Serum concentrations of per- and polyfluoroalkyl substances and mosaic chromosomal alterations in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial

Per- and polyfluoroalkyl substances (PFAS) are persistent organic pollutants detectable in the serum of most U.S. adults. Some PFAS are established or possible human carcinogens. Mechanistic studies in human cells and animals suggest PFAS may have genotoxic effects through indirect DNA damage caused by oxidative stress or other pathways; however, evidence from human populations remains limited. We investigated the relationship between serum PFAS concentrations and mosaic chromosomal alterations (mCAs), including autosomal mCAs among both men and women and mosaic loss of chromosome Y (mLOY) among men, as biomarkers of genotoxicity and genomic instability. We analyzed blood-derived DNA from 2,377 men and 696 women in three nested case-control studies within the PLCO Cancer Screening Trial. mCAs were detected using high-density genotyping array intensity data for the autosomes in men and women and separately in the male-specific region of the Y chromosome for mLOY. Pre-diagnostic serum concentrations of four PFAS [perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), perfluorononanoate (PFNA)] were measured. Using study-specific multivariable logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between serum PFAS concentrations and any detectable autosomal mCA, any mLOY, and mLOY affecting ≥10% of cells (expanded mLOY) among cancer cases and cancer-free controls, separately. Study- and case-control-specific results were summarized using random effects meta-analyses. Overall, autosomal mCAs were detected in 7% of men and 8% of women. Among men, 22% had mLOY, including 8.3% with expanded mLOY. 2% of men had both autosomal mCAs and mLOY. We found a suggestive positive association between serum PFOS concentrations and autosomal mCAs (per doubling in serum concentration, summary OR continuous =1.43, 95%CI=0.93-2.21; I-squared=49%, P-heterogeneity=0.08). Among men, serum PFHxS was marginally positively associated with mLOY (any mLOY, summary OR continuous =1.14, 95%CI=0.83-1.40; I-squared=59%, P-tenerogeneity=0.03), and the magnitude of the association was stronger for those with a higher proportion of affected cells (expanded mLOY; summary OR continuous =1.19, 95% CI=0.89-1.59; I-squared=58%, P-tenerogeneity=0.03). No associations were observed for other PFAS. In conclusion, in this large population-based study, we observed suggestive evidence of a positive association between elevated serum PFOS concentrations and autosomal mCAs among men and women, and between serum PFHxS and mLOY among men. As the first study to evaluate PFAS in relation to mCAs, our findings, if confirmed, may provide new insights into PFAS-related effects on genome maintenance that are relevant to cancer development.