Placental Methylation Profile in Women Exposed to Fluoride and Its Association with Kidney Volume at Birth

Placental DNA methylation patterns were associated with neonatal kidney volume in a population with high fluoride exposure. Newborns with high fluoride exposure and low kidney volume showed methylation changes in genes involved in kidney development pathways. These placental epigenetic patterns revealed early markers of altered kidney development, potentially linked to reduced nephron endowment.

Mexico has a high burden of CKD. The state of Aguascalientes is among the regions with the highest reported prevalence of ESKD worldwide. In this setting, CKD of unknown etiology predominates and has been associated with a low number of nephrons of prenatal origin. This study examines the DNA methylation profile following maternal exposure to fluoride and its relationship with lower kidney volume (KV) in neonates.

This cross-sectional study included at-term pregnant women without concomitant comorbidities. Neonatal total kidney volume was calculated using ultrasound imaging. Maternal urine was collected to quantify xenobiotics, and placental DNA methylation was analyzed using the Illumina MethylationEPIC BeadChip. Neonates were classified by total kidney volume percentile (low kidney volume = <10th percentile; control = >10th percentile), and fluoride (F - ) exposure (F - ≥1.5 mg/L; NF - <1.5 mg/L). Bioinformatic analyses were performed to identify differentially methylated genes and enriched biologic pathways associated with KV status and fluoride exposure.

Thirty-two women were included in the study between March 2023 and April 2024. Principal component analysis revealed distinct placental methylation profiles between the groups (low kidney volume/F - and control/NF). Epigenome-wide analysis identified 7540 differentially methylated sites (6635 hypomethylated and 905 hypermethylated; adjusted P value [ false discovery rate ] < 0 . 01 and Δ β ≥0.1). Integration of stratified comparisons across KV and fluoride exposure identified a shared epigenetic signature of 244 differentially methylated genes, including protocadherin clusters and genes related to kidney development, cell adhesion, and developmental signaling. Functional enrichment analyses highlighted pathways involved in calcium signaling, focal adhesion, and organogenesis.

Placental DNA methylation profiles associated with neonatal KV were identified in a population with prenatal fluoride exposure. The consistency and biologic relevance of the identified epigenetic signature support an association between fluoride exposure and alterations in placental DNA methylation involving pathways critical for early kidney development.