Associations of Urinary Phthalate Metabolites and Inflammatory Biomarkers Characteristic of the Preeclamptic Pathway Among Pregnant Women in Puerto Rico

Abstract

Phthalates are ubiquitous environmental exposures that may be implicated in inflammatory processes, as demonstrated by previous in vivo and in vitro studies. Few human studies have substantiated these observations. This study sought to examine whether maternal phthalate exposures impact inflammatory processes, as measured by circulating inflammatory biomarkers, in the PROTECT cohort in northern Puerto Rico. Inflammatory biomarkers included matrix metalloproteinases 1, 2, and 9 (MMPs), C-reactive protein (CRP), vascular cell adhesion molecule-1 (VCAM), and intercellular cell adhesion molecule-1 (ICAM). Biomarkers were measured in maternal serum samples collected during pregnancy. 19 phthalate metabolites were assessed in urinary samples collected at three study visits across pregnancy. Phthalates with <50% of measurements above the limit of detection were excluded from analysis. We utilized linear mixed effect models to estimate associations between interquartile range increases in phthalate metabolite concentrations and percent changes in inflammatory biomarkers. Our results revealed significant associations between mono- n -butyl phthalate (MBP) and higher MMP1 by 7.86% (95% CI: 0.49, 15.76) and between mono oxononyl phthalate (MONP) and higher MMP2 by 8.30% (95% CI: 2.22, 14.75). We observed negative or null associations between phthalate metabolites and MMP2, MMP9, ICAM, VCAM, and CRP. Many results were significantly modified by fetal sex, particularly those between di-2-ethylhexyl phthalate (DEHP) metabolites and MMP1 (p-interaction: MEHHP=0.01, MEOHP= 0.04, MECPP= 0.01) and MMP2 (p-interaction: MEHHP=0.03, MEOHP=0.01, MECPP=0.01), for which associations were positive among only women carrying female fetuses. MMPs have been previously investigated as preeclamptic biomarkers given their role in artery remodeling. Hence, our findings suggest a potential role for phthalates in mediating the maternal inflammatory response, as well as significant sexual dimorphism in these relationships, which has implications for preeclampsia and other adverse pregnancy outcomes.

Note:

Funding Information: 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 R01ES032203, P30ES017885 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.

Declaration of Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethical Approval Statement: 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. The patients/participants provided their written informed consent to participate in this study.

Keywords: phthalates, inflammation, matrix metalloproteinase, PROTECT, pregnancy