Longitudinal Mediation by Hormone Concentrations on the Associations between Exposure to Phthalate Mixtures and Adverse Birth Outcomes

Abstract

Background: Phthalates are used in manufacturing of a myriad of consumer products, resulting in ubiquitous human exposure to a mixture of phthalate compounds. Previous work has suggested that phthalates display endocrine disrupting capabilities, and exposure is associated with adverse birth outcomes including preterm birth. This work therefore aimed to assess the mediating effects of hormone concentrations on associations between phthalate mixtures and adverse birth outcomes. Methods: Repeated phthalate metabolites (13) were measured in urine at three time points and hormones (9) were measured in serum at two time points, spanning 16-28 weeks gestation, among 1011 women in the PROTECT (Puerto Rico Testsite for Exploring Contamination Threats) birth cohort. We utilized ridge regression to create phthalate environmental risk scores (ERS) at each study visit grouped by phthalates of high versus low molecular weight (HMW, LMW), which represent a weighted sum of exposure to the mixture of metabolites. Causal mediation analyses were conducted on a subset of 705 women for whom complete phthalate and hormone data were available. We additionally conducted exploratory analyses stratified by fetal sex. Findings: Positive associations between HMW phthalate ERS at the first study visit and odds of spontaneous PTB and reduced gestational age at delivery among all pregnancies were modestly mediated by changes in fT4 (8.81% (-0.55, 51.2) and 9.60% (1.07, 29.9) mediated, respectively). Though total effects of the corresponding ERS on the outcome were not significant, we also observed significant mediating effects for the ratio of testosterone to SHBG at visit 1 on the association between LMW phthalate ERS and spontaneous PTB, and for progesterone at visit 3 on the associations between visits 1 and 2 HMW phthalate ERS and spontaneous PTB among all pregnancies. Among only pregnancies with a male fetus, the inverse association between visit 2 LMW phthalate ERS and spontaneous PTB was marginally mediated by visit 3 CRH (10.8% (-2.5, 32.9) mediated). Interpretation: These results provide introductory evidence of hormone disruption on the causal pathway between phthalate exposure and early delivery. We also provide evidence of differences by fetal sex, but a larger sample size is necessary to validate our findings. Funding: National Institutes of Health, National Institute of Environmental Health Sciences Declaration of Interest: None to declare. Ethical Approval: This study was approved by the research and ethics committees of the University of Michigan School of Public Health, University of Puerto Rico, Northeastern University, and participating hospitals and clinics. All study participants provided full informed consent prior to participation.