Reproductive outcomes of neonatal exposure to betamethasone in male and female rats.

Betamethasone (BM) is the drug of choice for antenatal corticosteroid therapy for women at risk of preterm delivery because it induces fetal lung maturation and enhances survival after birth. However, our group reported evidence of fetal programming and impaired reproductive development and function in rats exposed during the critical window of genital system development. Therefore, we aimed to investigate the effects of BM on the sexual development of rats in the period that corresponds to antenatal corticosteroid therapy in humans. Male and female rats were exposed subcutaneously to BM at 0.1 µg/g of pups' body weight or to a NaCl 0.9% solution (control) on postnatal days 1-3. It was observed that neonatal exposure to BM decreased body weight and weight gain in male and female rats during treatment. The estrous cycle was deregulated and LH level was decreased in female rats. In male rats, the sperm concentration in the caput-corpus of the epididymis was decreased, whereas the sperm transit time and sperm concentration in the cauda of the epididymis were increased. Our results demonstrated that neonatal exposure to BM impaired body growth of male and female rats, deregulated the estrous cycle of female rats, and altered sperm quality of male rats. Therefore, BM exposure from postnatal days 1 to 3 corroborated results previously observed after prenatal exposure to this drug. Despite the recognized importance of human antenatal corticosteroid therapy, the findings of this study should encourage further studies in order to minimize possible adverse postnatal effects.

Rosuvastatin exposure in female Wistar rats alters uterine contractility and do not show evident (anti)estrogenic effects.

Statins are 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitor drugs that lead to serum-cholesterol-lowering effects. Rosuvastatin, a third-generation statin, has shown better results in reducing cholesterol concentrations when compared to other widely prescribed statins. Recent studies by our group reported that rosuvastatin impairs reproductive function in rats possibly by disrupting the reproductive-endocrine axis. In this study, we evaluated whether rosuvastatin presents estrogenic or antiestrogenic effects, by an in vivo uterotrophic assay in rats, and investigated the direct effect of this drug upon rat uterine tissue contractility both in non-gravid and gravid periods. Rosuvastatin exposure in vivo at doses of 0 (control), 3, and 10 mg/kg/d was not associated with estrogenic or antiestrogenic effects on uterine tissue. However, in vivo (doses of 0, 3, and 10 mg/kg/d) and ex vivo (concentrations of 0, 1, 10, and 100 µg/mL) exposures to this drug were related to alterations in uterine basal contraction pattern. Furthermore, in vivo and ex vivo rosuvastatin exposures potentially modulate the action of uterine contraction inducers carbachol, norepinephrine, and prostaglandin E2. Thus, rosuvastatin can affect uterine physiology not necessarily by an endocrine mechanism related to the estrogen signaling, but possibly by its pleiotropic effects, with indirect tissue and cellular interactions, since in vivo and ex vivo exposures of uterine fragments to rosuvastatin presented different responses in uterine contractile parameters, which require further studies upon the precise mechanism of action of this drug in female reproductive function.

Lorcaserin Administration has Pro-Ejaculatory Effects in Rats via 5-HT2C Receptors Activation: A Putative Pharmacologic Strategy to Delayed Ejaculation?

BACKGROUND: Lorcaserin is an anti-obesity drug whose weight loss effect results from 5-hydroxytryptamin (5-HT)2C receptors activation. The 5-HT2C receptor was shown to participate in the physiological control of ejaculation, but no data addressing a putative effect of lorcaserin on ejaculation exist. AIM: To investigate the effects of lorcaserin in different in vitro and in vivo experimental models of ejaculation in rats. METHODS: Contractile responses to lorcaserin in rat seminal emission organs in vitro (prostatic and epididymal vas deferens, cauda epididymis, and seminal vesicles), analysis of male rat copulatory behavior, and electromyographic recording of bulbospongiosus muscle in anesthetized animals were studied. MAIN OUTCOME MEASURES: The main outcome measures included in vitro contraction of seminal emission organs and evaluation of the male rat copulatory behavior. The male rat sexual behavior in terms of copulation latency, ejaculation latency, mount and intromission frequency, and ejaculation frequency of sexually experienced adult male rats with a receptive female were also recorded. RESULTS: Lorcaserin (1.0 nM to 1.0 mM) had no significant effects on the in vitro contractility of seminal emission organs smooth muscle (cauda epididymis, vas deferens, and seminal vesicles). On the other hand, lorcaserin administration (0.3-1.0 mg/kg, intravenous) induced ejaculation in anesthetized rats, which was prevented by the 5-HT2C-selective antagonist SB 242084 (0.1 and 0.3 mg/kg, intravenous). Single-dose treatment of non-anesthetized male rats with lorcaserin (1.0, 4.0, or 10 mg/kg, per os) induced non-copulating ejaculations in sexually naïve rats. Lorcaserin also had pro-ejaculation effects by decreasing the ejaculation threshold of copulating rats by half. The pro-ejaculatory effects of lorcaserin were reversible as the ejaculation threshold of treated rats recovered after a 1-week washout period. CLINICAL IMPLICATIONS: Due to its reported clinical safety, repurposing lorcaserin for the treatment of delayed ejaculation may be suggested. STRENGTHS & LIMITATIONS: The pro-ejaculatory effect of lorcaserin administration and the role of 5-HT2C were demonstrated in different experimental models of ejaculation in rats. The lack of studies in putative experimental models of delayed ejaculation is a limitation of this study. CONCLUSION: Our results demonstrate that the clinically approved 5-HT2C agonist lorcaserin is a strong facilitator of ejaculation in rats. de Almeida Kiguti LR, Pacheco TL, Antunes E, et al. Lorcaserin Administration has Pro-Ejaculatory Effects in Rats via 5-HT2C Receptors Activation: A Putative Pharmacologic Strategy to Delayed Ejaculation? J Sex Med 2020;17:1060-1071.

Effects of isolated or combined exposure to sibutramine and rosuvastatin on reproductive parameters of adult male rats.

Many obese patients are exposed to hypolipidemic and serotonin-norepinephrine reuptake inhibitor (SNRI) drugs. Statins are one of the most marketed drugs in the world to treat dyslipidemia, while sibutramine, a SNRI drug, is prescribed in some countries to treat obesity and is detected as an additive in many adulterated weight loss supplements marketed worldwide. Previous studies reported adverse effects of isolated exposure to these drugs on male rat reproductive parameters. In the present work, we further investigated male reproductive toxicity of these drugs, administered in isolation or combination in adult rats for a longer period of treatment. Adult male rats (90 days) were treated (gavage) for 70 days with saline and dimethyl sulfoxide (control), sibutramine (10 mg/kg), rosuvastatin (5 mg/kg), or rosuvastatin combined with sibutramine. Sibutramine alone or with rosuvastatin, promoted a reduction in food intake and body weight gain, weight of the epididymis, ventral prostate and seminal vesicle; as well as decreased sperm reserves and transit time through the epididymis; androgen depletion; and increased index of cytoplasmic droplet. The rosuvastatin-treated group showed reduced frequency of ejaculation. Exposure to this drug alone or combined with sibutramine impaired epididymal morphology. Co-exposed rats had altered epididymal morphometry, and seminal vesicle and testis weights. The rats also showed decreased fertility after natural mating and a trend toward a delay in ejaculation, suggesting a small synergistic effect of these drugs. Given the greater reproductive efficiency of rodents, the results obtained in the present study raise concern regarding possible fertility impairment in men taking statins and SNRI drugs.

Ascorbic acid supplementation ameliorates testicular hormonal signaling, sperm production and oxidative stress in male rats exposed to rosuvastatin during pre-puberty.

Dyslipidemias are occurring earlier in the population due to the augmentation of obesity. Rosuvastatin reduces cholesterol and triglycerides; however, previous studies have shown that it may affect male reproduction. Ascorbic acid (AA), an antioxidant compound, plays a protective role in the male reproductive system. This study aimed to evaluate whether pre-pubertal exposure to rosuvastatin may impair testicular structure and antioxidant status in male rats and if supplementation with AA may alleviate these damages. Male rats were randomly divided into six experimental groups (n = 10) on postnatal day (PND) 23 and received the different treatments by gavage from PND 23 to 53. The experimental groups received vehicle (saline solution 0.9%), 3 or 10 mg/kg/day of rosuvastatin diluted in saline solution 0.9%, supplementation with 150 mg/day of AA, 3 mg/kg/day of rosuvastatin in association with 150 mg/day of AA or 10 mg/kg/day of rosuvastatin associated with 150 mg/day of AA. Testicular parameters were assessed on PND 53 and 110. There were diminished androgen receptors staining in the Sertoli cells and increased germ cell death in rosuvastatin-exposed groups, in both periods. Spermatids showed lower estrogen alpha-receptors staining in the group exposed to 10 mg of statin at adulthood. There were androgen depletion and increased lipid peroxidation and catalase activity in statin-exposed groups. Rosuvastatin exposure during pre-puberty impaired testicular structure, steroid receptor distribution and increased oxidative stress; however, AA was able to ameliorate the impairment provoked by statin exposure.

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

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.

Lower sperm quality and testicular and epididymal structural impairment in adult rats exposed to rosuvastatin during prepuberty.

The increase of obesity, bad eating habits and the lack of physical exercises are highly related to dyslipidemias. Rosuvastatin is a lipid-lowering drug and has been indicated to prevent cardiovascular diseases and to treat dyslipidemias due to its higher efficiency to reduce serum cholesterol concentrations. This study aimed to evaluate the reproductive adverse effects on sexual maturity due to rosuvastatin exposure in juvenile male rats during prepuberty. Three groups were randomly formed with newly weaned rats: control, whose rats received saline solution 0.9% and rosuvastatin at doses of 3 or 10 mg kg-1 day-1 , administered orally by gavage, from postnatal day 21 until preputial separation (average of 45 days for controls and 49 days for statin-treated animals), indicative of puberty onset. Male rats were maintained until sexual maturity and were killed on postnatal day 110. In the rosuvastatin-treated groups, the results showed diminished follicle-stimulating hormone, luteinizing hormone and testosterone concentrations, increased estradiol and prolactin concentrations, histopathologic alterations on testis and epididymis and decreased sperm quality. Moreover, statin-exposed groups showed decreased expression of androgen receptor on testis and epididymis and lower expression of aquaporin-9 on epididymal epithelium. In conclusion, administration of rosuvastatin to prepubertal male rats provoked long-term hormonal deregulation and impaired reproduction at adulthood.

Lack of Reproductive Toxicity in Adult Male Rats Exposed to Interferon-Alpha.

Interferon-alpha (IFN- α), a type I IFN, is a protein with antiviral, antiproliferative, and immunoregulatory activities, widely used in the treatment of several types of cancers as well as hepatitis B and C. Decrease of libido and erectile dysfunction are commonly reported by male patients during treatment of chronic hepatitis C with IFN- α . However, IFN therapy-associated underlying factors attributed to sexual dysfunction are still not well defined. Currently, there are few studies investigating the effects of IFN on male reproductive system functions. Given that, the aim of the present investigation was to examine effects of subchronic exposure to IFN- α (5 × 10(4) U/kg and 10 × 10(4) U/kg, 30 d) on serum hormones, sperm parameters, fertility, and testicular and epididymal hystopathology and morphometry in adult male Wistar rats. None of the evaluated parameters was markedly altered by IFN- α . Thus, our results suggest that exposure to IFN- α , in this experimental design, did not adversely affect sperm quality and fertile capacity of male rats.

Absence of effects on the rat sperm quality after subacute exposure to low doses of fungicide prochloraz.

Prochloraz (PCZ) is a fungicide and androgen-receptor antagonist used worldwide in horticulture and agriculture. Pre- and perinatal exposure to this pesticide during sexual differentiation is deleterious for male offspring. Since data on the effects of PCZ on epididymal functions are scarce, and because sperm maturation occurs in this organ, the present investigation aimed to determine whether low PCZ doses administered to rats during the phase of sperm transit through the epididymis might affect the morphophysiology of this organ and sperm quality. Adult male Wistar rats were assigned to 4 different groups: 0 (control, vehicle) or 10, 15, or 30 mg/kg bw/d PCZ diluted in corn oil administered orally for 4 consecutive days. Morphofunctional parameters of the male reproductive tract, hormone concentrations, sperm evaluations, and fertility and histopathologic analysis of testis and epididymis were assessed. There were no statistically significant differences between treated and control groups in relation to all evaluated parameters. Data demonstrated show that PCZ exposure for a brief 4-d exposure and low doses did not produce reproductive toxicity or compromise sperm quality in adult rats.

Effect of Himatanthus sucuuba in Maternal Reproductive Outcome and Fetal Anomaly Frequency in Rats.

The aim of this study was to evaluate the effect of Himatanthus sucuuba on the maternal reproductive outcome and fetal anomaly incidence in rats. Pregnant rats were randomly divided into three experimental groups as follows: Control = treated with water (vehicle), treated 250 = treated with H. sucuuba at dose 250 mg/kg, and treated 500 = treated with H. sucuuba at dose 500 mg/kg. The rats were orally treated, by gavage, with H. sucuuba or vehicle (water) during preimplantation and organogenic period (from gestational day 0-14). At day 21 of pregnancy, all rats were killed to obtain maternal-fetal data. The treatment with H. sucuuba at dose of 250 mg/kg caused reduction in placental efficiency and an increase preimplantation loss rate and placenta weight compared with the control. The treated 500 group presented a significant decrease in maternal weight gain, maternal weight gain minus gravid uterus weight, fetal weight, and placental efficiency compared with the control. In this group, there was a decrease in body weight at day 20 of pregnancy and metacarpus ossification and an increase in the preimplantation loss rate and skeletal anomalies compared with other groups. Himatanthus sucuuba extract caused intrauterine growth restriction, preimplantation loss, and developmental delay in the high doses tested.

Perinatal androgenic exposure and reproductive health effects female rat offspring.

Environmental contaminants known as endocrine-disrupting chemicals (EDC) have been associated with adverse effects on reproductive processes. These chemicals may mimic or antagonize endogenous hormones, disrupting reproductive functions. Although preliminary studies focused on environmental estrogens, the presence of compounds with androgenic activity has also been described. This study examines exposure of female pregnant and lactating rats to low doses of androgens and assesses potential effects on female offspring. Pregnant Wistar rats were exposed to testosterone propionate (TP) at doses of 0.05, 0.1, or 0.2 mg/kg or corn oil (vehicle), subcutaneously, to determine influence on reproductive health of female offspring. There were two exposure groups: (1) rats treated from gestational day (GD) 12 until GD 20; and (2) animals treated from GD 12 until the end of lactation. Perinatal exposure to TP produced increased anogenital distance after birth and diminished height of uterine glandular epithelium at puberty in animals exposed to 0.2 mg/kg. However, these alterations were not sufficient to impair sexual differentiation and normal physiology of the female rat reproductive tract.

Multiple flow cytometry analysis for assessing human sperm functional characteristics.

Multiparametric analysis by flow cytometry solves one of the major problems in sperm evaluation, the inability to test multiple attributes simultaneously in a single cell, which would increase the precision to predict fertility potential since several sperm parameters are tested. The association of fluorochromes and compounds conjugated to fluorochromes in multiparametric sperm analysis is well-established in microscopy techniques. However, these techniques are subjective and limit the assessment in small cell numbers, thereby harming analytic accuracy. Therefore, the current study aimed to present new possibilities for assessing the integrity and stability of the sperm plasma membrane, acrosome status, mitochondrial potential, and superoxide anion production in the mitochondrial matrix in only 2 cytometric assays using cytometers equipped with 2 and 3 lasers. For this, human semen samples collected by masturbation and selected by the swim-up technique were divided into 3 treatments: T0 (flash-frozen semen), T50 (flash-frozen semen + fresh semen, V: V), and T100 (fresh semen) for the validation of the multiparametric protocols by flow cytometry. For both protocols, sperm percentage with positive stain for all fluorophores differed significantly between treatments. The determination coefficients presented values close to 1, which validated objective, sensitive, rapid, and reproducible methodologies. Therefore, we concluded that the results reflect the status of analyzed structure, enabling a more accurate diagnosis of male infertility that has become an increasingly prevalent worldwide setback due to exposure to a variety of environmental toxicants.

SP22 sperm protein as a potential biomarker of fertility in humans: A preliminary study.

Infertility affects approximately 15% of couples of reproductive age, and 50% of the cases are directly related to men. The evaluation of male fertility is based on analyses of routine seminal parameters and the use of more advanced techniques can help identify fertility biomarkers. SP22 sperm protein is considered a biomarker in murine species since its concentration is highly correlated with sperm fertility. As the role of this protein as a biomarker is already well-established in other species, we hypothesized that this same correlation could apply to human. Thus, the present study aimed to investigate possible correlations between SP22 concentration and sperm parameters in fertile and infertile men. For this, a study was carried out on 21 volunteers' seminal samples who were grouped according to fertility as fertile (n = 10) or infertile (n = 11). Conventional and functional sperm analyses, membrane protein extraction, quantification and immunolocalization of SP22 were performed. The infertile volunteers showed an increase in the percentage of sperm with abnormalities in head morphology and a decrease in the percentage of sperm with intact plasma membrane and damaged acrosomal membrane. Serum concentration of the hormone SHBG was also decreased in infertile volunteers. The damage to the plasma membrane was positively correlated with the superoxide anion production. Although none of the functional parameters were correlated with SP22 concentration, type D sperm motility was negatively correlated and type A+B sperm motility was positively correlated. This preliminary study opens new paths in the characterization of SP22 as a non-invasive biomarker for predicting fertility/infertility.

Exposure of pregnant rats to stress and/or sertraline: Side effects on maternal health and neurobehavioral development of male offspring.

AIMS: Sertraline (SE) is one of the most prescribed medications for treating gestational depression, anxiety and stress. However, little is known about its effects on nervous-system development in offspring. Therefore, this study investigated the somatic, reflex and neurobehavioral development of rats exposed to SE during pregnancy, associated or not with stress. MAIN METHODS: Pregnant Wistar rats were assigned to the following groups (n = 10-8 rats/group): CO - control animals administered filtered water by gavage; SE - animals administered 20 mg/kg SE by gavage; ST - animals subjected to restraining stress and administered filtered water; ST/SE - animals subjected to restraining stress and administered 20 mg/kg SE. The treatment was administered between gestational days (GD) 13 to 20. Somatic and reflex developments were investigated in the male offspring from postnatal day (PND) 1 to 21. The elevated plus maze was performed on PND 25 and 80. The open field and light/dark box test were performed on PND 90 and 100, respectively. KEY FINDINGS: Body weight reduction and vaginal bleeding were observed in pregnant rats exposed to SE. The male offspring of the SE group showed delay in incisor eruption, fur development and negative geotaxis. In addition, the SE group was less exploratory (anxious personality) compared to the CO and ST groups. SIGNIFICANCE: The results obtained in the present study demonstrate that sertraline not only impairs maternal health, but also, associated or not with stress, can compromise the somatic, reflex and neurobehavioral development of male rats.

Sibutramine effects on the reproductive performance of pregnant overweight and non-overweight rats.

It is well established that sibutramine produces weight loss and is used frequently in women of childbearing age. However, the potential adverse consequences attributed to sibutramine use by women who may become pregnant is not known. It was thus of interest to determine the effects of sibutramine on the reproductive performance of pregnant rats. Overweight as well as non-overweight female Wistar rats were treated with sibutramine (6 mg/kg) orally, daily for 15 d and then mated with normal male rats. Pregnancy was confirmed and treatment continued with sibutramine until d 14 of pregnancy. On d 20 of pregnancy all rats were anesthetized for determination of various maternal and fetal parameters. There was a significant maternal weight reduction at the end of pregnancy in the non-overweight drug-treated group compared to the control (non-overweight, no drug). Sibutramine alone and overweight condition alone produced a significant increase in postimplantation loss and placental index. In the overweight with or without sibutramine groups a significant decrease in fetal weight was noted. Data suggest that sibutramine alone or the condition of excess weight in the absence of drugs produced impaired reproductive performance. However, treatment of overweight rats with sibutramine did not further exacerbate fetal loss compared to sibutramine alone or the effects noted with excess weight alone.

Decreased sperm motility in rats orally exposed to single or mixed pesticides.

The Brazilian Agency of Sanitary Vigilance (ANVISA) conducted a study that demonstrated the presence of residues of several pesticides in fresh fruits and vegetables that were available for purchase by the general populace. In order to evaluate potential adverse health effects of low-level exposure to agrochemicals, the reproductive toxicity of the pesticides dicofol, dichlorvos, permethrin, endosulfan, and dieldrin was evaluated in rats dosed with these chemicals individually or as mixtures. Sixty male Lewis rats (6 wk old, 200 x g) were randomly allocated to 8 groups: (1) control group, received basal diet; (2) 5 groups designated a to e received the diet containing each pesticide individually, at the respective effective doses: lowest-observed-adverse-effect level (LOAEL) for dieldrin and endosulfan, lowest-observed-effect level (LOEL) for dicofol, and lowest effect level (LEL) for dichlorvos and permethrin, respectively, depending on the published data; (3) effective dose group, which received a mixture of pesticides added to basal diet at the respective doses reported to produce adverse effects; and (4) low dose group, which received a pesticide mixture added to the basal diet, where each pesticide was at its no-observed-effect level (NOEL). After 8 wk of treatment, reproductive parameters were evaluated. Sperm morphology, daily sperm production (DSP), sperm transit time through the epididymis, hormonal levels, and histopathological evaluation of testis and epididymis did not differ significantly among the groups. However, sperm motility was significantly decreased in animals that received a mixture of dieldrin, endosulfan, dicofol, dichlorvos, and permethrin, as well as in the group receiving dicofol alone. Exposure to the individual pesticides endosulfan, dichlorvos, and permethrin did not markedly affect sperm motility. The impairment of sperm motility in the mixture of pesticides at the NOEL level indicates that reproductive effects not seen with individual pesticides may occur in presence of several pesticides due to an additive effect. However, the pesticide mixtures did not appear to affect DSP or spermatogenesis despite reduced sperm motility.

Effects of altered epididymal sperm transit time on sperm quality.

The epididymal sperm transit time seems to have an important role in the process of sperm maturation, and it seems that alterations to the transit can harm the process. The aim of the present work was to evaluate the influence of altered sperm transit time through the epididymis on sperm parameters and fertility of rats, as well as the role of testosterone in the alterations. Sprague-Dawley adult male rats were randomly assigned to four different groups and were treated for 12 days: (i) 10 microg/rat/day DES, to accelerate the transit; (ii) 6.25 mg/kg/day guanethidine sulphate, to delay the transit; (iii) same treatment as group 1, plus androgen supplementation; (iv) control animals received the vehicles. Guanethidine treatment delayed the sperm transit time through the epididymal cauda, provoking increased sperm reserves in this region. Animals exposed to DES showed an acceleration of sperm transit time in the epididymis, and consequently decreased sperm density in both epididymal regions, the caput-corpus and cauda, and diminished sperm motility. In both cases sperm production was not altered. Testosterone supplementation was able to restore the transit time to values close to normality, as they were higher than in the control rats. The same occurred in relation to sperm motility. Rats exposed to DES presented lower fertility after in utero artificial insemination using sperm collected from the proximal cauda epididymis. Therefore, it was concluded that the acceleration of rat sperm transit time appeared to harm normal sperm maturation, thus decreasing sperm quality and fertility capacity, in an androgen-dependent way.

Ascorbic acid co-administered with rosuvastatin reduces reproductive impairment in the male offspring from male rats exposed to the statin at pre-puberty.

Obesity during childhood and adolescence is closely related to dysfunctions on lipid profile in children. Rosuvastatin is a statin that decreases serum total cholesterol. Ascorbic acid is an important antioxidant compound for male reproduction. Pre-pubertal male rats were distributed into six experimental groups that received saline solution 0.9% (vehicle), 3 or 10 mg/kg/day of rosuvastatin, 150 mg/day of ascorbic acid, or 3 or 10 mg/kg/day of rosuvastatin co-administered with 150 mg/day of ascorbic acid by gavage from post-natal day (PND)23 until PND53. Rats were maintained until adulthood and mated with nulliparous females to obtain the male offspring, whose animals were evaluated at adulthood in relation to reproductive parameters. This study is a follow up of a previous paper addressing potential effects on F0 generation only (Leite et al., 2017). Male offspring from rosuvastatin-exposed groups showed increased sperm DNA fragmentation, androgen depletion and impairment on the testicular and epididymal structure. Ascorbic acid coadministered to the fathers ameliorated the reproductive damage in the offspring. In summary, paternal exposure to rosuvastatin may affect the reproduction in the male offspring; however, paternal supplementation with ascorbic acid was able to reduce the reproductive impairment in the male offspring caused by statin treatment to the fathers.

Vitamin C partially prevents reproductive damage in adult male rats exposed to rosuvastatin during prepuberty.

Pediatric obesity is closely associated with dyslipidemias and environmental factors, such as diet and lack of physical exercises, which may alter lipid profile in children. Rosuvastatin decreases serum total cholesterol and triglycerides concentrations. Vitamin C (ascorbic acid) plays an important role on sperm integrity and fertility. Juvenile male rats were distributed into six experimental groups that received saline solution 0.9%, 3 or 10 mg/kg/day of rosuvastatin, 150 mg/day of ascorbic acid, or 3 or 10 mg/kg/day of rosuvastatin co-administered with 150 mg/day of ascorbic acid from PND23 until PND53 and then the rats were maintained until sexual maturity. Rosuvastatin-exposed groups showed lower sperm quality, androgen depletion and germ cell death. Ascorbic acid was capable to prevent partially the reproductive adverse effects provoked by rosuvastatin. In conclusion, prepubertal exposure to rosuvastatin provokes long-term reproductive damages at sexual maturity and ascorbic acid supplementation at prepuberty may be a preventive mode against these reproductive adverse effects.

Ascorbic acid supplementation partially prevents the delayed reproductive development in juvenile male rats exposed to rosuvastatin since prepuberty.

Dyslipidemias are occurring earlier in the population due to the increase of obesity and bad eating habits. Rosuvastatin inhibits the enzyme HMG-CoA reductase, decreasing total cholesterol. Ascorbic acid is an important antioxidant compound for male reproductive system. This study aimed to evaluate whether ascorbic acid supplementation may prevent the reproductive damage provoked by rosuvastatin administration at prepuberty. Male pups were distributed into six experimental groups that received saline solution 0.9%, 3 or 10mg/kg/day of rosuvastatin, 150mg/day of ascorbic acid, or 150mg/day of ascorbic acid associated with 3 or 10mg/kg/day of rosuvastatin from post-natal day (PND) 23 until PND53. Rosuvastatin-treated groups showed delayed puberty installation, androgen depletion and impairment on testicular and epididymal morphology. Ascorbic acid partially prevented these reproductive damages. In conclusion, rosuvastatin exposure is a probable risk to reproductive development and ascorbic acid supplementation may be useful to prevent the reproductive impairment of rosuvastatin exposure.