Oxidative stress as a pathway linking maternal phthalate and bisphenol exposure to childhood allergy and lung function: Mediation and interaction analyses.

Phthalates and bisphenols may contribute to childhood allergies through oxidative stress (OS). We examined OS as a potential pathway using two approaches: maternal OS biomarkers to evaluate mediation, and an OS genetic pathway function score reflecting child-level susceptibility to evaluate gene-environment interactions. In an Australian population-based birth cohort (n = 797), nine phthalate metabolites, three bisphenols, and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were measured from spot urine samples at 36 weeks' gestation, with allergic and lung function outcomes assessed up to age four. Associations were estimated with generalised linear models for single exposures, and mixtures were analysed using weighted quantile sum regression (mediation) and quantile g-computation (interaction). The phthalate mixture (mainly driven by dimethyl and diethyl phthalates) was associated with a 14.6% increase in 8-OHdG (95% confidence interval [CI]: 9.4, 18.8). 8-OHdG mediated the association between the phthalate mixture and ventilation inhomogeneity (LCI2.5), with a mediated effect of 0.051 SD (95% CI: 0.002, 0.100). There were additive interactions between diethyl and dibutyl phthalates and genetic susceptibility for asthma and wheeze. The phthalate mixture was associated with higher LCI2.5 (β = 0.89 SD; 95% CI: 0.33, 1.45) and increased risks of asthma (risk ratio [RR] = 2.47; 95% CI: 1.31, 4.65) and wheeze (RR = 1.89; 95% CI: 1.21, 2.94), only in children genetically susceptible (p for interaction ≤0.002). No associations were observed for bisphenols or for other outcomes. This study suggests that OS may be a pathway through which maternal phthalate exposure impairs respiratory health in early childhood.