Neonatal urinary phthalate metabolite concentrations are associated with the development of atopic dermatitis

초록

Background Perinatal phthalate exposure has been suggested as a potential contributor to atopic dermatitis (AD). Objective To investigate whether neonatal urinary phthalate levels predict the development of AD and to explore mechanisms involving immune activation and skin barrier dysfunction. Methods Urinary phthalate metabolites collected within 48 hours after birth were analyzed by liquid chromatography-tandem mass spectrometry. AD at 12 months of age was identified based on physician diagnosis and treatment history. Logistic regression analysis was used to evaluate the associations between phthalate levels and AD development. Peripheral blood mononuclear cells, human neonatal epidermal keratinocytes (HEKs), and organotypic skin cultures were exposed to phthalates to assess cytokine and epidermal barrier protein expression and to evaluate transepidermal water loss. Results Among 61 neonates, 11 (18.0%) developed AD by 12 months of age. Neonatal urinary concentrations of di(2-ethylhexyl) phthalate metabolites were associated with AD development (adjusted odds ratio, 2.03; 95% CI, 1.12-3.68; P = .020). Phthalate exposure increased interleukin-1β expression in peripheral blood mononuclear cells and HEKs (1.54-fold; 95% CI, 1.27-1.81; and 1.23-fold; 95% CI, 1.11-1.36, respectively), tumor necrosis factor–α expression (1.29-fold; 95% CI, 1.16-1.42; and 1.80-fold; 95% CI, 1.22-2.39, respectively), and interleukin-6 expression (1.55-fold; 95% CI, 1.36-1.74; and 1.96-fold; 95% CI, 1.31-2.62, respectively). Phthalate (10 ng/mL) inhibited filaggrin (0.68 ± 0.08; P < .05) and loricrin (0.67 ± 0.07; P < .05) expression in HEKs compared with media alone (1.03 ± 0.06 and 1.05 ± 0.04, respectively) and increased transepidermal water loss in an organotypic skin model (47.73 ± 3.72 vs 33.46 ± 1.56 g/m2h, P < .01). Conclusion Elevated neonatal urinary phthalate metabolites are associated with an increased risk of AD development. Phthalate-induced skin barrier dysfunction may contribute to the development of early-onset AD. Clinical Trial Registration The study was registered in the Clinical Research Information Service, Republic of Korea, which is part of the World Health Organization International Clinical Trials Registry Platform (registration number: KCT0007286)