Association of exposure to per- and polyfluoroalkyl substances with liver injury in American adults

Abstract

Epidemiological data are scarce regarding the association of exposure to mixtures of per- and polyfluoroalkyl substances (PFASs) with liver injury in the general population. In the current study, therefore, we examined data from the National Health and Nutrition Examination Survey (2009-2018). The PFAS exposure levels were defined by the serum concentrations of PFASs with over 70% detection in samples, namely perfluorooctanoic acid, perfluorononanoic acid, perfluorohexane sulfonic acid, perfluorodecanoic acid, and perfluorooctane sulfonic acid (PFOS). We evaluated liver injury from two aspects: first, the degree of liver inflammation was determined based on levels of the serum alanine aminotransferase, aspartate aminotransferase, glutamyltransferase, and total bilirubin; second, the degree of liver fibrosis was determined based on the fibrosis-4 index. We assessed the associations of individual or total PFAS exposure with these liver injury outcomes using multivariable linear and logistic regression models, restricted cubic splines, and weighted quantile sum regression. Among the samples of 7484 American adults, the median concentration of PFOS was the highest, followed by perfluorooctanoic acid and perfluorohexane sulfonic acid. Using multivariable linear regression, we observed positive correlations between all PFAS exposure and liver enzyme levels, such as alanine aminotransferase, aspartate aminotransferase, and total bilirubin. Additionally, the weighted quantile sum model indicated an overall positive association between exposure to the five PFASs and liver injury risk. For liver function biomarkers and liver fibrosis, perfluorononanoic acid and PFOS were the most heavily weighted chemicals, respectively. Our findings provide new epidemiological evidence indicating potential associations between PFAS exposure and adverse effects on liver injury biomarkers, highlighting the potentially harmful effects of PFAS exposure on human liver health.

Keywords

PFASs / NHANES / liver function / WQS / liver injury

Fundings

This work received no funding from any source.

Acknowledgments

None.

References

[1] Kostallari E, Valainathan S, Biquard L, et al. Role of extracellular vesicles in liver diseases and their therapeutic potential[J]. Adv Drug Deliv Rev, 2021, 175: 113816. doi: 10.1016/j.addr.2021.05.026

[2] Li R, Zhan W, Ren J, et al. Associations between organophosphate esters concentrations and markers of liver function in US adolescents aged 12-19 years: a mixture analysis[J]. Environ Pollut, 2022, 314: 120255. doi: 10.1016/j.envpol.2022.120255

[3] Zhang Y, Mustieles V, Sun Y, et al. Association between serum per- and polyfluoroalkyl substances concentrations and common cold among children and adolescents in the United States[J]. Environ Int, 2022, 164: 107239. doi: 10.1016/j.envint.2022.107239

[4] Faithfull NS, Weers JG. Perfluorocarbon compounds[J]. Vox Sang, 1198, 74(Suppl 2): 243-248. doi: 10.1111/j.1423-0410.1998.tb05426.x

[5] Colicino E, Pedretti NF, Busgang SA, et al. Per- and poly-fluoroalkyl substances and bone mineral density: results from the Bayesian weighted quantile sum regression[J]. Environ Epidemiol, 2020, 4(3): e092. doi: 10.1097/EE9.0000000000000092

[6] Kirk AB, Plasse KM, Kirk KC, et al. Predicting exposure to perfluorinated alkyl substances (PFAS) among US infants[J]. Int J Environ Res Public Health, 2022, 19(14): 8402. doi: 10.3390/ijerph19148402

[7] Schlezinger JJ, Hyötyläinen T, Sinioja T, et al. Perfluorooctanoic acid induces liver and serum dyslipidemia in humanized PPARα mice fed an American diet[J]. Toxicol Appl Pharmacol, 2021, 426: 115644. doi: 10.1016/j.taap.2021.115644

[8] Roth K, Yang Z, Agarwal M, et al. Exposure to a mixture of legacy, alternative, and replacement per- and polyfluoroalkyl substances (PFAS) results in sex-dependent modulation of cholesterol metabolism and liver injury[J]. Environ Int, 2021, 157: 106843. doi: 10.1016/j.envint.2021.106843

[9] Das KP, Wood CR, Lin MT, et al. Perfluoroalkyl acids-induced liver steatosis: effects on genes controlling lipid homeostasis[J]. Toxicology, 2017, 378: 37-52. doi: 10.1016/j.tox.2016.12.007

[10] Borg D, Lund BO, Lindquist NG, et al. Cumulative health risk assessment of 17 perfluoroalkylated and polyfluoroalkylated substances (PFASs) in the Swedish population[J]. Environ Int, 2013, 59: 112-123. doi: 10.1016/j.envint.2013.05.009

[11] Liu J, Cui X, Tan Y, et al. Per- and perfluoroalkyl substances alternatives, mixtures and liver function in adults: a community-based population study in China[J]. Environ Int, 2022, 163: 107179. doi: 10.1016/j.envint.2022.107179

[12] Bai J, Ma Y, Zhao Y, et al. Mixed exposure to phenol, parabens, pesticides, and phthalates and insulin resistance in NHANES: a mixture approach[J]. Sci Total Environ, 2022, 851(Pt 2): 158218.

[13] Gu L, Wang Z, Pan Y, et al. Associations between mixed urinary phenols and parabens metabolites and bone mineral density: four statistical models[J]. Chemosphere, 2023, 311(Pt 2): 137065.

[14] Li W, Xiao H, Wu H, et al. Organophosphate pesticide exposure and biomarkers of liver injury/liver function[J]. Liver Int, 2022, 42(12): 2713-2723. doi: 10.1111/liv.15461

[15] Malin AJ, Lesseur C, Busgang SA, et al. Fluoride exposure and kidney and liver function among adolescents in the United States: NHANES, 2013-2016[J]. Environ Int, 2019, 132: 105012. doi: 10.1016/j.envint.2019.105012

[16] Gazzin S, Vitek L, Watchko J, et al. A novel perspective on the biology of bilirubin in health and disease[J]. Trends Mol Med, 2016, 22(9): 758-768. doi: 10.1016/j.molmed.2016.07.004

[17] Yu L, Yang M, Cheng M, et al. Associations between urinary phthalate metabolite concentrations and markers of liver injury in the US adult population[J]. Environ Int, 2021, 155: 106608. doi: 10.1016/j.envint.2021.106608

[18] Golabi P, Paik JM, Harring M, et al. Prevalence of high and moderate risk nonalcoholic fatty liver disease among adults in the United States, 1999-2016[J]. Clin Gastroenterol Hepatol, 2022, 20(12): 2838-2847.e7.

[19] Wen X, Wang M, Xu X, et al. Exposure to per- and polyfluoroalkyl substances and mortality in U.S. adults: a population-based cohort study[J]. Environ Health Perspect, 2022, 130(6): 067007. doi: 10.1289/EHP10393

[20] Jain RB, Wang RY. Limitations of maximum likelihood estimation procedures when a majority of the observations are below the limit of detection[J]. Anal Chem, 2008, 80(12): 4767-4772. doi: 10.1021/ac8003743

[21] Jain RB, Caudill SP, Wang RY, et al. Evaluation of maximum likelihood procedures to estimate left censored observations[J]. Anal Chem, 2008, 80(4): 1124-1132. doi: 10.1021/ac0711788

[22] Shi Y, Wang H, Zhu Z, et al. Association between exposure to phenols and parabens and cognitive function in older adults in the United States: a cross-sectional study[J]. Sci Total Environ, 2023, 858(Pt 3): 160129.

[23] Zhang F, Wang H, Cui Y, et al. Association between mixed dioxin exposure and hyperuricemia in U.S. adults: a comparison of three statistical models[J]. Chemosphere, 2022, 303(Pt 3): 135134.

[24] Zhang Y, Xing H, Hu Z, et al. Independent and combined associations of urinary arsenic exposure and serum sex steroid hormones among 6-19-year old children and adolescents in NHANES 2013-2016[J]. Sci Total Environ, 2023, 863: 160883. doi: 10.1016/j.scitotenv.2022.160883

[25] Eggers S, Gennings C, Malecki KMC, et al. Exposure to environmental chemical mixtures is associated with nasal colonization by Staphylococcus aureus: NHANES 2001-2004[J]. Environ Res, 2020, 190: 109994. doi: 10.1016/j.envres.2020.109994

[26] Kim OJ, Kim S, Park EY, et al. Exposure to serum perfluoroalkyl substances and biomarkers of liver function: the Korean national environmental health survey 2015-2017[J]. Chemosphere, 2023, 322: 138208. doi: 10.1016/j.chemosphere.2023.138208

[27] Brennan NM, Evans AT, Fritz MK, et al. Trends in the regulation of per- and polyfluoroalkyl substances (PFAS): a scoping review[J]. Int J Environ Res Public Health, 2021, 18(20): 10900. doi: 10.3390/ijerph182010900

[28] Costello E, Rock S, Stratakis N, et al. Exposure to per- and polyfluoroalkyl substances and markers of liver injury: a systematic review and meta-analysis[J]. Environ Health Perspect, 2022, 130(4): 046001. doi: 10.1289/EHP10092

[29] Butenhoff JL, Chang SC, Ehresman DJ, et al. Evaluation of potential reproductive and developmental toxicity of potassium perfluorohexanesulfonate in Sprague Dawley rats[J]. Reprod Toxicol, 2009, 27(3-4): 331-341. doi: 10.1016/j.reprotox.2009.01.004

[30] Wahlang B, Jin J, Beier JI, et al. Mechanisms of environmental contributions to fatty liver disease[J]. Curr Environ Health Rep, 2019, 6(3): 80-94. doi: 10.1007/s40572-019-00232-w

[31] Schlezinger JJ, Puckett H, Oliver J, et al. Perfluorooctanoic acid activates multiple nuclear receptor pathways and skews expression of genes regulating cholesterol homeostasis in liver of humanized PPARα mice fed an American diet[J]. Toxicol Appl Pharmacol, 2020, 405: 115204. doi: 10.1016/j.taap.2020.115204

[32] Zhang Y, Zhang Y, Klaassen CD, et al. Alteration of bile acid and cholesterol biosynthesis and transport by perfluorononanoic acid (PFNA) in mice[J]. Toxicol Sci, 2018, 162(1): 225-233. doi: 10.1093/toxsci/kfx237

[33] Marques ES, Agudelo J, Kaye EM, et al. The role of maternal high fat diet on mouse pup metabolic endpoints following perinatal PFAS and PFAS mixture exposure[J]. Toxicology, 2021, 462: 152921. doi: 10.1016/j.tox.2021.152921

[34] Jin R, McConnell R, Catherine C, et al. Perfluoroalkyl substances and severity of nonalcoholic fatty liver in Children: an untargeted metabolomics approach[J]. Environ Int, 2020, 134: 105220. doi: 10.1016/j.envint.2019.105220

[35] Deng P, Wang C, Wahlang B, et al. Co-exposure to PCB126 and PFOS increases biomarkers associated with cardiovascular disease risk and liver injury in mice[J]. Toxicol Appl Pharmacol, 2020, 409: 115301. doi: 10.1016/j.taap.2020.115301

[36] Stratakis N, Conti DV, Jin R, et al. Prenatal exposure to perfluoroalkyl substances associated with increased susceptibility to liver injury in children[J]. Hepatology, 2020, 72(5): 1758-1770. doi: 10.1002/hep.31483

[37] Artacho-Cordón F, León J, Sáenz JM, et al. Contribution of persistent organic pollutant exposure to the adipose tissue oxidative microenvironment in an adult cohort: a multipollutant approach[J]. Environ Sci Technol, 2016, 50(24): 13529-13538. doi: 10.1021/acs.est.6b03783

[38] E L, Zhang S, Jiang X. Association between perfluoroalkyl substances exposure and the prevalence of nonalcoholic fatty liver disease in the different sexes: a study from the National Health and Nutrition Examination Survey 2005-2018[J]. Environ Sci Pollut Res Int, 2023, 30(15): 44292-44303. doi: 10.1007/s11356-023-25258-4

[39] Fenton SE, Ducatman A, Boobis A, et al. Per- and polyfluoroalkyl substance toxicity and human health review: current state of knowledge and strategies for informing future research[J]. Environ Toxicol Chem, 2021, 40(3): 606-630. doi: 10.1002/etc.4890

[40] Jain RB, Ducatman A. Selective associations of recent low concentrations of perfluoroalkyl substances with liver function biomarkers: NHANES 2011 to 2014 data on US adults aged ≥20 years[J]. J Occup Environ Med, 2019, 61(4): 293-302. doi: 10.1097/JOM.0000000000001532

[41] Fabbrini E, Sullivan S, Klein S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications[J]. Hepatology, 2010, 51(2): 679-689. doi: 10.1002/hep.23280