S20-02 Sex-specific differences in the immunotoxicity of PFAS

Per- and polyfluoroalkyl substances (PFAS) are emerging environmental contaminants with multiple hazardous properties including immunotoxicity. This study aimed to investigate sex-specific differences in PFAS-associated effects on human immunity on two levels: 1) immune-mediated disease prevalence and 2) gene expression. This study involved 309 adults from the Czech Central European Longitudinal Study of Parents and Children: Young Adults (CEL-SPAC: YA). Associations between serum concentrations of nine PFAS and nine immune-mediated diseases were assessed using logistic regression. Furthermore, Bayesian kernel machine regression (BKMR) was applied to estimate the effect of the PFAS mixture on immune-mediated disease prevalence. In cases where a statistically significant interaction between PFAS exposure and sex was detected, sex-stratified analyses were performed. To explore transcriptomic profiles, RNA was isolated from participant's peripheral mononuclear blood cells, sequenced using QuantSeq library and Illumina sequencing, and analysed. Significantly expressed genes associated with perfluorooctanoic acid (PFOA) were identified in a sex-stratified manner and subjected to pathway enrichment analysis using Pathway Studio. All analyses were adjusted for relevant confounders (i.e., sex, age, BMI, smoking, education, and family history of immune-mediated diseases). Outcomes of both logistic regression and BKMR indicated that sex modifies the effect of PFAS exposure on immune-mediated diseases, particularly for PFOS and atopic eczema. The transcriptomic analysis also revealed sex-specific differences: 511 PFOA-associated genes were identified in women and 756 in men, with only 30 genes (2%) shared between the sexes. Similarly, pathway enrichment analysis showed differences in affected pathways and entities between men and women. Our findings highlight the immunomodulatory effects of PFAS exposure at both the disease and transcriptomic levels. The observed sex differences underscore the importance of conducting sex-stratified analyses when studying PFAS-associated effects.