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

Journal of Exposure Science & Environmental Epidemiology volume 32, pages 374–383 (2022)Cite this article

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%CI:1.07–29.9). 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.

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Fig. 1: Weights assigned from ridge regression depicting the relative importance of each phthalate metabolite for predicting birth outcomes at each study visit.
Fig. 2: Estimated -log10(p-values) of mediating effects by hormone concentrations on the associations between phthalate ERS and birth outcomes among all pregnancies.

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Data availability

The data dictionary for all variables used in this analysis is publicly available and can be found here: https://arecibo.ece.neu.edu/dictionary/. Any data requested will be made available by contacting the authors, who will forward to request to the PROTECT DMAC database manager. The request will be reviewed with the data owners, who will provide an export of the requested data after approval. All data from the database will be deidentified, individual level, participant data. All data is available now and will remain available until at least January 1, 2025. Any data requester must agree to acknowledge the NIEHS P42 Center grant that supported the collection of this data. Additional files, including analysis code, will also be provided by contacting the first and corresponding authors.

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Acknowledgements

We would like to extend our gratitude to all PROTECT study participants and their families. The authors also thank the nurses and research staff who participated in cohort recruitment and follow up, as well as the Federally Qualified Health Centers (FQHC) in Puerto Rico that facilitated participant recruitment, including Morovis Community Health Center, Prymed in Ciales, Camuy Health Services, Inc. and the Delta OBGyn Group in Manati, as well as the Manati Medical Center and the Metro Pavia Hospital in Arecibo.

Funding

This study was supported by the Superfund Research Program of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH; grant number P42ES017198). Additional support was provided from NIEHS grant numbers P30ES017885, R01ES031591, R01ES032202, and T32ES007062, and the Environmental influences on Child Health Outcomes (ECHO) program grant number UH3OD023251. ECHO is a nationwide research program supported by the NIH, Office of the Director to enhance child health.

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Authors and Affiliations

  1. Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA

    Amber L. Cathey, Deborah J. Watkins & John D. Meeker

  2. Program on Reproductive Health and the Environment, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, School of Medicine, San Francisco, CA, USA

    Max T. Aung

  3. Graduate School of Public Health, University of Puerto Rico, San Juan, PR, USA

    Zaira Y. Rosario & Carmen M. Vélez Vega

  4. College of Engineering, Northeastern University, Boston, MA, USA

    Akram N. Alshawabkeh

  5. College of Public Health, University of Georgia, Athens, GA, USA

    José F. Cordero

  6. Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA

    Bhramar Mukherjee

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  1. Amber L. Cathey
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Contributions

AC: Formal analysis, investigation, methodology, visualization, writing—original draft, writing—review and editing; MA: Methodology, writing—review and editing; DW: Supervision, writing—review and editing; ZR: Data curation, resources; CVV: Funding acquisition; AA: Funding acquisition, project administration; JC: Funding acquisition; BM: Conceptualization, methodology, supervision, writing—review and editing; JM: Conceptualization, funding acquisition, project administration, supervision, writing—review and editing.

Corresponding author

Correspondence to John D. Meeker.

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Cathey, A.L., Aung, M.T., Watkins, D.J. et al. Mediation by hormone concentrations on the associations between repeated measures of phthalate mixture exposure and timing of delivery. J Expo Sci Environ Epidemiol 32, 374–383 (2022). https://doi.org/10.1038/s41370-021-00408-3

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