Prenatal exposure to air pollution and BWGA Z-score: Modifying effects of placenta leukocyte telomere length and infant sex

Background: Air pollutants, such as fine particulate matter (PM_2.5), nitrogen dioxide (NO₂), and ozone (O₃), have been associated with adverse birth outcomes, including low birth weight, often exhibiting sex-specific effects. However, the modifying effect of placental telomere length (TL), reflecting cumulative lifetime oxidative stress in mothers, remains unexplored. Method: Using data from a Northeastern U.S. birth cohort (n = 306), we employed linear regression and weighted quantile sum models to assess trimester-average air pollution exposures and birth weight for gestational age (BWGA) z-scores. Placental TL, categorized by median split, was considered as an effect modifier. Interactions among air pollutants, placental TL, infant sex, and BWGA z-score were evaluated. Results: Without placental TL as a modifier, only 1^st trimester O₃ was significantly associated with BWGA z-scores (coefficient: 0.33, 95% CI: 0.03, 0.63). In models considering TL interactions, a significant modifying effect was observed between 3^rd trimester NO₂ and BWGA z-scores (interaction p-value = 0.02). Specifically, a one interquartile range (1-IQR) increase in 3^rd trimester NO₂ was linked to a 0.28 (95% CI: 0.06, 0.52) change in BWGA z-score among shorter placental TL group, with no significant association among longer TL group. Among male infants, there were significant associations between 3^rd trimester PM_2.5 exposure and BWGA z-scores in the longer TL group (coefficient: −0.34, 95% CI: −0.61, −0.02), and between 1^st trimester O₃ exposure and BWGA z-scores among males in the shorter TL group (coefficient: 0.59, 95% CI: 0.06, 1.08). For females, only a negative association in 2^nd trimester mixture model was observed within the longer TL group (coefficient: −0.10, 95% CI: −0.21, −0.01). Conclusion: These findings highlight the need to consider the complex interactions among prenatal air pollutant exposures, placental TL, and fetal sex to better elucidate those at greatest risk for adverse birth outcomes.