Associations of prenatal exposure to phthalates and their mixture with lung function in Mexican children

Abstract

Early life phthalates exposure has been associated with adverse respiratory outcomes. However, evidence linking prenatal phthalates exposure and childhood lung function has been inconclusive. Additionally, few studies have examined phthalates exposure as a mixture and explored sexually dimorphic associations. We aimed to investigate sex-specific associations of prenatal phthalates mixtures with childhood lung function using the PROGRESS cohort in Mexico (N = 476). Prenatal phthalate concentrations were measured in maternal urine collected during the 2^nd and 3^rd trimesters. Children's lung function was evaluated at ages 8-13 years. Individual associations were assessed using multivariable linear regression, and mixture associations were modeled using repeated holdout WQS regression and hierarchical BKMR; data was stratified by sex to explore sex-specific associations. We identified significant interactions between 2^nd trimester phthalates mixture and sex on FEV₁ and FVC z-scores. Higher 2^nd trimester phthalate concentrations were associated with higher FEV₁ (β = 0.054, 95 %CI: 0.005, 0.104) and FVC z-scores (β = 0.074, 95 % CI: 0.024, 0.124) in females and with lower measures in males (FEV₁, β = -0.017, 95 %CI: -0.066, 0.026; FVC, β = -0.014, 95 %CI: -0.065, 0.030). This study indicates that prenatal exposure to phthalates is related to childhood lung function in a sex-specific manner.

Keywords: Child health; Lung function; Mixture exposure; Phthalates.

Fig. 1.

Mean adjusted betas (A) and sex-specific relative weights (B) from a WQS (negative constraint) linear regression model with 100 repeated holdouts between 2^nd trimester phthalates mixture and FEV1 z-score. The model was adjusted for maternal age, BMI, ETS, education, parity. (A) Illustrates the distribution of the adjusted betas across the 100 repeated holdouts where each dot represents the estimate from each holdout. (B) Illustrates the mean estimated relative weight for each chemical of the phthalate mixtures across the 100 repeated holdouts. The relative weight is the percentage of weight attributable to each chemical in the phthalate mixtures within the total weight of each strata (males and females). The dotted line represents the threshold (11.1%) for chemicals of concern. Chemicals with relative weights above this threshold in at least 50% of the repeated holdouts were considered chemicals of concern. Abbreviations: FEV₁ = forced expiratory volume in 1 s; BMI = body mass index; ETS = environmental tobacco smoke; Notes: All chemicals were log₂ transformed to reduce skewness in the distribution of the concentrations.

Fig. 2.

Mean adjusted betas (A) and sex-specific relative weights (B) from a WQS (negative constraint) linear regression model with 100 repeated holdouts between 2^nd trimester phthalates mixture and FVC z-score. The model was adjusted for maternal age, BMI, ETS, education, parity. (A) Illustrates the distribution of the adjusted betas across the 100 repeated holdouts where each dot represents the estimate from each holdout. (B) Illustrates the mean estimated relative weight for each chemical of the phthalate mixtures across the 100 repeated holdouts. The relative weight is the percentage of weight attributable to each chemical in the phthalate mixtures within the total weight of each strata (males and females). The dotted line represents the threshold (11.1%) for chemicals of concern. Chemicals with relative weights above this threshold in at least 50% of the repeated holdouts were considered chemicals of concern. Abbreviations: FVC = forced vital capacity; BMI = body mass index; ETS = environmental tobacco smoke; Notes: All chemicals were log₂ transformed to reduce skewness in the distribution of the concentrations.

Fig. 3.

BKMR mixture associations of the 2^nd (A) and 3^rd (B) phthalate metabolites with sex-specific FEV₁ at ages 8 to 13 years. The models are adjusted for maternal age, BMI, ETS, education, and parity. A1 and B1. Exposure-response relationships for each phthalate metabolite while holding all other metabolites at their median concentrations. A2 and B2. Overall association of the phthalates mixture at different concentration percentiles compared to the 50th percentile and their 95 % credible intervals. FEV₁, forced expiratory volume in 1 s. DEHP, di(2-ethylhexyl) phthalate; DiNP, diisononyl phthalate; DiBP, diisobutyl phthalate; DBP, dibutyl phthalate; MECPTP, mono-2-ethyl-5-carboxypentyl terephthalate; MCNP, mono(carboxy-isononyl) phthalate; MCPP, mono-3-carboxypropyl phthalate; MBzP, monobenzyl phthalate; MEP, monoethyl phthalate.

Fig. 4.

BKMR mixture associations of the 2^nd (A) and 3^rd (B) phthalate metabolites with sex-specific FVC at ages 8 to 13 years. The models are adjusted for maternal age, BMI, ETS, education, and parity. A1 and B1. Exposure-response relationships for each phthalate metabolite while holding all other metabolites at their median concentrations. A2 and B2. Overall association of the phthalates mixture at different concentration percentiles compared to the 50th percentile and their 95 % credible intervals. FVC, forced vital capacity. DEHP, di(2-ethylhexyl) phthalate; DiNP, diisononyl phthalate; DiBP, diisobutyl phthalate; DBP, dibutyl phthalate; MECPTP, mono-2-ethyl-5-carboxypentyl terephthalate; MCNP, mono(carboxy-isononyl) phthalate; MCPP, mono-3-carboxypropyl phthalate; MBzP, monobenzyl phthalate; MEP, monoethyl phthalate.

Fig. 5.

BKMR mixture associations of the 2^nd (A) and 3^rd (B) phthalate metabolites with sex-specific EFV₁/FVC at ages 8 to 13 years. The models are adjusted for maternal age, BMI, ETS, education, and parity. A1 and B1. Exposure-response relationships for each phthalate metabolite while holding all other metabolites at their median concentrations. A2 and B2. Overall association of the phthalates mixture at different concentration percentiles compared to the 50th percentile and their 95 % credible intervals. DEHP, di(2-ethylhexyl) phthalate; DiNP, diisononyl phthalate; DiBP, diisobutyl phthalate; DBP, dibutyl phthalate; MECPTP, mono-2-ethyl-5-carboxypentyl terephthalate; MCNP, mono(carboxy-isononyl) phthalate; MCPP, mono-3-carboxypropyl phthalate; MBzP, monobenzyl phthalate; MEP, monoethyl phthalate.

Fig. 6.

BKMR mixture associations of the 2^nd (A) and 3^rd (B) phthalate metabolites with sex-specific FEF_25–75% at ages 8 to 13 years. The models are adjusted for maternal age, BMI, ETS, education, and parity. A1 and B1. Exposure-response relationships for each phthalate metabolite while holding all other metabolites at their median concentrations. A2 and B2. Overall association of the phthalates mixture at different concentration percentiles compared to the 50th percentile and their 95 % credible intervals. FEF_25–75%, forced expiratory flow between 25% and 75%; DEHP, di(2-ethylhexyl) phthalate; DiNP, diisononyl phthalate; DiBP, diisobutyl phthalate; DBP, dibutyl phthalate; MECPTP, mono-2-ethyl-5-carboxypentyl terephthalate; MCNP, mono(carboxy-isononyl) phthalate; MCPP, mono-3-carboxypropyl phthalate; MBzP, monobenzyl phthalate; MEP, monoethyl phthalate.