Baseline and long-term changes in phthalate exposure are differentially associated with lipid peroxidative but not DNA oxidative stress in adolescents and young adults: A 10-year prospective cohort study

Phthalate exposure has been linked to oxidative stress, but evidence is largely cross-sectional or short-term, and the impact of long-term exposure trajectories across adolescence and early adulthood on specific oxidative pathways remains unclear. In this prospective study of the Young Taiwanese Cohort (YOTA), 341 participants aged 12-30 years had paired assessments in 2006-2008 and 2017-2019. Eleven urinary phthalate metabolites and two oxidative stress biomarkers, including 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-iso-prostaglandin F2α (8-iso-PGF2α), were measured at both time points. A phthalate exposure index was calculated as the mean of standardized natural log-transformed phthalate metabolites. Joint linear models included baseline levels and decade-long changes (Δ) to assess their independent associations with follow-up oxidative stress biomarkers. In joint models, neither baseline nor Δ phthalates were associated with follow-up 8-OHdG after false discovery rate correction. In contrast, follow-up 8-iso-PGF2α was positively associated with higher baseline MiBP and the baseline phthalate exposure index (46.2% increase per 1-SD; 95% CI: 13.9%, 87.8%; q = 0.021), as well as with long-term increases (Δ) in ΣDEHP, MMP, MiBP, MnBP, and MBzP. The Δ phthalate exposure index showed the strongest association (85.0% increase per 1-SD; 95% CI: 43.9%, 137.7%; q < 0.001). Restricted cubic spline analyses indicated largely linear dose-response patterns, and findings were robust across subgroup, sensitivity, and principal component analyses. In conclusion, long-term increases in phthalate exposure were robustly associated with higher lipid oxidative stress, but not oxidative DNA damage, highlighting differential oxidative pathways linked to phthalate exposure during the transition into adulthood.