RESUMEN
To address the growing epidemic of liver disease, particularly in pediatric populations, it is crucial to identify modifiable risk factors for the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Per- and polyfluoroalkyl substances (PFAS) are persistent ubiquitous chemicals and have emerged as potential risk factors for liver damage. However, their impact on the etiology and severity of MASLD remains largely unexplored in humans. This study aims to bridge the gap between human and in vitro studies to understand how exposure to perfluoroheptanoic acid (PFHpA), one of the emerging PFAS replacements which accumulates in high concentrations in the liver, contributes to MASLD risk and progression. First, we showed that PFHpA plasma concentrations were significantly associated with increased risk of MASLD in obese adolescents. Further, we examined the impact of PFHpA on hepatic metabolism using 3D human liver spheroids and single-cell transcriptomics to identify major hepatic pathways affected by PFHpA. Next, we integrated the in vivo and in vitro multi-omics datasets with a novel statistical approach which identified signatures of proteins and metabolites associated with MASLD development triggered by PFHpA exposure. In addition to characterizing the contribution of PFHpA to MASLD progression, our study provides a novel strategy to identify individuals at high risk of PFHpA-induced MASLD and develop early intervention strategies. Notably, our analysis revealed that the proteomic signature exhibited a stronger correlation between both PFHpA exposure and MASLD risk compared to the metabolomic signature. While establishing a clear connection between PFHpA exposure and MASLD progression in humans, our study delved into the molecular mechanisms through which PFHpA disrupts liver metabolism. Our in vitro findings revealed that PFHpA primarily impacts lipid metabolism, leading to a notable increase of lipid accumulation in human hepatocytes after PFHpA exposure. Among the pathways involved in lipid metabolism in hepatocytes, regulation of lipid metabolism by PPAR-a showed a remarkable activation. Moreover, the translational research framework we developed by integrating human and in vitro data provided us biomarkers to identify individuals at a high risk of MASLD due to PFHpA exposure. Our framework can inform policies on PFAS-induced liver disease and identify potential targets for prevention and treatment strategies.
RESUMEN
Per- and polyfluoroalkyl substances (PFAS) are a diverse group of fluorinated compounds which have yet to undergo comprehensive investigation regarding potential adverse health effects and bioaccumulative properties. With long half-lives and accumulative properties, PFAS have been linked to several toxic effects in both non-clinical species such as rat and mouse as well as human. Although biological impacts and specific protein binding of PFAS have been examined, there is no study focusing on the species-specific fraction unbound (fu) in plasma and related toxicokinetics. Herein, a presaturation equilibrium dialysis method was used to measure and validate the binding of 14 individual PFAS with carbon chains containing 4 to 12 perfluorinated carbon atoms and several functional head-groups to albumin and plasma of mouse (C57BL/6 and CD-1), rat, and human. Equivalence testing between each species-matrix combination showed positive correlation between rat and human when comparing fu in plasma and binding to albumin. Similar trends in binding were also observed for mouse plasma and albumin. Relatively high Spearman correlations for all combinations indicate high concordance of PFAS binding regardless of matrix. Physiochemical properties of PFAS such as molecular weight, chain length, and lipophilicity were found to have important roles in plasma protein binding of PFAS.
RESUMEN
Exposure to per- and poly-fluoroalkyl substances (PFAS) is ubiquitous due to their persistence in the environment and in humans. Extreme weight loss has been shown to influence concentrations of circulating persistent organic pollutants (POPs). Using data from the multi-center perspective Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) cohort, we investigated changes in plasma-PFAS in adolescents after bariatric surgery. Adolescents (Mean age = 17.1 years, SD = 1.5 years) undergoing bariatric surgery were enrolled in the Teen-LABS study. Plasma-PFAS were measured at the time of surgery and then 6-, 12-, and 36 months post-surgery. Linear mixed effect models were used to evaluate longitudinal changes in plasma-PFAS after the time of bariatric surgery. This study included 214 adolescents with severe obesity who had available longitudinal measures of plasma-PFAS and underwent bariatric surgery between 2007 and 2012. Underlying effects related to undergoing bariatric surgery were found to be associated with an initial increase or plateau in concentrations of circulating PFAS up to 6 months after surgery followed by a persistent decline in concentrations of 36 months (p < 0.001 for all plasma-PFAS). Bariatric surgery in adolescents was associated with a decline in circulating PFAS concentrations. Initially following bariatric surgery (0-6 months) concentrations were static followed by decline from 6 to 36 months following surgery. This may have large public health implications as PFAS are known to be associated with numerous metabolic related diseases and the significant reduction in circulating PFAS in individuals who have undergone bariatric surgery may be related to the improvement of such metabolic related diseases following bariatric surgery.
Asunto(s)
Cirugía Bariátrica , Contaminantes Ambientales , Humanos , Adolescente , Masculino , Femenino , Estudios Longitudinales , Contaminantes Ambientales/sangre , Exposición a Riesgos Ambientales/estadística & datos numéricos , Fluorocarburos/sangre , Obesidad Mórbida/cirugía , Obesidad Mórbida/sangreRESUMEN
Per- and polyfluoroalkyl substances (PFAS) are a diverse class of highly persistent anthropogenic chemicals that are detectable in the serum of most humans. PFAS exposure has been associated with many adverse effects on human health including immunotoxicity, increased risk of certain cancers, and metabolic disruption. PFAS binding to the most abundant blood serum proteins (human serum albumin [HSA] and globulins) is thought to affect transport to active sites, toxicity, and elimination half-lives. However, few studies have investigated the competitive binding of PFAS to these proteins in human serum. Here, we use C18 solid-phase microextraction fibers to measure HSA-water and globulin-water distribution coefficients (DHSA/w, Dglob/w) for PFAS with carbon chains containing 4 to 13 perfluorinated carbons (ηpfc = 4-13) and several functional head-groups. PFAS with ηpfc < 7 were highly bound to HSA relative to globulins, whereas PFAS with ηpfc ≥ 7 showed a greater propensity for binding to globulins. Experimentally measured DHSA/w and Dglob/w and concentrations of serum proteins successfully predicted the variability in PFAS binding in human serum. We estimated that the unbound fraction of serum PFAS varied by up to a factor of 2.5 among individuals participating in the 2017-2018 U.S. National Health and Nutrition Examination Survey. These results suggest that serum HSA and globulins are important covariates for epidemiological studies aimed at understanding the effects of PFAS exposure.
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Ácidos Alcanesulfónicos , Agua Potable , Contaminantes Ambientales , Fluorocarburos , Globulinas , Humanos , Toxicocinética , Encuestas Nutricionales , Fluorocarburos/toxicidad , Fluorocarburos/análisis , Proteínas Sanguíneas , Carbono , Ácidos Alcanesulfónicos/análisis , Contaminantes Ambientales/análisisRESUMEN
In standardized sediment toxicity tests, the applied water exchange methods range from static to flow-through conditions and vary between protocols and laboratories even for the same test species. This variation potentially results in variable chemical exposure, hampering the interpretation of toxicity and bioaccumulation. To address these issues, we performed sediment toxicity tests with a mixture of three polycyclic aromatic hydrocarbons (PAHs) and the freshwater epibenthic amphipod Hyalella azteca as model chemicals and organism, respectively. Five standardized water exchange methods were applied: static, semi-static, or flow-through conditions. By measuring total (Cdiss) and freely dissolved concentrations (Cfree) of PAHs with water sampling and direct immersion solid-phase microextraction methods, respectively, we found that Cdiss in overlying water differed by a factor of up to 107 among water exchange conditions, whereas both Cdiss and Cfree in pore water did not differ by more than a factor of 2.6. Similar survival rates, growth rates, and bioaccumulation of PAHs between water exchange methods suggest that H. azteca was predominantly exposed to pore water rather than overlying water. By applying mechanistic kinetic modeling to simulate spatiotemporal concentration profiles in sediment toxicity tests, we discuss the importance of the water exchange rates and resulting temporal and spatial exposure variability for the extrapolation of laboratory sediment toxicity to field conditions, particularly for chemicals with relatively low hydrophobicity and sediments with low organic carbon content.
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Anfípodos , Hidrocarburos Policíclicos Aromáticos , Contaminantes Químicos del Agua , Animales , Agua , Bioacumulación , Pruebas de Toxicidad , Hidrocarburos Policíclicos Aromáticos/toxicidad , Hidrocarburos Policíclicos Aromáticos/análisis , Compuestos Orgánicos/toxicidad , Interacciones Hidrofóbicas e Hidrofílicas , Sedimentos Geológicos/química , Contaminantes Químicos del Agua/análisisRESUMEN
Understanding the changes in the temporal and spatial concentrations of chemical substances in sediment toxicity tests facilitates interpretation of their toxicity and accumulation in benthic organisms because benthic organisms are affected by chemicals via multiple exposure pathways. However, such investigations using chronic sediment toxicity tests have rarely been performed. To examine the concentration profiles of a hydrophobic organic chemical using chronic spiked-sediment toxicity tests, we performed 28-day sediment toxicity tests of fluoranthene with a freshwater amphipod, Hyalella azteca, using a semi-flow-through system and compared the results with those of 10-day tests. In these experiments, we measured various types of fluoranthene concentrations over the test periods: total dissolved (Cdiss ) and freely dissolved (Cfree ) concentrations in overlying water and porewater as well as sediment concentrations. We also examined which concentration correlated with the amphipod bioconcentration factor (BCF). We found that both overlying water and porewater Cfree did not differ significantly on days 10 and 28. Sediment concentrations remained almost stable for 28 days, whereas Cdiss in overlying water varied temporally. These results suggest that the 28-day test provides almost constant concentrations of fluoranthene, particularly in porewater, even in a semi-flow-through system. In addition, the comparison of BCF of fluoranthene on day 10 in the present study with that obtained from water-only tests reported in the literature suggested that Cfree in pore water was the most representative indicator of bioaccumulation in H. azteca. Our findings support the possible use of a water-exchange system in chronic spiked-sediment toxicity tests of hydrophobic organic chemicals. However, further studies using sediments and chemicals with different properties are warranted to generalize the findings of the present study. Environ Toxicol Chem 2022;41:2679-2687. © 2022 SETAC.
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Anfípodos , Contaminantes Químicos del Agua , Animales , Anfípodos/metabolismo , Bioacumulación , Sedimentos Geológicos/química , Contaminantes Químicos del Agua/análisis , Compuestos Orgánicos/metabolismo , Agua/metabolismoRESUMEN
Chemical exposure in flow-through sediment toxicity tests can vary in time, between pore and overlying water, and amid free and bound states, complicating the link between toxicity and observable concentrations such as free pore (Cfree,pore), free overlying (Cfree,over), or the corresponding dissolved concentrations (Cdiss, free + bound to dissolved organic carbon, DOC). We introduce a numerical model that describes the desorption from sediments to pore water, diffusion through pores and the sediment-water boundary, DOC-mediated transport, and mixing in and outflow from overlying water. The model explained both the experimentally measured gap between Cfree,over and Cfree,pore and the continuous decrease in overlying Cdiss. Spatially resolved modeling suggested a steep concentration gradient present in the upper millimeter of the sediment due to slow chemical diffusion in sediment pores and fast outflux from the overlying water. In contrast to continuous decrease in overlying Cdiss expected for any chemical, Cfree,over of highly hydrophobic chemicals was kept relatively constant following desorption from DOC, a mechanism comparable to passive dosing. Our mechanistic analyses emphasize that exposure will depend on the chemical's hydrophobicity, the test organism habitat and uptake of bound chemicals, and the properties of sediment components, including DOC. The model can help to re-evaluate existing toxicity data, optimize experimental setups, and extrapolate laboratory toxicity data to field exposure.
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Sedimentos Geológicos , Contaminantes Químicos del Agua , Monitoreo del Ambiente , Pruebas de Toxicidad , Agua , Contaminantes Químicos del Agua/análisis , Contaminantes Químicos del Agua/toxicidadRESUMEN
The sediment-water interface of spiked-sediment toxicity tests is a complex exposure system, where multiple uptake pathways exist for benthic organisms. The freely dissolved concentration (Cfree ) in sediment porewater has been proposed as a relevant exposure metric to hydrophobic organic contaminants (HOCs) in this system. However, Cfree has rarely been measured in spiked-sediment toxicity tests. We first developed a direct immersion solid-phase microextraction method for measuring Cfree in overlying water and porewater in a sediment test using polydimethylsiloxane-coated glass fibers, resulting in sensitive and repeatable in situ measurements of HOCs. Then, we measured Cfree and total dissolved concentrations (Cdiss ) in the sediment test systems with the freshwater amphipod Hyalella azteca and thoroughly evaluated the temporal and spatial profiles of four HOCs (phenanthrene, pyrene, benzo[a]pyrene, and chlorpyrifos). Furthermore, we examined the relationship between the measured concentrations and the lethality of H. azteca. We found that the test system was far from an equilibrium state for all four chemicals tested, where Cdiss in overlying water changed over the test duration and a vertical Cfree gradient existed at the sediment-water interface. In porewater Cdiss was larger than Cfree by a factor of 170 to 220 for benzo[a]pyrene because of the strong binding to dissolved organic carbon. Comparison of the median lethal concentrations of chlorpyrifos in the sediment test and those in water-only tests indicates that Cfree in porewater was the most representative indicator for toxicity of this chemical. The method and findings presented in the present study warrant further research on the chemical transport mechanisms and the actual exposure in sediment tests using different chemicals, sediments, and test species. Environ Toxicol Chem 2021;40:3148-3158. © 2021 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.