Activation of the Rap1 signalingpathway is found in cancer, and AGE-RAGE signaling is involved inthe pathogenesis of diabetes.159,160 Several studies haveshown that PCOS is associated with impaired insulin signaling, aberrantMAPK signaling, and abnormal AMPK signaling in ovarian cumulus andgranulosa cells.66,161,162 The present results, together with the published literature on PCOSdevelopment and progression, show that ancestral BPA exposure seemsto have activated deleterious signaling pathways in the ovary of theBPA lineage leading to advanced-stage ovarian disease. Here, INS is linked to polycystic ovary syndrome.