Construction of an Adverse Outcome Pathway Framework for Glyphosate-Induced Female Reproductive Toxicity Based on...

Glyphosate (GLY), the most widely used herbicide globally, is pervasive in the environment and has been detected in human tissues. Evidence from in vitro and in vivo studies suggests that GLY and its commercial formulations, glyphosate-based herbicides (GBHs), disrupt normal endocrine function, adversely affecting reproduction. This review synthesizes the current knowledge on GLY/GBHs-induced female reproductive toxicity, elucidating mechanisms across molecular, cellular, tissue, organ, and individual/population levels. Using the adverse outcome pathway (AOP) framework, we identify three key molecular initiating events (MIEs): (1) activation of estrogen receptor α (ERα), (2) inhibition of aromatase activity, and (3) disruption of mitochondrial electron transport chain complexes. These MIEs trigger key events (KEs) such as oxidative stress, DNA damage, mitochondrial dysfunction, and epigenetic modifications, leading to cell death. At the tissue/organ level, these changes cause hormonal homeostasis imbalance, impaired oocyte maturation, ovulatory dysfunction, ovarian reserve depletion, and abnormal endometrial hyperplasia, culminating in clinical conditions such as premature ovarian insufficiency and endometrial cancer. By constructing an AOP network, this review establishes causal relationships across biological levels, providing a theoretical basis for health risk assessment and environmental management of GLY. The AOP framework enhances our understanding of GLY-induced female reproductive toxicity and identifies potential biomarkers and intervention targets, offering critical insights for regulatory decision-making and public health protection.