Associations of Exposure to Air Pollution during the Male Programming Window and Mini-Puberty with Anogenital Distance and Penile Width at Birth and at 1 Year of Age in the Multicenter U.S. TIDES Cohort

Background: Ambient air pollution may be a developmental endocrine disruptor. In animal models, gestational and perinatal exposure to diesel exhaust and concentrated particulate matter alters anogenital distance (AGD), a marker of prenatal androgen activity, in both sexes. Little is known in humans.

Objectives: We examined exposure to fine particulate matter (${\mathrm{PM}}_{2.5}$) and nitrogen dioxide (${\mathrm{NO}}_2$) in relation to human AGD at birth and at 1 year of age, focusing on exposures during critical windows of reproductive development: the male programming window (MPW; gestational weeks 8-14) and mini-puberty (postnatal months 1-3).

Methods: The Infant Development and Environment Study (TIDES) recruited first trimester pregnant women ($n=687$) at four U.S. sites (Minneapolis, Minnesota; Rochester, New York; San Francisco, California; and Seattle, Washington) from 2010 to 2012. We measured anus to clitoris (AGD-AC) and anus to fourchette (AGD-AF) in female infants at birth; in males, we measured anus to penis (AGD-AP), anus to scrotum (AGD-AS), and penile width at birth and at 1 year of age. Using advanced spatiotemporal models, we estimated maternal exposure to ${\mathrm{PM}}_{2.5}$ and ${\mathrm{NO}}_2$ in the MPW and mini-puberty. Covariate-adjusted, sex-stratified linear regression models examined associations between ${\mathrm{PM}}_{2.5}$ and ${\mathrm{NO}}_2$ and AGD.

Results: In males, a $1{\text{-}\mu g/m}^3$ increase in ${\mathrm{PM}}_{2.5}$ exposure during the MPW was associated with shorter AGD at birth, but a longer AGD at 1 year of age (e.g., birth AGD-AP: $\beta =-0.35\mathrm{mm}$; 95% CI: $-0.62$, $-0.07$; AGD-AS: $\beta =0.37\mathrm{mm}$; 95% CI: 0.02, 0.73). Mini-pubertal ${\mathrm{PM}}_{2.5}$ exposure was also associated with shorter male AGD-AP ($\beta =-0.50\mathrm{mm}$; 95% CI: $-0.89$, $-0.11$) at 1 year of age. Although not associated with male AGD measures, $1\text{-ppb}$ increases in ${\mathrm{NO}}_2$ exposure during the MPW ($\beta =-0.07\mathrm{mm}$; 95% CI: $-0.02$, $-0.12$) and mini-puberty ($\beta =-0.04\mathrm{mm}$; 95% CI: $-0.08$, 0.01) were both associated with smaller penile width at 1 year of age. Results were similar in multipollutant models, where we also observed that in females AGD-AC was inversely associated with ${\mathrm{PM}}_{2.5}$ exposure, but positively associated with ${\mathrm{NO}}_2$ exposure.

Discussion: ${\mathrm{PM}}_{2.5}$ and ${\mathrm{NO}}_2$ exposures during critical pre- and postnatal windows may disrupt reproductive development. More work is needed to confirm these novel results and clarify mechanisms. https://doi.org/10.1289/EHP12627.