Per- and polyfluoroalkyl substances, vitamin D, and risk of preterm birth in a Canadian cohort

Background Vitamin D, which is essential for calcium and phosphorus homeostasis, may also influence immune regulation and offer protection against preterm birth (PTB). Per- and polyfluoroalkyl substances (PFAS) are associated with both increases and decreases in 25-hydroxyvitamin D (25OHD) concentrations and have been shown to compete for binding sites on the vitamin D receptor (VDR). We investigated associations between PFAS and preterm birth, and the potential modification by vitamin D status and single nucleotide polymorphisms (SNPs) of the VDR. Methods We used adjusted discrete-time survival models for individual PFAS, and quantile g-computation for the PFAS mixture. Effect modification was investigated (additive and multiplicative) by first-trimester vitamin D status (≥ vs. < 50 nmol/L 25OHD) and four VDR variants: ApaI (rs7975232), BsmI (rs1544410), TaqI (rs731236) and FokI (rs2228570). Results Among 1857 singleton births, 114 (6%) were PTBs. Each doubling of perfluorononanoic acid (PFNA) was associated with an approximate 30% increase in the odds of PTB. We found significant qualitative interactions between a number of PFAS and vitamin D status, with elevated risk specific to those with sufficent vitamin D status (≥ 50 nmol/L) for PFNA (OR=1.56, 95% CI :1.15, 2.12). We observed effect modification of the association between PFNA and PFDA by some VDR genotypes. The stratified analysis showed elevated odds among genotypes of ApaI (Aa, OR=1.78, 95% CI: 1.19, 2.60), BsmI (BB, OR=1.75, 95% CI: 1.13, 2.64), and TaqI (TT, OR=1.73, 95% CI: 1.13, 2.59) with each doubling in PFNA. Perfluorodecanoic acid (PFDA) was associated with an increased odds of PTB among those homozygous for the major alleles of BsmI (OR BB =1.76, 95% CI: 1.17, 2.58) and TaqI (OR TT =1.65, 95% CI: 1.13, 2.38). Conclusions PFNA exposure was associated with elevated odds of PTB, with evidence of modification by vitamin D status and VDR genotype. PFAS may disrupt receptor-mediated pathways, producing pleiotropic effects. We postulate the observed modification by vitamin D status is partly due to confounding by fish consumption. Further investigation into these associations in other pregnancy cohorts is warranted.