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.

KEYWORDS:

• Vitamin C
• rosuvastatin
• female offspring
• reproduction
• toxicology

Acknowledgments

The authors are grateful to to José Eduardo Bozano, from the Department of Morphology, Institute of Biosciences, UNESP, Botucatu/SP – Brazil, for his excellent technical assistance and to Dr. Ruither de Oliveira Gomes Carolino, from the Department of Morphology, Stomatology and Physiology, School of Dentistry, University of São Paulo – USP, Ribeirão Preto/SP, Brazil, for his contributions to hormonal measurements.

Conflicts of interest

The authors declare that there are no conflicts of interest.

Supplementary material

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Additional information

Funding

This research was financially supported by São Paulo Research Foundation (FAPESP) (Grants #013/22495-1 and #014/13659-3), National Council for Scientific and Technological Development (CNPq) (Grant 308842/2013-8) and Coordination for the Improvement of Higher Education Personnel (CAPES).