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. 2023 Mar 22;11:1154837. doi: 10.3389/fpubh.2023.1154837

Table 6.

Epidemiologic studies on the relationship between phthalates and NAFLD prevalence and biomarkers.

Substance Reference Country Population Sample size Biological materials Measurement Exposure assessment Outcomes Results Adjustment factors
DEHP Berman et al. (115) Australia 1989–1992 (prenatal) Mother–child pairs from the Raine Study 387 Maternal serum LCMS/MS Phthalate diesters NAFLD at 17 years old ALT, AST, GGT Mid-levels of prenatal exposures to MnBP were associated with a greater incidence of NAFLD. Age, household income at birth, maternal education level at birth, duration of breast feeding, BMI z-score, height
DEHP Chen et al. (116) USA 2017–2018 NHANES adults 1,450 Urine HPLC-ESI-MS/MS Mean ± SD MECPP: 1.89 ± 0.03 ug/g MEOHP: 0.99 ± 0.03 ug/g MEHHP: 1.44 ± 0.03 ug/g MCiNP: 0.16 ± 0.02 ug/g MCiOP: 1.51 ± 0.04 ug/g MCiNP: 0.19 ± 0.03 ug/g NAFLD prevalence Higher prevalence of NAFLD is correlated with MECPP and MEHHP. There is no significant relationship between phthalates and liver fibrosis. Age, sex, smoking status, education, race/ethnicity, physical activity, diabetes, blood pressure, BMI, total cholesterol levels
DEHP Fu et al. (90) China 2018.7–8 Children (5–14 years) 1,006 Serum HPLC Median DMP: 31.62 ng/mL ALT, AST, TBIL Serum DMP concentration and TBIL level were significantly positively correlated. Age, address, gender
DEHP Li et al. (117) USA 1999–2014 NHANES participants 17,878 (HIS-NAFLD) 8,487 (USFLI-NAFLD) Urine HPLC-ESI-MS/MS 13 phthalates OR (95%CI) Urinary phthalates: 1.18(1.09–1.4) NAFLD prevalence Urinary phthalates were positively associated with NAFLD development. Age, sex, race, education, family income-to-poverty ratio, marital status, employment, insurance, self-reported comorbidities, alcohol consumption, cigarettes smoking, leisure time physical activity, diet quality
DEHP Midya et al. (72) France, Greece, Lithuania, Norway, Spain, UK 2021–2022 Mother–child pairs from the Human Early-Life Exposome project 1,108 Serum GC-MS/MS 10 phthalates ALT, AST, GGT and CK-18 of children Decreased odds of liver injury were associated with high-molecular-weight phthalates. Subcohort, maternal age, maternal prepregnancy BMI, maternal educational level, parity, child age, child sex
DEHP Yang et al. (118) Korea 2012–2014 Adults with subclinical hypothyroidism from KoNEHS 2,308 Urine UPLC-MS Geometric mean(95%CI) ug/L MEHHP: 3.02(2.97–3.06) EH 3.10(2.98–3.23) SCH MEOHP: 2.66(2.61–2.71) EH 2.76(2.64–2.89) SCH MECPP: 3.15(3.10–3.19) EH 3.22(3.11–3.33) SCH MBzP: 1.13(1.05–1.21) EH 1.02(0.84–1.20) SCH MnBP: 3.32(3.26–3.39) EH 3.35(3.22–3.48) SCH Risk of NAFLD The levels of phthalate metabolites in urine are positively associated with NAFLD in adults with subclinical hypothyroidism (SCH). Age, gender, drinking, smoking, physical activity, monthly household income, education, marital status, clinical variables
DEHP Cai et al. (114) USA 2003–2016 NHANES adults (>20 years) 4,206 Urine HPLC-ESI-MS/MS 9 phthalates (MEOHP, MEP, MEHHP, MECPP, MnBP, MEHP, MiBP, MBzP, MCPP) ALT, AST, GGT Phthalates exposure was independently associated with NAFLD both in males and females. Age, gender, education levels, race/ethnicity, marital status, family poverty income ratio, BMI, total cholesterol, survey circle, smoking status, physical activity, hypertension, alcohol consumption
DEHP Yang et al. (119) Korea 2012–2014 KoNEHS adults 5,800 Urine UPLC-MS GM ± SE MEHHP: 2.922 ± 0.011 ug/L MEOHP: 2.571 ± 0.011 ug/L MECPP: 3.059 ± 0.010 ug/L MnBP: 3.211 ± 0.012 ug/L MBzP: 1.047 ± 0.015 ug/L NAFLD prevalence The prevalence of NAFLD was associated with urinary levels of MEHHP, MEOHP, MECPP, MBzP, MnBP compared to the reference group. Age, gender, smoking, drinking, exercise level, marital status, education level, socioeconomic status.
DEHP Yu et al. (120) USA 2007–2016 NHANES adults (≥20 years) 6,046 Urine HPLC-ESI-MS/MS 15 phthalate metabolites Median ΣDEHP: 3.1 ug/mmol ALT, AST, ALP, TBIL Positive dose–response relationships between urinary phthalate metabolites and ALT or AST, ΣDEHP and GGT were observed. Significant positive associations of ΣDEHP with TBIL were found after adjusting for potential confounders. Age, sex, race/ethnicity, education level, the ratio of family income to poverty, physical activity, alcohol consumption, medications
DEHP Milošević et al. (121) Serbia Adults (18–50 years) 305 Urine GC-MS 10 phthalates metabolites mean ± SD all phthalates: 304.55 ug/g MEP: 132.2 ± 188.6 ug/g MEHP: 80.36 ± 96.27 ug/g ALT, AST, GGT Phthalates exposure was associated with elevated AST levels. ALT and AST values were increased in MEP exposed while GGT levels were enhanced in MEHP exposed. Obesity, diabetes
DEHP Milošević et al. (104) Serbia 2015–2016 Male participants (18–55 years) 102 Urine GC-MS MEP, MEHP, MPP, MiAP, MnAP, MCHP, MBzP, MOP, MBP ALT, AST, GGT Significant increment in transaminase serum levels was observed in MEP-positive normal weight sub-group. The phthalates exposure may be related to statistically significant ALT and AST serum levels increment. NR

UPLC, ultra-high-performance liquid chromatography; HPLC, high-performance liquid chromatography; HPLC-MS, high-performance liquid chromatography-tandem mass spectrometry; UPLC-MS, ultra-high-performance liquid chromatography mass spectrometry; LC-MS, liquid chromatography-mass spectrometry; LC-MS/MS, liquid chromatography coupled to tandem-mass spectrometry; HPLC-ESI-MS/MS, High-performance liquid chromatography-electrospray ionization-tandem mass spectrometry; GC-MS, gas chromatograph-mass spectrometry; GC-MS/MS, gas chromatography coupled to tandem mass spectrometry.