Environ Pollut. 2025 Nov 27:127450. doi: 10.1016/j.envpol.2025.127450. Online ahead of print.
ABSTRACT
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.
PMID:41317780 | DOI:10.1016/j.envpol.2025.127450