PFAS Levels, Early Life Factors, and Mammographic Breast Density in Premenopausal Women

Background: Mammographic breast density (MBD) is a strong risk factor and an intermediate phenotype for breast cancer, yet there are limited studies on how environmental pollutants are associated with MBD.

Objective: We investigated associations of perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and perfluorohexane sulfonate (PFHxS) levels with measures of MBD and evaluated if early life factors modified any associations.

Methods: Metabolon performed metabolomics analysis using ultrahigh-performance liquid chromatography/tandem accurate mass spectrometry in fasting blood from 705 premenopausal women completing their annual screening mammogram in St. Louis, Missouri. We calculated least square means (LSM) of mammographic volumetric percent density (VPD), dense volume (DV), and nondense volume (NDV) by quartiles (Q) of PFOS, PFOA, and PFHxS from multivariable linear regression modeling overall and stratified by recruitment period, race, age at menarche, and body shape at age 10. Models were adjusted for age, age at menarche, body fat percentage, race, family history of breast cancer, oral contraceptive use, alcohol consumption, parity/age at first birth, and body shape at age 10.

Results: PFOS, PFOA, and PFHxS were not significantly associated with VPD or NDV. PFHxS was significantly positively associated with DV ($Q1=67.64{\mathrm{cm}}^3$, $Q2=69.91{\mathrm{cm}}^3$, $Q3=69.06{\mathrm{cm}}^3$, $Q4=75.79{\mathrm{cm}}^3$; $p\text{-trend}=0.03$). PFOS was positively associated with DV ($Q1=65.45{\mathrm{cm}}^3$, $Q2=70.74{\mathrm{cm}}^3$, $Q3=73.31{\mathrm{cm}}^3$, $Q4=73.52{\mathrm{cm}}^3$; $p\text{-trend}=0.06$) with DV being 8.1%, 12%, and 12.3% higher in Q2, Q3, and Q4 compared to Q1. Among women who were underweight/normal weight at age 10, PFOS was positively associated with VPD ($Q1=9.02\%$, $Q2=9.11\%$, $Q3=9.48\%$, $Q4=9.92\%$; $p\text{-trend}=0.04$) while there was an inverse association among women who were overweight/obese at age 10 ($Q1=7.46\%$, $Q2=6.94\%$, $Q3=6.78\%$, $Q4=5.47\%$; $p\text{-trend}=0.005$) ($p\text{-interaction}=0.04$).

Discussion: We report novel associations of PFHxS and PFOS with DV in premenopausal women. PFOS, PFOA, and PFHxS were not associated with VPD and NDV. In addition, body shape at age 10 may modify the associations of PFOS with MBD. Further studies are needed to validate our findings and to evaluate the associations of other per- and polyfluoroalkyl substances (PFAS), as well as mixtures of PFAS, with MBD. https://doi.org/10.1289/EHP14065.