Reproductive outcomes in rat female offspring from male rats co-exposed to rosuvastatin and ascorbic acid during pre-puberty

Abstract

Dyslipidemias are occurring earlier in different countries due to the increase of obesity, bad eating habits, and sedentary lifestyle. Rosuvastatin reduces serum cholesterol; however, several studies associated statin exposure with male reproduction impairment. Ascorbic acid (AA) is an antioxidant substance that plays a protective role in the male reproductive system. Male rats were randomly divided into 6 experimental groups (n = 10), which received saline solution 0.9%, 3 or 10 mg/kg/day of rosuvastatin, 150 mg/day of AA or 3 or 10 mg/kg/day of rosuvastatin associated with 150 mg/day of AA from post-natal day (PND) 23 until PND 53. On PND 100, males were mated with non-treated female rats to obtain the female pups. The day of vaginal opening and the first estrus were assessed in the offspring. Two sets of females were euthanized on the first estrus after PND 42 and PND 75 to evaluate the histology of reproductive organs and hormone levels. A third set was used for sexual behavior and fertility test around PND 75. Female offspring from males exposed or co-exposed to the higher dose of statin exhibited a lower number of corpora lutea during puberty. On sexual maturity, the experimental group from males that were exposed to 3 mg displayed lower uterine luminal epithelium area. Paternal exposure to rosuvastatin at pre-puberty diminished uterine luminal epithelium in female offspring suggesting epigenetic changes were initiated by statin. Ascorbic acid co-administered to pre-pubertal males was able to ameliorate the reproductive damage in rat female offspring in adulthood.

Statins and Male Fertility: Is There a Cause for Concern?

“…The results have been promising, with a study concluding that a grape seed extract and atorvastatin combination treatment showed a noticeable increase in serum testosterone and sperm count whilst reducing levels of superoxide dismutase, caspase, and glutathione. Some studies have also shown the enhanced effects of antioxidants given alongside a statin with the antioxidants’ ability to diminish the statins’ adverse effects [ 92 ]. Conversely, one study showed the dose-dependent antioxidant and anti-apoptotic properties of rosuvastatin on diabetes-induced reproductive damage [ 43 ].…”

Short- and long-term effects on reproductive parameters of female Wistar rats after exposure to rosuvastatin starting in pre-puberty

“…The rosuvastatin doses chosen for this study are based on the lowest and highest doses applied in human therapy for children ( Leite et al, 2018a , Leite et al, 2019b , Leite et al, 2018c ), adapted for rodents considering their body surface area, as proposed for Reagan-Shaw et al ( Reagan‐Shaw et al, 2008 ).…”

“…Rosuvastatin can delay pubertal development, reduce sperm quality, impair spermatogenesis, and alter hormonal signaling ( Leite et al, 2014 , Leite et al, 2018a , Leite et al, 2019b ). Also, rosuvastatin exposure in male rats might affect reproductive function in an intergenerational manner, by damaging ovarian and uterine histophysiology of female offspring ( Leite et al, 2018 ).…”

Efeitos da exposição ao agente hipolipemiante rosuvastatina sobre a função reprodutiva de ratas Wistar

“…Dados mais recentes publicados por nosso Laboratório indicam que a exposição à rosuvastatina em ratos durante a peri-puberdade tem potencial para alterar parâmetros reprodutivos de forma transgeracional, já que a prole masculina desses ratos apresenta aumento na fragmentação de DNA espermático, depleção androgênica, alterações estruturais nos testículos e epidídimos, além de prejuízos à qualidade espermática . A prole feminina, por sua vez, também mostra alterações na função reprodutiva, evidenciada pela diminuição da contagem de corpos lúteos nos ovários, além de alterações histomorfométricas no epitélio luminal uterino e desregulação dos níveis de LH durante a puberdade (Leite et al, 2018c).…”

“…Rosuvastatin is able to delay pubertal development, reduce sperm quality, impair spermatogenesis and alter hormonal signaling [13][14][15]. Also, rosuvastatin exposure in male rats might affect reproductive function in an intergeneration manner, by damaging ovarian and uterine histophysiology of female offspring [16].…”