Prolonged exposure to rosuvastatin from pre-puberty to adulthood impairs sperm quality in mice and leads to paternally mediated developmental toxicity

Abstract

Nowadays, changes in human lifestyle have increased dyslipidemia, reinforcing the necessity of using lipid-lowering drugs, such as statins, to control the lipid profile. Among the statins, rosuvastatin has shown greater efficacy in controlling dyslipidemia. Previous studies have shown adverse effects in adult men and pre-pubertal rodents after exposure to statins, such as reduced testosterone levels and delayed puberty. This study aimed to evaluate the reproductive parameters and fertility of male mice exposed to rosuvastatin from pre-puberty to sexual maturity by simulating human chronic exposure to rosuvastatin from pre-puberty to adulthood. This is the first study to evaluate male reproduction and developmental outcomes after prolonged rosuvastatin exposure since pre-puberty, mimicking the human exposure to relevant doses of the drug. Then, we hypothesize that prolonged exposure to rosuvastatin since pre-puberty may impair reproductive parameters in males and generate paternally mediated developmental toxicity. Male mice were divided into three experimental groups that received a 0.9 % saline solution, 1.5 or 5.5 mg/kg/day of rosuvastatin, by intragastric oral gavage, from postnatal day (PND) 23 to PND 80. Puberty onset was delayed and sperm quality was reduced in both rosuvastatin-treated groups. Furthermore, testicular interstitial tissue showed increased vascularization in a dose-dependent manner. After mating with non-treated females, the post-implantation loss rate increased in both rosuvastatin-exposed groups. There was an increase in the percentage of fetuses with opened eyelids in the offspring of males exposed to 1.5 mg/kg/day of the statin and a decrease in the craniocaudal distance of male offspring from males exposed to the higher dose. In summary, our hypothesis that rosuvastatin exposure would cause male reproductive toxicity and developmental impairment in the offspring of male mice was confirmed. This study raises concerns about the reproductive health of men who take this medication from infancy until adulthood in prolonged treatment.