Rosuvastatin exposure during adulthood increases ovarian follicular atresia and reduces reproductive performance in female mice

Statins are widely used to manage lipid disorders and reduce cardiovascular risk in humans. Rosuvastatin, one of the most effective statins, decreases cholesterol biosynthesis and exerts pleiotropic effects. However, recent studies indicate potential reproductive toxicity associated with statin use in animal and human studies. This study aimed to evaluate the reproductive parameters and fertility in adult female Swiss mice exposed to relevant doses of rosuvastatin. Female mice were divided into three experimental groups: control (0.9 % saline solution), 1.5 mg/kg of rosuvastatin, and 5.5 mg/kg of rosuvastatin. The treatments were administered via gavage from postnatal day (PND) 80 to PND 110, and the reproductive and developmental parameters, as well as the general health status of the animals, were assessed. There was a reduction in total serum cholesterol and triglyceride levels, a reduced total number of antral follicles, and an increased ovarian follicular atresia, as confirmed by increased cleaved caspase-9 and caspase-3 immunostaining in the granulosa cells of antral follicles, in the rosuvastatin-treated females. However, no adverse effects were observed in body mass gain and the hepatic markers of non-pregnant females. The treatment with rosuvastatin preceding gestation reduced pregnancy rate and increased post-implantation losses, resorptions, and fetal mortality, especially at the lower dose. In summary, the exposure to rosuvastatin during adulthood may compromise follicular dynamics and reduce female reproductive performance. These outcomes reinforce the need for caution in the use of statins by women of reproductive age.