Comparative effects of streptozotocin, dehydroepiandrosterone and letrozole with high fat diet on ovarian injury induction and functional impairment

This study investigates the mechanisms by which environmental factors affect ovarian function. Environmental toxins and unhealthy lifestyles adversely affect women's health, primarily impair ovarian function. Environmental toxins and unhealthy lifestyles can negatively impact women's health, particularly by impairing ovarian function. Streptozotocin (STZ), dehydroepiandrosterone (DHEA) and letrozole (LET) with high-fat diet (HFD) (only LET was combined with HFD), induced models have been experimentally demonstrated to induce ovarian dysfunction. This investigation aims to elucidate their individual and synergistic effects on ovarian function to inform evidence-based prevention and intervention strategies for ovarian dysfunction. ICR/JCL mice (age 4-5 weeks) were subjected to three distinct pathophysiological modeling approaches to simulate ovarian dysfunction. Multiparametric analysis systematically evaluated physiological changes, glycometabolism function, endocrine parameters, and molecular biology. Experimental outcomes demonstrated that STZ, DHEA and LET with HFD significantly affected mice's metabolic and ovarian functions. Mechanistically, the PI3K/AKT signaling pathway was identified as a critical mediator of ovarian dysfunction. In conclusion, this study systematically compared, for the first time, the individual and synergistic effects of STZ, DHEA and LET with HFD on ovarian function in mice, confirming that these environmental factors induce ovarian dysfunction through metabolic disruption and signal transduction pathway dysregulation. Future research should prioritize elucidating the specific molecular mechanisms by which environmental factors impair ovarian function to establish a scientific foundation for developing targeted intervention strategies.