PFOS Disrupts Oocyte Maturation and Early Embryonic Development via Ovarian FOXK1 O‐GlcNAcylation in Mice

Abstract Perfluorooctane sulfonate (PFOS) is of great concern due to its accumulation in living organisms and reproductive toxicity. Although prior studies indicate that PFOS exposure causes female reproductive disorders, the underlying mechanism remains obscure. This study investigates the molecular mechanisms underlying PFOS‐induced female reproductive toxicity at human‐relevant exposure levels. These results demonstrate that PFOS exposure (0.2 and 20 µ M ) significantly reduces polar body extrusion (PBE) and delays germinal vesicle breakdown (GVBD) in oocytes. Additionally, PFOS exposure (1 mg kg −1 day −1 ) decreases the proportion of two‐cell embryos and reduces progesterone (P4) levels. Elevated O‐GlcNAcylation levels are observed in both ovaries and granulosa cells (GCs) under PFOS treatment. Proteomic profiling of protein O‐GlcNAcylation identifies that the O‐GlcNAcylation of forkhead box k1 (FOXK1) at threonine (Thr) 573 cite involved in ovarian steroidogenesis. Mechanistically, co‐immunoprecipitation (Co‐IP) combined with LC‐MS/MS analysis reveals a physical interaction between FOXK1 and pescadillo ribosomal biogenesis factor 1 (PES1). Increased O‐GlcNAcylation of FOXK1 at Thr573 inhibits the ubiquitination‐mediated degradation of PES1, leading to elevated PES1 expression. Furthermore, PES1 promotes aldo‐keto reductase family 1, member C18 (AKR1C18) to reduce P4 levels, ultimately disrupting oocyte maturation and early embryonic development. Overall, this study provides valuable insights into the role of protein post‐translational modifications in oocyte maturation and embryonic development under PFOS exposure.