Associations Between Phthalate Exposure and Cardiometabolic Risk Factors in US Adults, and Potential Modification by Oxidative Balance Score, NHANES 2015–2018

Objectives: Phthalates are ubiquitous environmental endocrine-disrupting chemicals that may alter energy metabolism via oxidative stress mechanisms. We aimed to examine associations between phthalates and cardiometabolic risk factors in US adults and to explore whether oxidative balance score (OBS) modifies these associations. Methods: We analyzed cross-sectional data from 2,931 adults in NHANES 2015-2018. We categorized 14 urinary phthalate or terephthalate metabolites according to their parent compound as low molecular weight (LMW), high molecular weight (HMW), di-(2-ethylhexyl) phthalate (DEHP), or di-(2-ethylhexyl) terephthalate (DEHTP) metabolites and summed within each category. Using sex-stratified multivariable linear regressions, we analyzed associations of log-transformed phthalate sums with serum lipid (LDL-C, HDL-C, LDL-C/HDL-C, total cholesterol (TC), triglycerides (TGs)) and glucose levels (glucose, insulin, HOMA-IR, HbA1c), adjusting for relevant covariates. OBS was calculated using 4 pro-oxidant and 16 antioxidant dietary and lifestyle factors. We included product terms to explore potential association modification by OBS. Results: LMW phthalate and DEHTP metabolites were negatively associated with LDL-C (LMW: β = -8.9; 95% CI: -16.2, -1.7; DEHTP: β = -7.7; 95% CI: -13.7, -1.8) and LDL-C/HDL-C (LMW: β = -0.23; 95% CI: -0.44, -0.02; DEHTP: β = -0.18; 95% CI: -0.31, -0.05) in males. Associations between phthalates and lipids in females were limited to DEHP metabolites and TC (β: -13.4; 95% CI: -24.5, -2.4). For glucose-related outcomes, DEHP metabolites demonstrated significant positive associations with HOMA-IR (M: β = 0.11; 95% CI: 0.03, 0.20; F: β = 0.13; 95% CI: 0.01, 0.25) and HbA1c in all adults (M: β = 0.23; 95% CI: 0.04, 0.41; F: β = 0.26; 95% CI: 0.01, 0.51), and glucose in males (β = 9.0; 95% CI: 0.1, 17.8). DEHTP metabolites were also associated with HbA1c in all adults (M: β = 0.12; 95% CI: 0.04, 0.21; F: β = 0.10; 95% CI: 0.00, 0.20) and with glucose in males (β = 3.4; 95% CI: 0.1, 6.7). OBS did not significantly modify any associations. Conclusions: Phthalate exposure was associated with dyslipidemia and disturbed glucose homeostasis. OBS did not modify these associations, but future studies should explore the potential importance of oxidative stress using biomarkers (e.g., F2-isoprostanes, 8-OHdG). Funding Sources: None.