Hepatic histopathological and morphometric changes in male mice exposed to rosuvastatin from pre-puberty to adulthood: a possible adaptive hepatic response.

Lifestyle changes, such as poor eating habits and a reduction in physical exercise, have impaired human lipid profiles. Statins are widely used to treat dyslipidemias, of which rosuvastatin shows greater improvement in the lipid profile and may be used since childhood. This study aimed to assess the hepatic effects when male mice were given 0.9% saline solution or doses of rosuvastatin of 1.5 or 5.5 mg/kg/day from postnatal day (PND) 23 until PND 80. Body mass gain and water and food consumption were monitored during the treatment. Mice were euthanized on PND 80 when blood was collected for serum obtainment, and several organs were collected and weighed. Serum was used for evaluating lipid profiles and markers of hepatic injuries. The liver was assessed for histopathological, morphometric, and stereological changes. There was a temporary reduction in body mass gain and water and food consumption in the rosuvastatin-exposed groups. Both rosuvastatin-treated groups exhibited reduced total cholesterol levels and showed signs of hepatic tissue adaptation in response to prolonged exposure, such as sinusoidal dilation, inflammatory infiltrates, and cell death of hepatocytes. These results are considered side effects of the treatment and may indicate a hepatic adaptation to the chronic exposure.

Female Mice Exposed to Pyriproxyfen Since Prepuberty Showed Reproductive Impairment During Sexual Maturity and Increased Fetal Death in Their Offspring.

Pyriproxyfen (PPF) is an insecticide used in agriculture, which is approved for use in drinking water tanks for human consumption. However, some studies indicate that it may act as an endocrine disruptor and affect nontarget organisms. This study aimed to evaluate the effects of PPF on reproduction and general health status in female mice exposed from pre-puberty to adulthood. In the first experiment, females were treated by gavage from postnatal day (PND) 23 to (PND) 75 and were distributed into three experimental groups: control (vehicle), PPF 0.1 mg/kg, and PPF 1 mg/kg. Female mice were assessed for the age of puberty onset, body mass, water and food consumption, and the estrous cycle. On PDN 75, a subgroup was euthanized, when vital and reproductive organs were collected and weighed. The thyroid, ovary, and uterus were evaluated for histomorphometry. The other subgroup was assessed in relation to reproductive performance and fetal parameters. In a second experiment, the uterotrophic assay was performed with juvenile females (PND 18) using doses of 0.01, 0.1, or 1 mg/kg of PPF. PPF treatment reduced thyroid mass and increased liver mass. Furthermore, there was an increase in ovarian interstitial tissue and, in the uterus, a decrease in the thickness of the endometrial stroma with reduced content of collagen fibers. There was also a reduction of 30% in pregnancy rate in the treated groups and an increase in the frequency of fetal death. This study suggests that, based on this experimental model, the insecticide may pose a reproductive risk for females chronically exposed to the substance from the pre-pubertal period until adulthood. These results raise concerns about prolonged exposure of women to the same compound.

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

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.