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Effects of chemical mixtures on liver function biomarkers in the Korean adult population: thresholds and molecular mechanisms for non-alcoholic fatty liver disease involved

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Abstract

There is a scarcity of research on the effects of a mixture of chemicals on liver function biomarkers and non-alcoholic fatty liver disease (NAFLD) indices, including FSI, HIS, and FBI-4. Thus, we aimed to explore whether there is an association between chemical mixtures, including 26 chemicals found in blood and urine, liver function biomarkers, and non-alcoholic fatty liver disease (NAFLD) indices in Korean adults. The effects of exposure to chemical mixtures on liver function biomarkers and NAFLD indices were investigated using linear regression models, weighted quantile sum (WQS) regression, quantile g-computation (qgcomp), and Bayesian kernel machine regression (BKMR) among 3669 adults. In silico toxicogenomic data-mining, we evaluated molecular mechanisms associated with NAFLD, including pathways, diseases, genes, miRNAs, and biological processes. The linear regression models showed blood or urine Hg levels were the most important factors associated with AST, ALT, GGT, FSI, and HSI levels, and significant trends were observed for these chemical quartiles (p < 0.01). The WQS index was significantly associated with ALT, GGT, FSI, and HSI. The qgcomp index also found an association between chemicals and AST, ALT, GGT, and FSI. In the BKMR model, the overall effect of the mixture was significantly related to ALT, GGT, FSI, and HSI. In silico analysis, we found mixed chemicals interacted with the CYP1A2 gene and were associated with NAFLD. Seventy-eight percent of interactions were identified as physical interactions in the CYP1A2 gene related to NAFLD. Transcription factor regulation in adipogenesis and lipid metabolic processes are fundamental molecular mechanisms that could be influenced by NAFLD-related mixed chemicals. Cutoff thresholds for chemical exposure levels associated with liver function indicators and NAFLD indices were also reported. The strongest interactions and expression of miRNAs involved in NAFLD development were also identified.

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Data availability

The datasets examined during this study are available on request at the National Institute of Environmental Research, Environmental Health Research Department by dialing + 82–032–560–7129.

Abbreviations

BPb:

Blood lead

BHg:

Blood mercury

UHg:

Urine mercury

UCd:

Urine cadmium

ttMA:

T,t-muconic acid

BMA:

Benzylmercapturic acid

1OHP:

1-Hydroxypyrene

2NAP:

2-Naphthol

2OHFlu:

2-Hydroxyfluorene

1OHPhe:

1-Hydroxyphenanthrene

MEHHP:

Mono-(2-ethyl-5-hydroxyhexyl) phthalate

MEOHP:

Mono-(2-ethyl-5-oxohexyl) phthalate

MnBP:

Mono-n-butyl phthalate

MBzP:

Mono-benzyl phthalate

MECPP:

Mono-(2-ethyl-5-carboxypentyl) phthalate

MCOP:

Mono-carboxyoctyl phthalate

MCNP:

Mono-carboxy-isononly phthalate

MCPP:

Mono (3-carboxypropyl) phthalate

BPA:

Bisphenol A

BPF:

Bisphenol F

BPS:

Bisphenol S

TCS:

Triclosan

MeP:

Methylparaben

EtP:

Ethylparaben

PrP:

Propylparaben

3PBA:

3-Phenoxybenzoic acid

COT:

Cotinine

EDCs:

Endocrine disrupting chemicals

VOCs:

Volatile organic compounds

PAH:

Polycyclic aromatic hydrocarbon

BKMR:

Bayesian kernel machine regression

QWS:

Weighted quantile sum

Qgcomp:

Quantile g-computation

References

  • Abdolahi A, Vahabzadeh Z, Izadpanah E, Moloudi MR (2022) Vaspin attenuates steatosis-induced fibrosis via GRP78 receptor by targeting AMPK signaling pathway. J Physiol Biochem 78:185–197

    Article  CAS  Google Scholar 

  • Alkhouri N, Cikach F, Eng K, Moses J, Patel N, Yan C, Hanouneh I, Grove D, Lopez R, Dweik R. (2014) Analysis of breath volatile organic compounds as a noninvasive tool to diagnose nonalcoholic fatty liver disease in children. Eur J Gastroenterol Hepatol, 26

  • Artacho-Cordón F, Ríos-Arrabal S, León J, Frederiksen H, Sáenz JM, Martín-Olmedo P, Fernández MF, Olea N, Arrebola JP (2019) Adipose tissue concentrations of non-persistent environmental phenols and local redox balance in adults from Southern Spain. Environ Int 133:105118

    Article  Google Scholar 

  • Asrani SK, Devarbhavi H, Eaton J, Kamath PS (2019) Burden of liver diseases in the world. J Hepatol 70:151–171

    Article  Google Scholar 

  • Becker K, Kaus S, Krause C, Lepom P, Schulz C, Seiwert M, Seifert B (2002) German Environmental Survey 1998 (GerES III): environmental pollutants in blood of the German population. Int J Hyg Environ Health 205:297–308

    Article  Google Scholar 

  • Bobb JF, Valeri L, Claus Henn B, Christiani DC, Wright RO, Mazumdar M, Godleski JJ, Coull BA (2015) Bayesian kernel machine regression for estimating the health effects of multi-pollutant mixtures. Biostatistics 16:493–508

    Article  Google Scholar 

  • Cai S, Fan J, Ye J, Rao X, Li Y (2021) Phthalates exposure is associated with non-alcoholic fatty liver disease among US adults. Ecotoxicol Environ Saf 224:112665

    Article  CAS  Google Scholar 

  • Canada H (2010) Report on human biomonitoring of environmental chemicals in Canada. Results of the Canadian Health Measures Survey Cycle 1 (2007–2009). Book Report on human biomonitoring of environmental chemicals in Canada. Results of the Canadian Health Measures Survey Cycle 1 (2007–2009), City: Health Canada Ottawa, Ontario

  • Carrico C, Gennings C, Wheeler DC, Factor-Litvak P (2015) Characterization of Weighted Quantile Sum Regression for Highly Correlated Data in a Risk Analysis Setting. J Agric Biol Environ Stat 20:100–120

    Article  Google Scholar 

  • Cave M, Appana S, Patel M, Falkner KC, McClain CJ, Brock G (2010) Polychlorinated biphenyls, lead, and mercury are associated with liver disease in American adults: NHANES 2003–2004. Environ Health Perspect 118:1735–1742

    Article  CAS  Google Scholar 

  • Cave MC, Clair HB, Hardesty JE, Falkner KC, Feng W, Clark BJ, Sidey J, Shi H, Aqel BA, McClain CJ et al (2016) Nuclear receptors and nonalcoholic fatty liver disease. Biochem Biophys Acta 1859:1083–1099

    CAS  Google Scholar 

  • Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, Sanyal AJ (2018) The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology 67:328–357

    Article  Google Scholar 

  • Chavez-Tapia N-C, Lizardi-Cervera J, Perez-Bautista O, Ramos-Ostos MH, Uribe M (2006) Smoking is not associated with nonalcoholic fatty liver disease. World J Gastroenterol 12:5196–5200

    CAS  Google Scholar 

  • Chen J, Bardes EE, Aronow BJ, Jegga AG (2009) ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucleic Acids Res 37(Web Server issue):W305–W11. https://doi.org/10.1093/nar/gkp427

  • Chung SM, Moon JS, Yoon JS, Won KC, Lee HW (2020) The sex-specific effects of blood lead, mercury, and cadmium levels on hepatic steatosis and fibrosis: Korean nationwide cross-sectional study. J Trace Elem Med Biol 62:126601

    Article  CAS  Google Scholar 

  • Dallio M, Diano N, Masarone M, Gravina AG, Patanè V, Romeo M, Di Sarno R, Errico S, Nicolucci C, Abenavoli L et al (2019) Chemical Effect of Bisphenol A on Non-Alcoholic Fatty Liver Disease. Int J Environ Res Public Health 16:3134

    Article  CAS  Google Scholar 

  • Davis AP, Grondin CJ, Johnson RJ, Sciaky D, Wiegers J, Wiegers TC, Mattingly CJ (2020) Comparative Toxicogenomics Database (CTD): update 2021. Nucleic Acids Res 49:D1138–D1143

    Article  Google Scholar 

  • Dawson PAJPOTGT (2018) Bile formation and the enterohepatic circulation. 931–56

  • Degenhardt L, Fiona C, Alize F, Damian S, Holly E, Ana M-H, Harvey W (2018) The global burden of disease attributable to alcohol and drug use in 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Psychiatry 5:987–1012

    Article  Google Scholar 

  • Donato MT, Lahoz A, Jiménez N, Pérez G, Serralta A, Mir J, Castell JV, Gómez-Lechón MJ (2006) Potential impact of steatosis on cytochrome P450 enzymes of human hepatocytes isolated from fatty liver grafts. Drug Metabolism and Disposition: the Biological Fate of Chemicals 34:1556–1562

    Article  CAS  Google Scholar 

  • Du C, Shen L, Ma Z, Du J, Jin S (2021) Bioinformatic Analysis of Crosstalk Between circRNA, miRNA, and Target Gene Network in NAFLD, 12

  • Duc HN, Oh H, Kim MS (2021a) The effect of mixture of heavy metals on obesity in individuals ≥50 years of age. Biol Trace Elem Res. https://doi.org/10.1007/s12011-021-02972-z

  • Duc HN, Oh H, Kim MS (2021b) Effects of Antioxidant Vitamins, Curry Consumption, and Heavy Metal Levels on Metabolic Syndrome with Comorbidities: A Korean Community-Based Cross-Sectional Study. Antioxidants (Basel), 10

  • Duc HN, Oh H, Yoon IM, Kim M-S (2021c) Association between levels of thiamine intake, diabetes, cardiovascular diseases and depression in Korea: a national cross-sectional study. J Nutr Sci 10:e31

    Article  CAS  Google Scholar 

  • Duc Nguyen H, Hee Jo W, Hong Minh Hoang N, Kim MS (2022a) Anti-inflammatory effects of B vitamins protect against tau hyperphosphorylation and cognitive impairment induced by 1,2 diacetyl benzene: An in vitro and in silico study. Int Immunopharmacol 108:108736. https://doi.org/10.1016/j.intimp.2022.108736

  • Duc Nguyen H, Oh H, Kim MS (2022b) Association between exposure to chemical mixtures in relation to serum total IgE among adults 19-86 years old. Int Immunopharmacol 102:108428. https://doi.org/10.1016/j.intimp.2021.108428

  • Ercal N, Gurer-Orhan H, Aykin-Burns N (2001) Toxic metals and oxidative stress part I: mechanisms involved in metal-induced oxidative damage. Curr Top Med Chem 1:529–539

    Article  CAS  Google Scholar 

  • Eweda SM, Newairy ASA, Abdou HM, Gaber AS (2020) Bisphenol A-induced oxidative damage in the hepatic and cardiac tissues of rats: The modulatory role of sesame lignans. Exp Ther Med 19:33–44

    CAS  Google Scholar 

  • Fisher CD, Lickteig AJ, Augustine LM, Ranger-Moore J, Jackson JP, Ferguson SS, Cherrington NJ (2009) Hepatic cytochrome P450 enzyme alterations in humans with progressive stages of nonalcoholic fatty liver disease. Drug Metab Disposition: Biol Fate Chem 37:2087–2094

    Article  CAS  Google Scholar 

  • Fleischman MW, Budoff M, Zeb I, Li D, Foster T (2014) NAFLD prevalence differs among hispanic subgroups: the Multi-Ethnic Study of Atherosclerosis. World J Gastroenterol 20:4987–4993

    Article  Google Scholar 

  • Foulds CE, Treviño LS, York B, Walker CL (2017) Endocrine-disrupting chemicals and fatty liver disease. Nature reviews. Endocrinology 13:445–457

    CAS  Google Scholar 

  • Frediani JK, Naioti EA, Vos MB, Figueroa J, Marsit CJ, Welsh JA (2018) Arsenic exposure and risk of nonalcoholic fatty liver disease (NAFLD) among U.S. adolescents and adults: an association modified by race/ethnicity, NHANES 2005–2014. Environ Health 17:6

    Article  Google Scholar 

  • Gormaz JG, Rodrigo R, Videla LA, Beems M (2010) Biosynthesis and bioavailability of long-chain polyunsaturated fatty acids in non-alcoholic fatty liver disease. Prog Lipid Res 49:407–419

    Article  CAS  Google Scholar 

  • Greco D, Kotronen A, Westerbacka J, Puig O, Arkkila P, Kiviluoto T, Laitinen S, Kolak M, Fisher RM, Hamsten A et al (2008) Gene expression in human NAFLD. Am J Physiol Gastrointest Liver Physiol 294:G1281–G1287

    Article  CAS  Google Scholar 

  • Gupta R, Kumar P, Fahmi N, Garg B, Dutta S, Sachar S, Matharu AS, Vimaleswaran KS (2020) Endocrine disruption and obesity: A current review on environmental obesogens. Curr Res Green Sustain Chem 3:100009

    Article  Google Scholar 

  • Haenle MM, Brockmann SO, Kron M, Bertling U, Mason RA, Steinbach G, Boehm BO, Koenig W, Kern P, Piechotowski I et al (2006) Overweight, physical activity, tobacco and alcohol consumption in a cross-sectional random sample of German adults. BMC Public Health 6:233

    Article  Google Scholar 

  • Hamabe A, Uto H, Imamura Y, Kusano K, Mawatari S, Kumagai K, Kure T, Tamai T, Moriuchi A, Sakiyama T et al (2011) Impact of cigarette smoking on onset of nonalcoholic fatty liver disease over a 10-year period. J Gastroenterol 46:769–778

    Article  CAS  Google Scholar 

  • Hong W, Li S, Cai Y, Zhang T, Yang Q, He B, Yu J, Chen Z (2020) The Target MicroRNAs and Potential Underlying Mechanisms of Yiqi-Bushen-Tiaozhi Recipe against‐Non-Alcoholic Steatohepatitis, 11

  • Houston MC (2011) Role of mercury toxicity in hypertension, cardiovascular disease, and stroke. J Clin Hypertens (Greenwich), 13

  • Howe CG, Margetaki K, Vafeiadi M, Roumeliotaki T, Karachaliou M, Kogevinas M, McConnell R, Eckel SP, Conti DV, Kippler M et al (2021) Prenatal metal mixtures and child blood pressure in the Rhea mother-child cohort in Greece. Environ Health 20:1

    Article  CAS  Google Scholar 

  • Hu P, Kennedy RC, Chen X, Zhang J, Shen CL, Chen J, Zhao L (2016) Differential effects on adiposity and serum marker of bone formation by post-weaning exposure to methylparaben and butylparaben. Environ Sci Pollut Res Int 23:21957–21968

    Article  CAS  Google Scholar 

  • Hu Z, Li Y, Yang Y, Yu W, Xie W, Song G, Qian Y, Song Z (2021) Serum lipids mediate the relationship of multiple polyaromatic hydrocarbons on non-alcoholic fatty liver disease: A population-based study. Sci Total Environ 780:146563

    Article  CAS  Google Scholar 

  • Ipsen DH, Lykkesfeldt J, Tveden-Nyborg P (2018) Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease. Cell Mol Life Sci: CMLS 75:3313–3327

    Article  CAS  Google Scholar 

  • Jagadeesan G, Sankarsami PS (2007) Hepatoprotective effects of taurine against mercury induced toxicity in rats. J Environ Biol 28:753–756

    CAS  Google Scholar 

  • Jaishankar M, Tseten T, Anbalagan N, Mathew BB, Beeregowda KN (2014) Toxicity, mechanism and health effects of some heavy metals. Interdiscip Toxicol 7:60–72

    Article  Google Scholar 

  • Jan AT, Ali A, Haq Q (2011) Glutathione as an antioxidant in inorganic mercury induced nephrotoxicity. J Postgrad Med 57:72–77

    Article  CAS  Google Scholar 

  • Jiang X, Jiang L, Shan A, Su Y, Cheng Y, Song D, Ji H, Ning G, Wang W, Cao Y (2018) Targeting hepatic miR-221/222 for therapeutic intervention of nonalcoholic steatohepatitis in mice. EBioMedicine 37:307–321

    Article  Google Scholar 

  • Jung TY, Kim MS, Hong HP, Kang KA, Jun DW (2020) Comparative Assessment and External Validation of Hepatic Steatosis Formulae in a Community-Based Setting. J Clin Med, 9

  • Keil AP, Buckley JP, O’Brien KM, Ferguson KK, Zhao S, White AJJEHP (2020) A quantile-based g-computation approach to addressing the effects of exposure mixtures, 128: 047004

  • Kim D, Yoo ER, Li AA, Cholankeril G, Tighe SP, Kim W, Harrison SA, Ahmed A (2019) Elevated urinary bisphenol A levels are associated with non-alcoholic fatty liver disease among adults in the United States, 39: 1335-42

  • Kim NH, Jung YS, Hong HP, Park JH, Kim HJ, Park DI, Cho YK, Sohn CI, Jeon WK, Kim BI (2018) Association between cotinine-verified smoking status and risk of nonalcoholic fatty liver disease, 38: 1487-94

  • Klaassen CD (2013) Casarett and Doull's toxicology: the basic science of poisons: McGraw-Hill New York

  • Kojima M, Nemoto K, Murai U, Yoshimura N, Ayabe Y, Degawa M (2002) Altered gene expression of hepatic lanosterol 14alpha-demethylase (CYP51) in lead nitrate-treated rats. Arch Toxicol 76:398–403

    Article  CAS  Google Scholar 

  • Lee JH, Kim D, Kim HJ, Lee CH, Yang JI, Kim W, Kim YJ, Yoon JH, Cho SH, Sung MW et al (2010) Hepatic steatosis index: a simple screening tool reflecting nonalcoholic fatty liver disease. Dig Liver Dis 42:503–508

    Article  CAS  Google Scholar 

  • Leite NC, Salles GF, Araujo AL, Villela-Nogueira CA, Cardoso CR (2009) Prevalence and associated factors of non-alcoholic fatty liver disease in patients with type-2 diabetes mellitus. Liver Int 29:113–119

    Article  CAS  Google Scholar 

  • Li Y, Chen C, Lu L, Guo W, VanWagner LB, Shikany JM, Zhang S, Kahe K (2021) Cadmium Exposure in Young Adulthood Is Associated with Risk of Nonalcoholic Fatty Liver Disease in Midlife. Dig Dis Sci

  • Licursi V, Conte F, Fiscon G, Paci P (2019) MIENTURNET: an interactive web tool for microRNA-target enrichment and network-based analysis. BMC Bioinformatics 20:545

    Article  Google Scholar 

  • Lind PM, Roos V, Rönn M, Johansson L, Ahlström H, Kullberg J, Lind L (2012) Serum concentrations of phthalate metabolites are related to abdominal fat distribution two years later in elderly women. Environ Health 11:21

    Article  CAS  Google Scholar 

  • Liu P, Xu Y, Tang Y, Du M, Yu X, Sun J, Xiao L, He M, Wei S, Yuan J et al (2017) Independent and joint effects of moderate alcohol consumption and smoking on the risks of non-alcoholic fatty liver disease in elderly Chinese men. PLoS ONE 12:e0181497-e181597

    Article  Google Scholar 

  • Liu Y, Dai M, Bi Y, Xu M, Xu Y, Li M, Wang T, Huang F, Xu B, Zhang J et al (2013) Active smoking, passive smoking, and risk of nonalcoholic fatty liver disease (NAFLD): a population-based study in China. J Epidemiol 23:115–121

    Article  Google Scholar 

  • Long MT, Pedley A, Colantonio LD, Massaro JM, Hoffmann U, Muntner P, Fox CS (2016) Development and Validation of the Framingham Steatosis Index to Identify Persons With Hepatic Steatosis. Clin Gastroenterol Hepatol 14:1172–80.e2

    Article  Google Scholar 

  • Matović V, Buha A, Ðukić-Ćosić D, Bulat Z (2015) Insight into the oxidative stress induced by lead and/or cadmium in blood, liver and kidneys. Food Chem Toxicol 78:130–140

    Article  Google Scholar 

  • McGill MRJEJ (2016) The past and present of serum aminotransferases and the future of liver injury biomarkers, 15: 817

  • Meng Z, Wang D, Yan S, Li R, Yan J, Teng M, Zhou Z, Zhu W (2018) Effects of perinatal exposure to BPA and its alternatives (BPS, BPF and BPAF) on hepatic lipid and glucose homeostasis in female mice adolescent offspring. Chemosphere 212:297–306

    Article  CAS  Google Scholar 

  • Milošević N, Milić N, Bosić DŽ, Bajkin I, Perčić I, Abenavoli L, Stojanoska MMJEM, Assessment (2018) Potential influence of the phthalates on normal liver function and cardiometabolic risk in males, 190: 1-17

  • Mir BA, Reyer H, Komolka K, Ponsuksili S, Kühn C, Maak S (2020) Differentially Expressed miRNA-Gene Targets Related to Intramuscular Fat in Musculus Longissimus Dorsi of Charolais × Holstein F(2)-Crossbred Bulls. Genes 11:700

    Article  CAS  Google Scholar 

  • Mitra S, De A, Chowdhury A (2020) Epidemiology of non-alcoholic and alcoholic fatty liver diseases. Transl Gastroenterol Hepatol 5:16–16

    Article  Google Scholar 

  • Nan Y, Niu X, Wang R, Zhao S, Fu N, Du J, Wang Y, Wang B, Zhang Y (2019) microRNA-1273g-3p is a useful non-invasive test for the prediction of liver fibrosis in patients with chronic hepatitis C. Exp Ther Med 17:1817–1824

    CAS  Google Scholar 

  • National Institute of Environmental Research SK. (2015) Research development and planning for Korean National Environmental Health Survey (KoNEHS) (III). Book Research development and planning for Korean National Environmental Health Survey (KoNEHS) (III), City

  • Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, Mullany EC, Biryukov S, Abbafati C, Abera SF et al (2014) Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 384:766–781

    Article  Google Scholar 

  • Nguyen HD, Kim M-S (2021a) Effects of heavy metal, vitamin, and curry consumption on metabolic syndrome during menopause: a Korean community-based cross-sectional study. J Menopause 28:1

    Google Scholar 

  • Nguyen HD, Kim MS (2021b) Effects of heavy metal, vitamin, and curry consumption on metabolic syndrome during menopause: a Korean community-based cross-sectional study. J Menopause, 28

  • Nguyen HD, Kim MS (2021c) Exposure to a mixture of heavy metals induces cognitive impairment: Genes and microRNAs involved. Toxicology 471:153164. https://doi.org/10.1016/j.tox.2022.153164

  • Nguyen HD, Oh H, Hoang NHM, Jo WH, Kim MS (2021a) Environmental science and pollution research role of heavy metal concentrations and vitamin intake from food in depression: a national cross-sectional study (2009–2017). Environ Sci Pollut Res Int, 1–13

  • Nguyen HD, Oh H, Hoang NHM et al (2021b) Association between heavy metals, high sensitivity C-reaction protein and 10-year risk of cardiovascular diseases among adult Korean population. Sci Rep 11:14664. https://doi.org/10.1038/s41598-021-94158-9

  • Nguyen HD, Oh H, Jo WH, Hoang NHM, Kim MS (2021d) Mixtures modeling identifies heavy metals and pyrethroid insecticide metabolites associated with obesity. Environ Sci Pollut Res Int

  • Nguyen HD, Oh H, Kim M-S (2021e) Effects of heavy metals on hypertension during menopause: a Korean community-based cross-sectional study. Menopause, 28

  • Nguyen HD, Oh H, Kim MS (2021f) Effects of heavy metals on hypertension during menopause: a Korean community-based cross-sectional study. Menopause

  • NIER (2015) Research development and planning for Korean National Environmental Health Survey (KoNEHS) (III). Available at: http://www.ndsl.kr/ndsl/commons/util/ndslOriginalView.do?dbt=TRKO&cn=TRKO201700007756&rn=&url=&pageCode=PG18. Accessed 1 Mar 2022

  • Obeng-Gyasi E (2020) Cumulative Effects of Low-Level Lead Exposure and Chronic Physiological Stress on Hepatic Dysfunction-A Preliminary Study. Med Sci (Basel), 8

  • Olszowski T, Baranowska-Bosiacka I, Gutowska I, Chlubek D (2012) Pro-inflammatory properties of cadmium. Acta Biochim Pol 59:475–482

    Article  CAS  Google Scholar 

  • Pan JJ, Fallon MB (2014) Gender and racial differences in nonalcoholic fatty liver disease. World J Hepatol 6:274–283

    Article  Google Scholar 

  • Park CG, Sung B, Ryu CS, Kim YJJCB (2020) Mono-(2-ethylhexyl) phthalate induces oxidative stress and lipid accumulation in zebrafish liver cells. Toxicol PPC Pharmacol 230:108704

    CAS  Google Scholar 

  • Park E, Kim J, Kim B, Park EY (2021) Association between environmental exposure to cadmium and risk of suspected non-alcoholic fatty liver disease. Chemosphere 266:128947

    Article  CAS  Google Scholar 

  • Park SH, Jeon WK, Kim SH, Kim HJ, Park DI, Cho YK, Sung IK, Sohn CI, Keum DK, Kim BI (2006) Prevalence and risk factors of non-alcoholic fatty liver disease among Korean adults. J Gastroenterol Hepatol 21:138–143

    Article  Google Scholar 

  • Pei K, Gui T, Kan D, Feng H, Jin Y, Yang Y, Zhang Q, Du Z, Gai Z, Wu J et al (2020) An Overview of Lipid Metabolism and Nonalcoholic Fatty Liver Disease. Biomed Res Int 2020:4020249–4020349

    Article  Google Scholar 

  • Poursafa P, Ataee E, Motlagh ME, Ardalan G, Tajadini MH, Yazdi M, Kelishadi R (2014) Association of serum lead and mercury level with cardiometabolic risk factors and liver enzymes in a nationally representative sample of adolescents: the CASPIAN-III study. Environ Sci Pollut Res Int 21:13496–13502

    Article  CAS  Google Scholar 

  • Pratt DS, Kaplan MM (2000) Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Engl J Med 342:1266–1271

    Article  CAS  Google Scholar 

  • Qin J, Ru S, Wang W, Hao L, Ru Y, Wang J, Zhang X (2020) Long-term bisphenol S exposure aggravates non-alcoholic fatty liver by regulating lipid metabolism and inducing endoplasmic reticulum stress response with activation of unfolded protein response in male zebrafish. Environ Pollut 263:114535

    Article  CAS  Google Scholar 

  • Rani A, Kumar A, Lal A, Pant M (2014) Cellular mechanisms of cadmium-induced toxicity: a review. Int J Environ Health Res 24:378–399

    Article  CAS  Google Scholar 

  • Reid DT, McDonald B, Khalid T, Vo T, Schenck LP, Surette MG, Beck PL, Reimer RA, Probert CS, Rioux KP, et al (2016) Unique microbial-derived volatile organic compounds in portal venous circulation in murine non-alcoholic fatty liver disease. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1862: 1337–44

  • Rupprecht LE, Smith TT, Donny EC, Sved AF (2017) Self-administered nicotine differentially impacts body weight gain in obesity-prone and obesity-resistant rats. Physiol Behav 176:71–75

    Article  CAS  Google Scholar 

  • Sanyal AJ, Brunt EM, Kleiner DE, Kowdley KV, Chalasani N, Lavine JE, Ratziu V, McCullough A (2011) Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology 54:344–353

    Article  Google Scholar 

  • Shao M, Ye Z, Qin Y, Wu T (2020) Abnormal metabolic processes involved in the pathogenesis of non-alcoholic fatty liver disease (Review). Exp Ther Med 20:26

    Article  CAS  Google Scholar 

  • Sinha R, Lockman KA, Homer NZM, Bower E, Brinkman P, Knobel HH, Fallowfield JA, Jaap AJ, Hayes PC, Plevris JN (2020) Volatomic analysis identifies compounds that can stratify non-alcoholic fatty liver disease. JHEP Reports 2:100137

    Article  Google Scholar 

  • Stohs SJ, Bagchi D, Hassoun E, Bagchi M (2001) Oxidative mechanisms in the toxicity of chromium and cadmium ions. J Environ Pathol Toxicol Oncol, 20

  • Suzuki A, Lindor K, Saver JS, Lymp J, Mendes F, Muto A, Okada T, Angulo P (2005) Effect of changes on body weight and lifestyle in nonalcoholic fatty liver disease. J Hepatol 43:1060–1066

    Article  CAS  Google Scholar 

  • Tchounwou PB, Yedjou CG, Patlolla AK, Sutton DJ (2012) Heavy metal toxicity and the environment. Exp Suppl 101:133–164

    Google Scholar 

  • Vallet-Pichard A, Mallet V, Nalpas B, Verkarre V, Nalpas A, Dhalluin-Venier V, Fontaine H, Pol S (2007) FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection. comparison with liver biopsy and fibrotest. Hepatology 46:32–36

    Article  CAS  Google Scholar 

  • Verstraete SG, Wojcicki JM, Perito ER, Rosenthal P (2018) Bisphenol a increases risk for presumed non-alcoholic fatty liver disease in Hispanic adolescents in NHANES 2003–2010. Environ Health 17:12

    Article  Google Scholar 

  • Wahlang B, Appana S, Falkner KC, McClain CJ, Brock G, Cave MC (2020) Insecticide and metal exposures are associated with a surrogate biomarker for non-alcoholic fatty liver disease in the National Health and Nutrition Examination Survey 2003–2004. Environ Sci Pollut Res Int 27:6476–6487

    Article  CAS  Google Scholar 

  • Wang J, Yu P, Xie X, Wu L, Zhou M, Huan F, Jiang L, Gao R (2021a) Bisphenol F induces nonalcoholic fatty liver disease-like changes: Involvement of lysosome disorder in lipid droplet deposition. Environ Pollut 271:116304

    Article  CAS  Google Scholar 

  • Wang X, Seo YA, Park SK (2021) Serum selenium and non-alcoholic fatty liver disease (NAFLD) in U.S. adults: National Health and Nutrition Examination Survey (NHANES) 2011–2016. Environ Res 197:111190

    Article  CAS  Google Scholar 

  • Warde-Farley D, Donaldson SL, Comes O, Zuberi K, Badrawi R, Chao P, Franz M, Grouios C, Kazi F, Lopes CT et al (2010) The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res 38:W214–W220

    Article  CAS  Google Scholar 

  • Yalcinkaya E, Celik M, Gursoy E (2014) Determining the combined effects of smoking and obesity on insulin resistance and inflammation. Eur Rev Med Pharmacol Sci 18:760

    CAS  Google Scholar 

  • Yang YJ, Kim T, Hong YP. (2021) Urinary Phthalate Levels Associated with the Risk of Nonalcoholic Fatty Liver Disease in Adults: The Korean National Environmental Health Survey (KoNEHS) 2012–2014. Int J Environ Res Public Health, 18

  • Younossi Z, Stepanova M, Ong JP, Jacobson IM, Bugianesi E, Duseja A, Eguchi Y, Wong VW, Negro F, Yilmaz Y et al (2019a) Nonalcoholic Steatohepatitis Is the Fastest Growing Cause of Hepatocellular Carcinoma in Liver Transplant Candidates. Clin Gastroenterol Hepatol 17:748–55.e3

    Article  Google Scholar 

  • Younossi Z, Tacke F, Arrese M, Chander Sharma B, Mostafa I, Bugianesi E, Wai-Sun Wong V, Yilmaz Y, George J, Fan J et al (2019b) Global Perspectives on Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. Hepatology 69:2672–2682

    Article  Google Scholar 

  • Yueh M-F, He F, Chen C, Vu C, Tripathi A, Knight R, Karin M, Chen S, Tukey RH (2020) Triclosan leads to dysregulation of the metabolic regulator FGF21 exacerbating high fat diet-induced nonalcoholic fatty liver disease. Proc Natl Acad Sci USA 117:31259–31266

    Article  CAS  Google Scholar 

  • Zambrano-Huailla R, Guedes L, Stefano JT, de Souza AAA, Marciano S, Yvamoto E, Michalczuk MT, Vanni DS, Rodriguez H, Carrilho FJ et al (2020) Diagnostic performance of three non-invasive fibrosis scores (Hepamet, FIB-4, NAFLD fibrosis score) in NAFLD patients from a mixed Latin American population. Ann Hepatol 19:622–626

    Article  CAS  Google Scholar 

  • Zeng N, Huang Y-Q, Yan Y-M, Hu Z-Q, Zhang Z, Feng J-X, Guo J-S, Zhu J-N, Fu Y-H, Wang X-P et al (2021) Diverging targets mediate the pathological role of miR-199a-5p and miR-199a-3p by promoting cardiac hypertrophy and fibrosis. Molecular Therapy - Nucleic Acids 26:1035–1050

    Article  CAS  Google Scholar 

  • Zhang CX, Guo LK, Qin YM, Li GY (2016) Association of polymorphisms of adiponectin gene promoter-11377C/G, glutathione peroxidase-1 gene C594T, and cigarette smoking in nonalcoholic fatty liver disease. J Chin Med Assoc 79:195–204

    Article  Google Scholar 

  • Zhang Y, Dong T, Hu W, Wang X, Xu B, Lin Z, Hofer T, Stefanoff P, Chen Y, Wang X et al (2019) Association between exposure to a mixture of phenols, pesticides, and phthalates and obesity: Comparison of three statistical models. Environ Int 123:325–336

    Article  CAS  Google Scholar 

  • Zhao Z-b, Ji K, Shen X-y, Zhang W-w, Wang R, Xu W-p, Wei WJET (2019) Di (2-ethylhexyl) phthalate promotes hepatic fibrosis by regulation of oxidative stress and inflammation responses in rats. Pharmacology 68:109–19

    CAS  Google Scholar 

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Acknowledgements

The authors are grateful to all research staff for their excellent contributions in data collection in the survey.

Funding

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST) (grant nos. NRF2013R1A1A3008851, and 2018R1D1A1B07049610).

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Authors and Affiliations

  1. Department of Pharmacy, College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Sunchon, Jeonnam, 57922, Republic of Korea

    Hai Duc Nguyen & Min-Sun Kim

Authors
  1. Hai Duc Nguyen
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  2. Min-Sun Kim
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Contributions

Hai Duc Nguyen: Conceptualization, methodology, formal analysis, investigation, resources, data curation, writing (original draft), writing (review and editing), visualization. Min-Sun Kim: Visualization.

Corresponding author

Correspondence to Min-Sun Kim.

Ethics declarations

Ethics approval and consent to participate

All participants in KoNEHS provided written informed consent. The KoNEHS dataset has been de-identified and made publicly available. This survey was approved by the institutional review board of the NIER in Korea (NIER-2016-BR-003–01, NIER-2016-BR-003–03).

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

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Responsible Editor: Ludek Blaha

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Highlights

• Mixed chemicals were linked with the risk of non-alcoholic fatty liver disease (NAFLD).

• CYP1A2 gene was linked with mixed chemicals and NAFLD development.

• Key molecular mechanisms affected by NAFLD-related mixed chemicals were provided.

• Chemicals’ cutoff thresholds linked with the risk of suspected NAFLD were reported.

• miRNAs involved in NAFLD development were also identified.

Supplementary Information

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Supplementary file1 (DOCX 788 KB)

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Nguyen, H.D., Kim, MS. Effects of chemical mixtures on liver function biomarkers in the Korean adult population: thresholds and molecular mechanisms for non-alcoholic fatty liver disease involved. Environ Sci Pollut Res 29, 78555–78587 (2022). https://doi.org/10.1007/s11356-022-21090-4

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  • DOI: https://doi.org/10.1007/s11356-022-21090-4

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