Mediating role of oxidative/nitrosative stress biomarkers in the associations between phthalate exposure and thyroid function in Taiwanese adults

Abstract

Phthalate exposure was shown to alter thyroid function, however it is unclear, whether oxidative and nitrosative stress explains the intermediate biological mechanism. This study aimed to investigate the associations between phthalate exposure, oxidative/nitrosative stress, and thyroid function in adults, and to examine the mediating role of oxidative/nitrosative stress in the associations between phthalate exposure and thyroid function. Levels of eleven urinary phthalate metabolites, three urinary biomarkers of oxidative/nitrosative stress (malondialdehyde [MDA], 8-OHdG, and 8-NO₂Gua) and five serum thyroid hormones (thyroxine [T₄], free T₄, triiodothyronine, thyroid-stimulating hormone, and thyroxine-binding globulin) were measured in 266 Taiwanese adults. Cross-sectional associations between phthalate metabolites, biomarkers of oxidative/ nitrosative stress and thyroid hormones were analyzed using multivariate regression models. Mediation analysis was conducted to assess the role of oxidative/nitrosative stress in the associations between phthalate metabolites and thyroid hormone levels. Sum of di-(2-ethylhexyl) phthalate (DEHP) metabolites was positively associated with MDA (β_T1-T2 = 0.253, 95%CI [0.060, 0.447]; β _{≧ T2} = 0.317, 95% CI [0.098, 0.536]; P_trend = 0.005) and 8-NO₂Gua (β_T1-T2 = -0.010, 95%CI [-0.138, 0.118]; β _{≧ T2} = 0.144, 95% CI [-0.001, 0.289]; P_trend = 0.045). Mono-n-butyl phthalate (MnBP) was positively associated with 8-NO₂Gua (β_T1-T2 = 0.201, 95% CI [0.078, -0.324]; β _{≧ T2} = 0.161, 95% CI [0.031, -0.292]; P_trend = 0.018). T₄ was negatively associated with MDA (β_T1-T2 = -0.027, 95% CI [-0.088, 0.0034]; β_≧T2 = -0.094, 95% CI [-0.161, -0.028]; P_trend = 0.005) and 8-NO₂Gua (β_T1-T2 = -0.068, 95% CI [-0.127, -0.010]; β_≧T2 = -0.125, 95% CI [-0.184, -0.066]; P_trend < 0.001). Free T₄ was positively associated with MDA (P_trend = 0.047) and with 8-NO₂Gua (P_trend < 0.001). 8-NO₂Gua mediated 11% of the association between the sum of DEHP metabolites and T₄, and 17% of the association between MnBP and free T₄. These results suggest that phthalate exposure may influence thyroid hormone levels through induced oxidative/nitrosative stress.

Keywords: Mediation analysis; Nitrosative stress; Oxidative stress; Phthalates; Thyroid hormones.