Phthalates are detected in the follicular fluid of adolescents and oocyte donors with associated changes in the cumulus cell transcriptome.

Purpose:To investigate follicular fluid (FF) phthalate levels in adolescents undergoing fertility preservation compared to oocyte donors and explore its association with ovarian reserve and cumulus cell gene expression. Methods:20 Adolescents (16.7 ± 0.6 years old) and 24 oocyte donors (26.2 ± 0.4 years old) undergoing fertility preservation were included in the study. Patient demographics, ovarian stimulation and oocyte retrieval outcomes were analyzed for each group. FF levels of 9 phthalate metabolites were assessed individually and as molar sums representative of common compounds (all phthalates: ΣPhthalates; DEHP: ΣDEHP), exposure sources (plastics: ΣPlastic; personal care products: ΣPCP), and modes of action (anti-androgenic: ΣAA) and compared between the two groups. Results:Follicular fluid ΣPlastic and ΣPCP levels were significantly higher in adolescents compared to oocyte donors (p<0.05). Follicular fluid ΣDEHP, ΣPlastic, ΣPCP, ΣAA, and ΣPhthalates levels were positively associated with antral follicle count (AFC) (p<0.05) in oocyte donors when adjusted for age, BMI, and race/ethnicity. RNA-seq analysis revealed 248 differentially expressed genes (DEGs) in cumulus cells of adolescents within the top quartile (n=4) of FF ΣPhthalates levels compared to the adolescents within the bottom half (n=9). Genes enriched in pathways involved in cell motility and development were significantly downregulated. Conclusion:Adolescents undergoing fertility preservation cycles demonstrate higher levels of phthalate metabolites in their follicular fluid compared to oocyte donors. Phthalate metabolite levels in FF are associated with higher AFC levels in oocyte donors. Higher phthalate levels in FF are associated with alterations in the cumulus cells transcriptome in adolescents.