenatal and childhood plasma PFAS concentrations with ALT levels at age 8 years.…”

Section: Introductionmentioning

confidence: 99%

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Perfluoroalkyl substances and severity of nonalcoholic fatty liver in Children: An untargeted metabolomics approach

Jin

McConnell

Catherine

et al. 2020

Environment International

155

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Background: Toxicant-associated steatohepatitis has been described in adults but less is known regarding the role of toxicants in liver disease of children. Perfluoroalkyl substances (PFAS) cause hepatic steatosis in rodents, but few previous studies have examined PFAS effects on severity of liver injury in children. Objectives: We aimed to examine the relationship of PFAS to histologic severity of nonalcoholic fatty liver disease (NAFLD) in children. Methods: Seventy-four children with physician-diagnosed NAFLD were recruited from Children’s Healthcare of Atlanta between 2007 and 2015. Biopsy-based liver histological features were scored for steatosis, lobular and portal inflammation, ballooning, and fibrosis. Plasma concentrations of perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonic acid (PFHxS), and untargeted plasma metabolomic profiling, were determined using liquid chromatography with high-resolution mass spectrometry. A metabolome-wide association study coupled with pathway enrichment analysis was performed to evaluate metabolic dysregulation associated with PFAS. A structural integrated analysis was applied to identify latent clusters of children with more severe form of NAFLD based on their PFAS levels and metabolite pattern. Results: Patients were 7-19 years old, mostly boys (71%), Hispanic (51%), and obese (85%). The odds of having nonalcoholic steatohepatitis (NASH), compared to children with steatosis alone, was significantly increased with each interquartile range (IQR) increase of PFOS (OR: 3.32, 95% CI: 1.40-7.87) and PFHxS (OR: 4.18, 95% CI: 1.64-10.7). Each IQR increase of PFHxS was associated with increased odds for liver fibrosis (OR: 4.44, 95% CI: 1.34-14.8), lobular inflammation (OR: 2.87, 95% CI: 1.12-7.31), and higher NAFLD activity score (β coefficient 0.46; 95% CI: 0.03, 0.89). A novel integrative analysis identified a cluster of children with NASH, characterized by increased PFAS levels and altered metabolite patterns including higher plasma levels of phosphoethanolamine, tyrosine, phenylalanine, aspartate and creatine, and decreased plasma levels of betaine. Conclusions: Higher PFAS exposure was associated with more severe disease in children with NAFLD. PFAS may be an important toxicant contributing to NAFLD progression; however larger, longitudinal studies are warranted to confirm these findings.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Perfluoroalkyl substances and severity of nonalcoholic fatty liver in Children: An untargeted metabolomics approach

Jin

McConnell

Catherine

et al. 2020

Environment International

155

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“…[38][39][40][41] Studies also indicate that exposure is associated with metabolic effects, ulcerative colitis and adverse effects on liver and kidney function. [42][43][44][45] Several firefighter biomonitoring studies measured PFAS levels and found higher levels among firefighters compared to the general population. 25,27,28 These studies, however, included few or no women.…”

Section: Introductionmentioning

confidence: 99%

Exposure to perfluoroalkyl substances in a cohort of women firefighters and office workers in San Francisco

Trowbridge

Gerona

Lin

et al. 2019

Preprint

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Background: Studies in male firefighters have demonstrated increased exposures to carcinogenic compounds and increased rates of certain cancers compared to the general population. Many chemicals related to these occupational exposures have been associated with breast tumor development in animal and human studies, yet, there have been no studies on women firefighters due to their low numbers in most fire departments. To address this data gap, the Women Firefighters Biomonitoring Collaborative (WFBC) created a biological sample archive and analyzed levels of perfluoroalkyl substances (PFAS) among women firefighters and office workers in San Francisco. Methods: Active duty women firefighters (n=86) and office workers (n=84) were recruited from the San Francisco Fire Department and the City and County of San Francisco, respectively. Serum samples were collected and analyzed using liquid chromatography tandem mass spectrometry (LC MS/MS) to measure and compare PFAS levels between firefighters and office workers. For PFAS congeners detected in at least 70% of our study population, we examined differences in serum PFAS levels controlling for dietary, demographic and other confounders. Among firefighters, we assessed associations between occupational activities and PFAS levels. Results: Eight of 12 PFAS congeners were detected at levels above the limit of detection and seven were detected in at least 70% of the study population. Four PFAS were detected in all study participants (PFNA, PFOA, PFOS, PFHxS). In regression models comparing PFAS levels by occupation and adjusting for potential confounders, firefighters had higher geometric mean (GM) concentrations of PFAS compared to office workers: 2.39 (95%CI = 1.64,3.48), 2.32 (95% CI = 1.17,4.62) and 1.26 (95% CI = 0.99, 1.59) times higher for PFHxS, PFUnDA and PFNA, respectively. In analyses limited to firefighters, PFAS levels varied by assigned position in the fire department. Firefighters and officers had higher PFNA, PFOA, PFDA, and PFUnDA compared to drivers. Additionally, firefighters who reported having used firefighting foam had higher concentrations of PFOA compared firefighters who reported never having used foam. Conclusion: Our study found ubiquitous exposures to PFAS among WFBC participants, with women firefighters exposed to higher levels of some PFAS compared to office workers, suggesting that some of these exposures may be occupationally related.

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“…In humans, several studies have shown that elevated levels of PFASs are linked to altered levels of markers of liver function, such as ALP, ALT, AST, and GGT. 42 43 44 …”

Section: Pfas and Liver Fatmentioning

confidence: 99%

“…In two hundred individuals in the C8 Health Study, several of the PFASs—PFHxS, PFOA, PFNA—were related to circulating levels of cytokeratin 18 M30, a marker of liver cell apoptosis. 42 However, we are still lacking studies clearly showing that background exposure to PFAS in the general population will induce NAFLD.…”

Section: Pfas and Liver Fatmentioning

confidence: 99%

Are Persistent Organic Pollutants Linked to Lipid Abnormalities, Atherosclerosis and Cardiovascular Disease? A Review

Lind

2020

J Lipid Atheroscler

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The term persistent organic pollutants (POPs) denotes chemicals with known or suspected adverse health effects in animals or humans and with chemical properties that make them accumulate in the environment, including animals or humans. Lipid-soluble POPs, like dioxins, polychlorinated biphenyls (PCBs) and organochlorine pesticides are transported by lipoproteins and accumulate in adipose tissue. High levels of these compounds in the circulation have been associated with elevated cholesterol and triglycerides in crosssectional studies and with an increase in mainly low-density lipoprotein cholesterol in a longitudinal study. Also, non-lipid-soluble POPs, such as perfluoroalkyl substances (PFASs) compounds have been associated with increased total cholesterol levels. Carotid artery atherosclerosis has been related to elevated levels of mainly highly chlorinated PCBs and to highly fluorinated PFASs, but in this case only in women. Both cross-sectional and prospective studies have shown dioxins, PCBs, as well as PFASs to be linked to cardiovascular disease (CVD) and mortality. In conclusion, as highlighted in this review, several lines of evidence support the view that POPs of different chemical classes could be linked to lipid abnormalities, carotid atherosclerosis and overt CVD like myocardial infarction and stroke.

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Environmental perfluoroalkyl acid exposures are associated with liver disease characterized by apoptosis and altered serum adipocytokines

Cited by 151 publications

References 57 publications

Perfluoroalkyl substances and severity of nonalcoholic fatty liver in Children: An untargeted metabolomics approach

Perfluoroalkyl substances and severity of nonalcoholic fatty liver in Children: An untargeted metabolomics approach

Exposure to perfluoroalkyl substances in a cohort of women firefighters and office workers in San Francisco

Are Persistent Organic Pollutants Linked to Lipid Abnormalities, Atherosclerosis and Cardiovascular Disease? A Review

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