Association of exposure to phenols, pesticides, and phthalates with hepatic steatosis and MASLD in adolescents: the potential role of inflammation and lifestyle factors

Abstract

Aim: Limited evidence exists on the effects of endocrine-disrupting chemical exposure on metabolic dysfunction-associated steatotic liver disease (MASLD) in adolescents. We aimed to assess the effects of multiple chemicals on the hepatic steatosis index (HSI) and MASLD in adolescents, and to further explore the potential roles of inflammation and lifestyle factors.

Methods: Associations between chemical exposures and HSI/MASLD were examined using generalized linear models, restricted cubic spline analysis, weighted quantile sum regression, and Bayesian kernel machine regression. Mediation analysis was conducted to evaluate whether inflammation mediated these relationships.

Results: Among 2,163 adolescents (median age 15 years), 490 (22.7%) were diagnosed with MASLD. Bisphenol A, mono-ethyl phthalate, mono-(carboxyoctyl) phthalate, and mono-benzyl phthalate (MBzP) were significantly associated with HSI or MASLD. Both weighted quantile sum and Bayesian kernel machine regression consistently indicated a positive correlation between chemical mixtures and MASLD, with MBzP and bisphenol A identified as key contributors. Mediation analysis showed that white blood cells partially mediated the associations of MBzP with HSI and MASLD, and of mono-(carboxynonyl) phthalate with MASLD. Sedentary behavior and physical activity further modulated the combined effects of chemical mixtures on MASLD.

Conclusion: Exposure to phenols, pesticides, and phthalates was significantly associated with HSI or MASLD, with white blood cells acting as a mediator. Reducing sedentary behavior and increasing physical activity may mitigate the adverse impacts of chemical mixtures on MASLD.

Keywords

EDCs / HSI / MALSD / inflammatory markers / lifestyle factors

References

[1] Rinella ME,Ratziu V.A multisociety Delphi consensus statement on new fatty liver disease nomenclature.Hepatology2023;78:1966-86

[2] Zhang L,Baur LA.An international multidisciplinary consensus on pediatric metabolic dysfunction-associated fatty liver disease.Med2024;5:797-815.e2

[3] Lee EJ,Ahn SB.Prevalence of nonalcoholic fatty liver disease in pediatrics and adolescents: a systematic review and meta-analysis.World J Pediatr2024;20:569-80

[4] Miao L,Byrne CD,Zheng MH.Current status and future trends of the global burden of MASLD.Trends Endocrinol Metab2024;35:697-707

[5] Sun DQ,Byrne CD.An international Delphi consensus statement on metabolic dysfunction-associated fatty liver disease and risk of chronic kidney disease.Hepatobiliary Surg Nutr2023;12:386-403

[6] Zhou XD,Byrne CD.An international multidisciplinary consensus statement on MAFLD and the risk of CVD.Hepatol Int2023;17:773-91 PMCID:PMC10198034

[7] Mann JP,Scorletti E,Nobili V.Nonalcoholic fatty liver disease in children.Semin Liver Dis2018;38:1-13

[8] Deierlein AL,Park S.Persistent endocrine-disrupting chemicals and fatty liver disease.Curr Environ Health Rep2017;4:439-49

[9] Pan K,Xu Y,Yu J.The association between endocrine disrupting chemicals and nonalcoholic fatty liver disease: a systematic review and meta-analysis.Pharmacol Res2024;205:107251

[10] Ghassabian A,Kannan K.Endocrine-disrupting chemicals and child health.Annu Rev Pharmacol Toxicol2022;62:573-94

[11] Gore AC.Endocrine-disrupting chemicals.JAMA Intern Med2016;176:1705-6

[12] Dong Y,Zhang L,Wang X.Bisphenol A impairs mitochondrial function in spleens of mice via oxidative stress.Mol Cell Toxicol2013;9:401-6

[13] Shaibi T,Ben-Othman ME.Exposure to low-dose bisphenol A induces spleen damage in a murine model: potentially through oxidative stress?.Open Vet J2022;12:23-32

[14] Li D.Health risks of chemicals in consumer products: a review.Environ Int2019;123:580-7

[15] Rivera-Núñez Z,Zhang Y.Phenols, parabens, phthalates and puberty: a systematic review of synthetic chemicals commonly found in personal care products and girls' pubertal development.Curr Environ Health Rep2022;9:517-34 PMCID:PMC9742306

[16] Braun JM.Early-life exposure to EDCs: role in childhood obesity and neurodevelopment.Nat Rev Endocrinol2017;13:161-73 PMCID:PMC5322271

[17] Cai S,Ye J,Li Y.Phthalates exposure is associated with non-alcoholic fatty liver disease among US adults.Ecotoxicol Environ Saf2021;224:112665

[18] Kim D,Li AA.Elevated urinary bisphenol A levels are associated with non-alcoholic fatty liver disease among adults in the United States.Liver Int2019;39:1335-42

[19] Lei R,Tian X.The association between endocrine disrupting chemicals and MAFLD: evidence from NHANES survey.Ecotoxicol Environ Saf2023;256:114836

[20] Park B,Kim CH,Park B.Association between endocrine-disrupting chemical mixtures and non-alcoholic fatty liver disease with metabolic syndrome as a mediator among adults: A population-based study in Korea.Ecotoxicol Environ Saf2024;276:116310

[21] Verstraete SG,Perito ER.Bisphenol a increases risk for presumed non-alcoholic fatty liver disease in Hispanic adolescents in NHANES 2003-2010.Environ Health2018;17:12 PMCID:PMC5796302

[22] Midya V,Conti DV.Association of prenatal exposure to endocrine-disrupting chemicals with liver injury in children.JAMA Netw Open2022;5:e2220176

[23] Xiang S,Li X.Urine phthalate levels and liver function in US adolescents: analyses of NHANES 2007-2016.Front Public Health2022;10:843971 PMCID:PMC8934389

[24] Zhang Y,Hu W.Association between exposure to a mixture of phenols, pesticides, and phthalates and obesity: comparison of three statistical models.Environ Int2019;123:325-36

[25] Billionnet C,Annesi-Maesano I.Estimating the health effects of exposure to multi-pollutant mixture.Ann Epidemiol2012;22:126-41

[26] Huc L,Guéraud F.Low concentrations of bisphenol A induce lipid accumulation mediated by the production of reactive oxygen species in the mitochondria of HepG2 cells.Toxicol In Vitro2012;26:709-17

[27] Su HY,Lee KH,Chen CC.Prenatal exposure to low-dose di-(2-ethylhexyl) phthalate (DEHP) induces potentially hepatic lipid accumulation and fibrotic changes in rat offspring.Ecotoxicol Environ Saf2024;269:115776

[28] Nowak K,Ratajczak-Wrona W.Immunomodulatory effects of synthetic endocrine disrupting chemicals on the development and functions of human immune cells.Environ Int2019;125:350-64

[29] Liu K,Liu C.Systemic immune-inflammatory biomarkers (SII, NLR, PLR and LMR) linked to non-alcoholic fatty liver disease risk.Front Immunol2024;15:1337241 PMCID:PMC10933001

[30] He P,Ye Z.A healthy lifestyle, life's essential 8 scores and new-onset severe NAFLD: a prospective analysis in UK biobank.Metabolism2023;146:155643

[31] Wang L,Guo X.Associations between life's essential 8 and non-alcoholic fatty liver disease among US adults.J Transl Med2022;20:616 PMCID:PMC9789599

[32] Aimuzi R,Qu Y,Luo K.Associations of urinary organophosphate esters metabolites and diet quality with nonalcoholic/metabolic dysfunction-associated fatty liver diseases in adults.Ecotoxicol Environ Saf2023;254:114720

[33] Liu Q,Bi J.Associations of polychlorinated biphenyls and organochlorine pesticides with metabolic dysfunction-associated fatty liver disease among Chinese adults: effect modification by lifestyle.Environ Res2024;240:117507

[34] Zhang Y,Guan X.Associations of ambient air pollution exposure and lifestyle factors with incident dementia in the elderly: a prospective study in the UK Biobank.Environ Int2024;190:108870

[35] Lee JH,Kim HJ.Hepatic steatosis index: a simple screening tool reflecting nonalcoholic fatty liver disease.Dig Liver Dis2010;42:503-8

[36] Yang M,Li H.Association of per- and polyfluoroalkyl substances with hepatic steatosis and metabolic dysfunction-associated fatty liver disease among patients with acute coronary syndrome.Ecotoxicol Environ Saf2023;264:115473

[37] Hu P,Su W.Associations between exposure to a mixture of phenols, parabens, and phthalates and sex steroid hormones in children 6-19 years from NHANES, 2013-2016.Sci Total Environ2022;822:153548

[38] Rinella ME,Ratziu V.A multisociety Delphi consensus statement on new fatty liver disease nomenclature.J Hepatol2023;79:1542-56

[39] Tudurachi BS,Tudurachi A,Stătescu C.Assessment of inflammatory hematological ratios (NLR, PLR, MLR, LMR and monocyte/HDL-cholesterol ratio) in acute myocardial infarction and particularities in young patients.Int J Mol Sci2023;24:14378 PMCID:PMC10531986

[40] Hu B,Xu Y.Systemic immune-inflammation index predicts prognosis of patients after curative resection for hepatocellular carcinoma.Clin Cancer Res2014;20:6212-22

[41] World Health Organization (WHO). Child growth standards; 2006. Available from: https://www.who.int/toolkits/child-growth-standards/standards/body-mass-index-for-age-bmi-for-age [Last accessed on 12 Sep 2025]

[42] Ku PW,Liao Y,Chen LJ.A cut-off of daily sedentary time and all-cause mortality in adults: a meta-regression analysis involving more than 1 million participants.BMC Med2018;16:74 PMCID:PMC5998593

[43] Lau JH,Abdin E.Prevalence and patterns of physical activity, sedentary behaviour, and their association with health-related quality of life within a multi-ethnic Asian population.BMC Public Health2021;21:1939 PMCID:PMC8544627

[44] Chau JY,Chey T.Daily sitting time and all-cause mortality: a meta-analysis.PLoS One2013;8:e80000 PMCID:PMC3827429

[45] Piercy KL,Ballard RM.The physical activity guidelines for Americans.JAMA2018;320:2020-8 PMCID:PMC9582631

[46] Hirshkowitz M,Albert SM.National sleep foundation's sleep time duration recommendations: methodology and results summary.Sleep Health2015;1:40-3

[47] Shams-White MM,Lerman JL.Healthy eating index-2020: review and update process to reflect the dietary guidelines for Americans,2020-2025.J Acad Nutr Diet2023;123:1280-8

[48] Huang S,Lv Z.Associations of multiple plasma metals with the risk of metabolic syndrome: A cross-sectional study in the mid-aged and older population of China.Ecotoxicol Environ Saf2022;231:113183

[49] Carrico C,Wheeler DC.Characterization of weighted quantile sum regression for highly correlated data in a risk analysis setting.J Agric Biol Environ Stat2015;20:100-20 PMCID:PMC6261506

[50] Bobb JF,Claus Henn B.Bayesian kernel machine regression for estimating the health effects of multi-pollutant mixtures.Biostatistics2015;16:493-508 PMCID:PMC5963470

[51] Wu L,Xin Y.Associations between phenols, parabens, and phthalates and depressive symptoms: The role of inflammatory markers and bioinformatic insights.Ecotoxicol Environ Saf2024;286:117191

[52] Feng C,Wang Z.Relationship of long-term exposure to air pollutant mixture with metabolic-associated fatty liver disease and subtypes: a retrospective cohort study of the employed population of Southwest China.Environ Int2024;188:108734

[53] Takefuji Y.Drug-induced inflammation: a review of literature.Chem Biol Interact2024;404:111282

[54] Gofton C,Zheng MH.MAFLD: how is it different from NAFLD?.Clin Mol Hepatol2023;29:S17-31 PMCID:PMC10029949

[55] Kasongo AA,Amrouche-Mekkioui I,Aguer C.BPA exposure in L6 myotubes increased basal glucose metabolism in an estrogen receptor-dependent manner but induced insulin resistance.Food Chem Toxicol2022;170:113505

[56] Gear RB.Impacts of bisphenol A and ethinyl estradiol on male and female CD-1 mouse spleen.Sci Rep2017;7:856 PMCID:PMC5429804

[57] Shi X,Feng J,Xu M.Gender-specific abdominal fat distribution and insulin resistance associated with organophosphate esters and phthalate metabolites exposure.Environ Pollut2024;349:123959

[58] Shoshtari-Yeganeh B,Mansourian M.Systematic review and meta-analysis on the association between phthalates exposure and insulin resistance.Environ Sci Pollut Res Int2019;26:9435-42

[59] Zhou J,Yu C.Exposure to low concentration of trifluoromethanesulfonic acid induces the disorders of liver lipid metabolism and gut microbiota in mice.Chemosphere2020;258:127255

[60] Somani SM.Distribution and metabolism of 2,4-dichlorophenol in rats.J Toxicol Environ Health1982;9:889-97

[61] Zhang W,Zhang WW,Xu WP.Di-(2-ethylhexyl) phthalate could disrupt the insulin signaling pathway in liver of SD rats and L02 cells via PPARγ.Toxicol Appl Pharmacol2017;316:17-26

[62] Kratochvil I,Rother S.Mono(2-ethylhexyl) phthalate (MEHP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) but not di(2-ethylhexyl) phthalate (DEHP) bind productively to the peroxisome proliferator-activated receptor γ.Rapid Commun Mass Spectrom2019;33 Suppl 1:75-85 PMCID:PMC6367069

[63] Ding Y,Liu Y.Transcriptome analysis revealed the mechanism of the metabolic toxicity and susceptibility of di-(2-ethylhexyl)phthalate on adolescent male ICR mice with type 2 diabetes mellitus.Arch Toxicol2019;93:3183-206

[64] Yu L,Cheng M.Associations between urinary phthalate metabolite concentrations and markers of liver injury in the US adult population.Environ Int2021;155:106608

[65] Lucas A,Lucas M.The role of endocrine-disrupting phthalates and bisphenols in cardiometabolic disease: the evidence is mounting.Curr Opin Endocrinol Diabetes Obes2022;29:87-94 PMCID:PMC8915988

[66] Chen L,Xie CM,Wang X.Maternal disononyl phthalate exposure activates allergic airway inflammation via stimulating the phosphoinositide 3-kinase/akt pathway in rat pups.Biomed Environ Sci2015;28:190-8

[67] Zhang Y,Wang J.Di-(2-ethylhexyl) phthalate (DEHP) promoted hepatic lipid accumulation by activating Notch signaling pathway.Environ Toxicol2023;38:1628-40

[68] Michalopoulou E,Lampsas S.The triad of risk: linking MASLD, cardiovascular disease and type 2 diabetes; from pathophysiology to treatment.J Clin Med2025;14:428 PMCID:PMC11765821

[69] Kim H,Han C.Urinary phthalate metabolites and anemia: findings from the Korean national environmental health survey (2015-2017).Environ Res2022;215:114255

[70] Li CL,Zhang YF.Bisphenols exposure and non-alcoholic fatty liver disease: from environmental trigger to molecular pathogenesis.Front Endocrinol2025;16:1606654 PMCID:PMC12137076

[71] Pirozzi C,Annunziata C.Oral bisphenol A worsens liver immune-metabolic and mitochondrial dysfunction induced by high-fat diet in adult mice: cross-talk between oxidative stress and inflammasome pathway.Antioxidants2020;9:1201 PMCID:PMC7760359

[72] Zhang Y,Zhao T.Mono-2-ethylhexyl phthalate (MEHP) promoted lipid accumulation via JAK2/STAT5 and aggravated oxidative stress in BRL-3A cells.Ecotoxicol Environ Saf2019;184:109611

[73] Yang BY,Li S.Long-term exposure to ambient air pollution (including PM₁) and metabolic syndrome: the 33 Communities Chinese Health Study (33CCHS).Environ Res2018;164:204-11