Association between prenatal phthalate exposure and preschoolers' blood pressure: Mediating role of DNA methylation in hypertension-related genes.

BACKGROUND

Emerging evidence links prenatal phthalate (PAE) exposure to offspring cardiovascular risks, yet mechanisms underlying early-life hypertension remain elusive. Epigenetic regulation may represent a critical pathway connecting environmental exposures to developmental origins of cardiovascular disease.

OBJECTIVE

To investigate whether DNA methylation of hypertension-related genes mediates the association between gestational PAEs exposure and elevated blood pressure in preschoolers.

METHODS

In this prospective cohort of 198 mother-preschooler pairs (preschoolers aged 3-7 years), we quantified eight PAE metabolites (mPAEs) in third-trimester maternal urine. Preschoolers' blood pressure (BP) was measured clinically, with hypertension defined per the 2017 American Academy of Pediatrics guidelines. We assessed methylation in cardiovascular-related genes using targeted bisulfite sequencing. Generalized linear models (GLMs) examined associations between prenatal PAE exposure, DNA methylation levels, and BP z-scores. Mediation analysis evaluated whether DNA methylation mediated the effect of prenatal PAEs on SBP/DBP z-scores. Mediation analysis evaluated whether weighted methylation risk scores (wMRS) mediated the effect of prenatal PAEs on SBP/DBP z-scores.

RESULT: The wMRS of Endothelin-converting Enzyme 1 (ECE1) significantly mediated the associations of maternal urinary monomethyl phthalate (MMP), monoethyl phthalate (MEP), and mono(2-ethylhexyl) phthalate (MECPP) with increased systolic blood pressure (SBP) z-scores in preschoolers. Methylation at a specific site in the ECE1 gene (ECE1_position2) also significantly mediated the associations of prenatal MMP, MEP, and MECPP with increased systolic blood pressure z-scores. Positive associations were observed between MEP and MECPP with elevated SBP/DBP z-scores (β = 0.11-0.24, all P < 0.05). MMP, MEP, and MECPP were associated with methylation levels in ECE1 and the epithelial sodium channel gamma subunit (SCNN1G) genes, which in turn were linked to BP changes.

CONCLUSIONS

Our findings suggest that prenatal phthalate exposure programs later cardiovascular risk through an epigenetic pathway, highlighting ECE1 as a potential biomarker for early-life hypertension prevention.