Phthalate and Terephthalate Mixtures, Cardiometabolic Risk Factors, and the Role of Oxidative Stress: Evidence from NHANES 2015–2018

Phthalates are a class of endocrine-disrupting chemicals that may impair glucose and lipid metabolism through oxidative stress pathways. In this study, we analyzed NHANES 2015-2018 data on 2,336 U.S. adults and assessed fifteen phthalate and terephthalate metabolites, four glycemic outcomes, and five lipid outcomes. We used multivariable weighted quantile sum (WQS) regression to examine negative and positive associations of phthalate/terephthalate mixtures with glycemic and lipid outcomes. We assessed mediation by oxidative stress via gamma-glutamyltransferase (GGT) and explored modification by a composite score of dietary and lifestyle anti- and pro-oxidants (i.e., oxidative balance score, OBS) through the inclusion of product terms (WQS index*OBS) in linear regressions. A one-decile increase in phthalate/terephthalate mixtures dominated by mono(2-ethyl-5-hydroxyhexyl) terephthalate was associated (Estimate; 95% CI) with higher fasting glucose (1.95; 0.75, 3.14), fasting insulin (9.10%; 6.32%, 11.95%), HOMA-IR (9.86%; 6.86%, 12.94%), and HbA1c (0.05; 0.03, 0.07). Phthalate/terephthalate mixtures were associated with lower HDL-C (-0.93; -1.26, -0.60), LDL-C (-2.28; -3.54, -1.02), and total cholesterol (TC) (-1.89; -2.86, -0.93), and with higher fasting triglycerides (2.98%; 0.77%, 5.23%). GGT mediated a limited number of associations. OBS attenuated adverse associations between phthalate/terephthalate mixtures and select lipid outcomes, including HDL-C and TC/HDL-C ratio, among females. Overall, exposure to a mixture of phthalate/terephthalate metabolites was associated with disrupted glucose and lipid metabolism markers in this cross-sectional study. Oxidative stress may play a role in some of these associations, potentially providing a target for intervention, but longitudinal and randomized trials are needed to confirm these findings.