Mediation by hormone concentrations on the associations between repeated measures of phthalate mixture exposure and timing of delivery.

ABSTRACT

BACKGROUND: Phthalates are used in the manufacturing of consumer products, resulting in ubiquitous human exposure to phthalate mixtures. Previous work has suggested that phthalates display endocrine-disrupting capabilities, and exposure is associated with early delivery. OBJECTIVE: To assess mediating effects of hormone concentrations on associations between phthalate mixtures and preterm birth (PTB). METHODS: Repeated urinary phthalates and serum hormones were measured among 1011 women in the PROTECT Puerto Rico birth cohort from 2011-2019. We utilized ridge regression to create phthalate environmental risk scores (ERS), which represent weighted summaries of total phthalate exposure. Mediation analyses were conducted on a subset of 705 women. We additionally conducted fetal sex-specific analyses. RESULTS: Free thyroxine (FT4) mediated 9.6% of the association between high molecular weight (HMW) ERS at 18 weeks and reduced gestational age at delivery (95%CI1.07-29.9). Progesterone at 26 weeks mediated 21.1% and 16.2% of the association between HMW ERS at 18 and 22 weeks, and spontaneous PTB, respectively. Among male fetuses, corticotropin releasing hormone (CRH) at 18 weeks mediated 28.2% of the association between low molecular weight ERS and spontaneous PTB. SIGNIFICANCE: We provide introductory evidence of hormone disruption on the causal pathway between phthalate exposure and early delivery. We also show differences by fetal sex, but larger sample size is necessary to validate our findings. IMPACT STATEMENT This study provides introductory evidence that an alteration of hormone concentrations occurs on the causal pathway between gestational phthalate mixture exposure and subsequent PTB. In addition to the novel application of repeated biomarker measurements and mixtures methods in causal mediation analyses, we also explored differences between classes of phthalate compounds and between fetal sexes. We show that differential endocrine pathways may be disrupted with exposures to low versus HMW phthalate compounds, and that pregnancies with a male fetus may be more susceptible to endocrine disruption than those with a female fetus.