Maternal Hyperhomocysteinemia Compromises Female Offspring Fertility Through Over-Activation of Primordial Follicles

Hyperhomocysteinemia (HHcy), characterized by elevated plasma homocysteine levels exceeding 15 µmol/L, has been associated with various issues impacting personal health and offspring's well-being. This study examines the impact of maternal HHcy, induced by a high-methionine diet, on the fertility of female offspring mice. The results showed that maternal HHcy caused the over-activation of primordial follicles in female offspring mice by promoting the phosphorylation of key factors, including RPS6, MTOR, FOXO3A, and AKT. Meanwhile, the number of mitochondria in mature oocytes decreases, and mitochondrial function declines, further leading to an increase in reactive oxygen species (ROS) levels, an increase in the proportion of DNA damage, and spindle abnormalities, ultimately impairing the quality of oocytes. These findings demonstrate that maternal HHcy decreases offspring fertility by inducing primordial follicle over-activation and impairing oocyte quality. This provides new insights into the pathological mechanisms of HHcy affecting offspring's reproductive potential.