Phthalate and gallstones: the mediation of insulin

Abstract

Background: Exposure to a mixture of environmental chemicals may cause gallstone, but the evidence remains equivocal. The current study aims to investigate the association between phthalate metabolites and gallstones, and to explore their mediators.

Methods: Data from the National Health and Nutrition Examination Survey 2017-2018 on U.S. adults (≥20 years) were analyzed to explore the association between phthalate metabolites and gallstones by employed survey-weighted logistic regression, restricted cubic spline (RCS), weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR). Mediation analyses examined the role of oxidative stress markers, inflammatory markers, metabolic syndrome, body composition, diabetes, and insulin.

Results: The current study included 1,384 participants, representing 200.6 million U.S. adults. Our results indicated a significant association between phthalate metabolites, particularly high molecular weight metabolites such as Di(2-ethylhexyl) phthalate (DEHP) and 1,2-Cyclohexane dicarboxylic acid diisononyl ester (DINCH), and gallstones. Furthermore, mediation analyses indicated that phthalate metabolites may play a role in the development of gallstones by influencing insulin secretion. Subgroup analyses did not reveal significant interaction.

Conclusion: The association between exposure to phthalates and the occurrence of gallstones, potentially mediated by hyperinsulinemia from a nationally representative epidemiological perspective. These insights contribute to a better understanding of the potential health implications of plasticizers, emphasizing the need for proactive management measures.

Keywords: NHANES; cholelithiasis; hyperinsulinemia; mediation; plasticizer.

Figure 1

Association between individual phthalate metabolite and gallstone. CI, confidence interval; Ln, natural logarithm; MBP, mono-n-butyl phthalate (ng/mL); MBzP, monobenzyl phthalate; MCNP, monocarboxy-isononyl phthalate; MCOCH, cyclohexane-1,2-dicarboxylic acid mono(carboxyoctyl) ester; MCOP, monocarboxyisooctyl phthalate; MCPP, mono (3-carboxypropyl) phthalate; MECPP, mono(2-ethyl-5-carboxypentyl) phthalate; MECPTP, mono-2-ethyl-5-carboxypentyl terephthalate; MEHP, mono(2-ethyl-5-carboxypentyl) phthalate; MEHHP, mono(2-ethyl-5-hydroxyhexyl) phthalate; MEHHTP, mono(2-ethyl-5-hydroxyhexyl) terephthalate; MEOHP, mono-(2-ethyl-5-oxohexyl) phthalate; MEP, mono-ethyl phthalate; MHBP, mono-3-hydroxybutyl phthalate; MHiBPP, mono-2-hydroxy-iso-butyl phthalate; MHINCH, cyclohexane-1,2-dicarboxylic acid mono(hydroxy-isononyl) ester; MiBP, Mono-isobutyl phthalate; MONP, mono-oxo-isononyl phthalate; OR, odds ratios; T2, second tertile; T3, third tertile. ^aTertile 1 is the reference category. ^bThe crude model did not account for covariates, while the adjusted model accounted for age, sex, race/ethnicity, poverty income ratio, marital status, education level, body mass index, physical activity, smoking and drinking status, and creatinine.

Figure 2

Association between sums phthalate metabolite and gallstone. CI, confidence interval; DBP, di-n-butyl phthalate; DEHP, di(2-ethylhexyl) phthalate; DEHTP, di(2-ethylhexyl) terephthalate; DiBP, di-isobutyl phthalate; DINCH, 1,2-Cyclohexane dicarboxylic acid, diisononyl ester; DNP, di-isononyl phthalate; WQS, weighted quantile sum; High−MWP, high molecular-weight phthalate; Ln, natural logarithm; Low−MWP, low molecular-weight phthalate; MW, Molecular Weight; OR, odds ratios; T2, second tertile; T3, third tertile. ^aHigh-MWP is the molar sum of MCPP, MBzP, MHiBP, MEHP, MECPP, MEHHP, MEOHP, MCOP, MONP, MCNP, MHINCH, MCOCH, MEHHTP, and MECPTP. Low-MWP is the molar sum of MEP, MiBP, MHiBP, MBP, and MHBP. ΣDBP is the molar sum of MBP and MHBP. ΣDEHP is the molar sum of MECPP, MEHPP, MEOHP, and MEHP. ΣDEHTP is the molar sum of MEHHTP and MECPTP. ΣDiBP is the molar sum of MiBP and MHiBP. ΣDINCH is the molar sum of MHINCH and MCOCH. ΣDNP is the molar sum of MCOP and MONP. ^bTertile 1 is the reference category. ^cThe crude model did not account for covariates, while the adjusted model accounted for age, sex, race/ethnicity, poverty income ratio, marital status, education level, body mass index, physical activity, smoking and drinking status, and creatinine.

Figure 3

Association between sums phthalate metabolite and gallstone estimated by RCS and BKMR. Models were adjusted for age, sex, race/ethnicity, poverty income ratio, marital status, education level, body mass index, physical activity, smoking and drinking status, and creatinine.

Figure 4

Mediation analysis of oxidative stress, inflammation, body composition, metabolic syndrome, diabetes mellitus, and insulin resistance in the association between sums phthalate metabolite and gallstone. Bold lines and fonts are used to indicate statistical significance (p < 0.05). Models were adjusted for age, sex, race/ethnicity, poverty income ratio, marital status, education level, body mass index (except when it was used as a mediator), physical activity, smoking and drinking status, and creatinine. ALP, alkaline phosphatase; BMI, body mass index; CI, confidence interval; CRP, C-reaction protein; DEHP, di(2-ethylhexyl) phthalate; DM, diabetes mellitus; DINCH, 1,2-Cyclohexane dicarboxylic acid, diisononyl ester; FBG, fasting blood glucose; FINS, fasting serum insulin; GGT, gamma glutamyl transferase; HDL, High-Density Lipoprotein; HOMA-IR, homeostatic model assessment of insulin resistance; HOMA-IS, homeostasis model assessment of insulin sensitivity; HOMA-β, homeostasis model assessment of β-cell function; MetS, metabolic syndrome; OR, odds ratios; TG, Triglyceride; TyG, triglyceride glucose index; VAI, visceral adiposity index; WBC, white blood cell; WC, waist circumference.