4-Vinylcyclohexene diepoxide (VCD), an industrial occupational health hazard chemical associated with premature ovarian insufficiency (POI) and reproductive failure. Recently, investigators have paid an increasing attention on VCD model of menopause recapitulates the natural, physiological transition through perimenopause to menopause. The current study sought to examining the mechanisms of follicular loss and exploring the effect of the model on systems outside of the ovaries. In this study, 28 days female SD rats were injected with VCD (160 mg/kg) vehicle for 15 consecutive days, euthanized in the diestrus phase approximately 100 days after the onset of treatment. Reproductive system injury, Neuroendocrine, sex hormone levels and receptor were observed, the levels of N6-methyladenosine (m6A) RNA modification and the expression of modulator genes were first measured. The VCD treated rats showing irregular estrous cycles, significantly reduced in the number of primordial follicles, the preantral and antral follicles also decreased significantly, accompanied by the plasma level of FSH increased and anti-Mullerian hormone (AMH) were decreased. The total m6A level was significantly decreased after exposure to VCD. Moreover, ALKBH5-mediated YAP m6A modification changed in VCD - induced premature ovarian insufficiency. These present work provides a new perspective on m6A modification in the VCD-induced POI rat model, which could provide valuable insights into the mechanisms underlying follicle development and finding new therapeutic targets for follicle prematurely exhausted. Also provide novel methodological guidance and endocrine basis to guide research and extend the applications in premature ovarian insufficiency model.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.