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BACKGROUND: After the Coronavirus Disease pandemic, depression became more present, including in adolescents. Escitalopram, a selective serotonin reuptake inhibitor, was approved in 2009 for treatment of the major depressive disorder, both in children and adolescents. The undesirable effects of antidepressants on sexual dysfunction are usually underestimated. AIMS: To investigate the effects of chronic mild stress, induced from peripuberty up to adulthood, on male sexual behavior parameters, with or without the escitalopram treatment, using rats as experimental model in a translational study. MATERIALS AND METHODS: Forty-four peripubertal male rats were distributed into four groups: Sham control, escitalopram, stress, and stress + escitalopram. The chronic mild stress consisted of nine different stressors randomly applied one per day, for 8 weeks (from 41 to 97 days postpartum). Escitalopram therapy by gavage (10 mg/kg) started at 70 days postpartum and lasted for 4 weeks. The male sexual behavior parameters were evaluated at 114 days postpartum. After that, euthanasia was performed for blood and testis collection. Histopathology of the testes and plasmatic testosterone level were carried out. RESULTS: There was a reduction in sexual activity and motivation in rats exposed to the stress protocol, which were treated or not with escitalopram, as well as an increase in the total number of mounts in animals exposed to the stress and treated with escitalopram. The testosterone levels were lower in animals exposed to the stress, which were or not treated with escitalopram (stress and stress + escitalopram). The frequency of histologically normal seminiferous tubule sections was lower in animals that were exposed to the stress and/or received escitalopram (escitalopram, stress, and stress + escitalopram). CONCLUSION: Chronic mild stress induced from peripuberty, associated or not to escitalopram treatment, altered the testosterone levels and testicular histoarchitecture and seems to be related to the reduction in male sexual motivation.

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BACKGROUND: The prevalence of depression in adolescents has significantly increased worldwide. Escitalopram is a selective serotonin reuptake inhibitor approved for treatment of psychiatric disorders in children and adolescents by the Food and Drugs Administration. AIMS: This study aimed to evaluate the sperm parameters of adult rats exposed to chronic mild stress (CMS), from peripuberty to adulthood, treated or not with escitalopram. MATERIALS AND METHODS: Sixty-two male rats were distributed into four groups: S - submitted to CMS; E - Escitalopram (10 mg / kg, via gavage); ES - CMS + ES; SC - Sham control. The induced depression protocol consisted of the exposure of the animals to nine different stressors (one stressor/day), randomly for 8 weeks, from peripuberty (41 days postpartum, dpp) to adulthood (97 dpp). The escitalopram treatment period started at 70 dpp and lasted 4 weeks. The euthanasia was performed for biological material collection at 114 dpp. Morphometric, biometric, sperm parameters, oxidative stress analyses, and corticosterone dosage were carried out. RESULTS: There was a reduction of the sperm daily production and sperm concentration in the epididymis of rats treated and/or submitted to CMS. These groups (E, S, ES) also showed reduction of the mitochondrial activity; acrosome integrity; sperm chromatin compaction; sperm motility and vitality, besides an increased frequency of morphologically abnormal sperm. The sperm transit time through the epididymis was significantly higher in the escitalopram-treated rats (E, ES). No differences were observed regarding the sperm DNA fragmentation. The lipid peroxidation was significantly increased at the epididymal (E, S, and ES group) and testicular levels (S group). CONCLUSION: The CMS with or without escitalopram treatment altered the oxidative status in sperm and male organs, worsening the qualitative and quantitative sperm parameters, which can probably compromise the male fertility.

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BACKGROUND: Methylphenidate hydrochloride (MPH) is a psychostimulant widely used in the treatment of attention-deficit hyperactive disorder (ADHD), as well as a performance enhancer, for at least 60 years. Despite the notable effectiveness as a psychostimulant, ADHD is a chronic disorder and has a two-third chance of accompanying the individual throughout life. Long-term use of MPH has been associated not only with an increase in the development of neurodegenerative diseases, but it also causes side effects on male fertility in experimental animals. OBJECTIVES: To investigate whether methylphenidate poses a risk to sperm DNA structure and to the quality of embryos conceived after treatment during adolescence in rats. MATERIALS AND METHODS: Wistar rats at 38 days of age were treated either with 5 mg/kg body weight of MPH, in a single daily dose for 30 days, via gavage or with distilled water-only protocol. Levels of oxidative stress in testicular and epididymal tissues were evaluated. Sperm chromatin quality and acrosome integrity was assessed under flow cytometry. From 107 days of age, animals were mated with untreated females. The effects of the paternal contribution at two different embryo development moments-cleavage stage (2.5 days post coitum) and late gestation (20 days post coitum) -were analyzed. RESULTS: MPH caused high levels of sperm DNA damage, which was reflected in 40% of decrease in early embryo quality and a lower number of live pups at 20 dpc. DISCUSSION: The high level of fragmentation seen in the embryos sired from the MPH group is consistent with the poor chromatin structure of the sperm and does not seem to be a result of oxidative stress in the reproductive tissues. CONCLUSIONS: The results presented here suggest that the subchronic use of MPH during male prepubertal phase may cause long-term subfertility and compromise embryo survival.

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BACKGROUND: Nicotine leads to reproductive changes culminating in male infertility and subfertility. Resveratrol, a polyphenol, is a biological modulator. Sirtuin 1 (SIRT1) protein can positively act on male reproduction, and its expression can be affected by nicotine and modulated by resveratrol. OBJECTIVES: The capability of resveratrol to reverse the reproductive damage in adult male offspring, which was nicotine-exposed during the intrauterine phase and breastfeeding, was investigated. MATERIALS AND METHODS: Four groups were established with male offspring born from nicotine-exposed and non-exposed rat dams during pregnancy and lactation. Forty-eight male Wistar rats were distributed into four groups: sham control (SC), resveratrol (R), nicotine (N), and nicotine + resveratrol (NR). Rat dams of the N and NR offspring were exposed to nicotine (2 mg/kg/day) during pregnancy and lactation using a subcutaneously implanted minipump. The offspring of the R and NR groups received resveratrol (300 mg/kg of body weight, gavage) for 63 days from puberty. At 114 days of age, the male rats were euthanized. RESULTS: Nicotine did not alter the body weight, biometry of reproductive organs, or quantitative sperm parameters of adult offspring but caused an evident worsening of all sperm qualitative parameters studied. Daily treatment with resveratrol from puberty up to adulthood improved all qualitative sperm parameters significantly, leading some of them close to the control values. Resveratrol also improved the morphological integrity and expression of SIRT1 in the seminiferous epithelium of nicotine-exposed offspring. CONCLUSION AND DISCUSSION: Resveratrol reversed the male reproductive damage caused by nicotine. Nicotine crosses the blood-placental membrane and is present in the breast milk of mothers who smoke. Resveratrol restored the altered reproductive parameters in the male adult offspring that were nicotine-exposed during intrauterine life and breastfeeding. The epigenetic modulating action of resveratrol can be involved in this nicotine damage reversion. Resveratrol may be a promising candidate to be investigated regarding the adjuvant strategies in the treatment of male infertility.

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In varicocele, the main cause of sperm DNA damage is oxidative stress (OS). Resveratrol, a polyphenol with antioxidant properties, can protect cells from injuries caused by OS. We investigated the benefits of resveratrol against reproductive damage caused by experimental varicocele induced from peripuberty. Eighty peripubertal male rats were distributed into 4 groups: sham-control (S), varicocele (V), resveratrol (R) and varicocele treated with resveratrol (VR). Varicocele was induced through the partial ligature of the left renal vein. Resveratrol was given in a daily dose of 300 mg/kg body weight (gavage). Sperm samples were collected at 100 days of age for vitality, DNA fragmentation and chromatin protamination evaluations. OS analyses were carried out. Rats from all groups were mated with healthy primiparous females for evaluation of reproductive capacity and embryonic quality. The V group showed reduction of sperm vitality, altered chromatin protamination and sperm DNA integrity and high levels of OS. The VR group showed an improvement of oxidative status, sperm vitality, DNA integrity and chromatin structure, and an enhancement in the gestational index and embryonic quality. Therefore, we showed in this experimental model that resveratrol is a promising nutraceutical adjuvant and should be deeply studied to mitigate subfertility in varicocele.

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Carbamazepine (CBZ), an anticonvulsant drug, is used by pregnant women and crosses the placental barrier, reaching the embryo/foetus. CBZ inhibits testicular steroidogenesis and may lead to alterations in testicular development, spermatogenesis and male fertility. The purpose of this study was to evaluate the CBZ effects on testicular parameters in the neonatal and pubertal phases, as well as the spermatic parameters of pubertal rats, originated from dams treated during different periods of the pregnancy. Pregnant rats were treated with CBZ (20 mg/kg/day; intraperitoneal route), from 12-20 gestation day (GD) (CBZ12 group) and 15-20 GD (CBZ15 group). The testicular morphometric and stereological analysis of rats aged 4 and 63 days was performed. The oestradiol and testosterone plasmatic levels, as well as spermatic parameters, were achieved at 63 days. CBZ12 group showed a reduction in testicular weight and volume at 4 days post-partum (dpp); however, there was an increase in the seminiferous cords' length of the CBZ12 and CBZ15 groups. At 63 days, the CBZ12 group showed increases of the daily sperm production and damage in the seminiferous epithelium. The results suggest that CBZ interferes with the testis development and the establishment of the spermatogenic process, which can be detected in the puberty phase.

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The aim of this study was to investigate carnitine action against negative effects of etoposide on stem/progenitor spermatogonia and on sperm production. Carnitine (250 mg/kg body weight/day) and etoposide (5 mg/kg body weight/day) were administered from 25-days postpartum to 32-days postpartum. Testes were collected at 32-days postpartum, 64-days postpartum, and 127-days postpartum, and submitted to the immuno-labeling of UTF1, SOX2, and PLZF proteins to identify undifferentiated spermatogonia populations. At 127-days postpartum, sperm were collected for analysis. Carnitine+etoposide group showed a higher numerical density of spermatogonia labeled for all studied proteins at 64-days postpartum (critical age) compared to the etoposide group. Moreover, there was an improvement of spermatic parameters and sperm DNA integrity in rats of the carnitine+etoposide group in comparison with rats of the etoposide group. The results suggest that carnitine improves the self-renewal of undifferentiated spermatogonia and promotes a partial protection on them, alleviating the etoposide harmful late effects and leading to an enhancement of the sperm parameters in adulthood.

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Idiopathic varicocele is closely associated with male infertility or subfertility. Sertoli cell is a very important regulator of spermatogenesis. We investigated the morphofunctional alterations in the Sertoli cell and its possible involvement in the establishment of testicular primary lesion in experimental left-sided varicocele, induced from peripuberty. Twenty-five male peripubertal rats (44 days postpartum [dpp]) were distributed into two groups: control (C) and varicocele (V). Experimental left varicocele was induced in rats through the partial ligature of the left renal vein. Euthanasia was performed at 100 dpp. Testicular histopathology and testosterone plasmatic level were evaluated. Transferrin and vimentin proteins were, respectively, used as immunomarkers of Sertoli cell function and structure. Significant reductions in vimentin and transferrin expressions were noticed in androgen-dependent stages (VII and VIII) of the seminiferous epithelium cycle in V rats; testosterone plasmatic level was also reduced. Bilateral testicular histopathological alterations were found in V rats, mainly massive germ cell desquamation. The histological damage and changes in protein expressions occurred bilaterally. The relevant impairment of the functional and structural characteristics of the Sertoli cell, together with the typical massive germ cell desquamation, indicates that Sertoli cell changes can primarily contribute to the significant testicular dysfunction associated with varicocele.

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Cimetidine, used as an anti-ulcer and adjuvant treatment in cancer therapy, causes disorders in the male reproductive tract, including steroidogenesis. However, its effect on sperm quality and male fertility has been poorly addressed. Since vitamin B12 has demonstrated to recover spermatogonia number and sperm concentration in cimetidine-treated rats, we evaluated the impact of cimetidine on sperm quality and fertility potential and whether vitamin B12 is able to prevent the harmful effect of this drug on steroidogenesis and sperm parameters. Adult male rats were treated for 52 consecutive days as follows: cimetidine group (100 mg/kg of cimetidine), cimetidine/vitamin B12 group (100 mg/kg of cimetidine + 3 µg vitamin B12), vitamin B12 group (3 µg vitamin B12) and control group (saline). Serum testosterone levels and immunofluorescence associated to western blot for detection of 17ß-HSD6 were performed. Sperm morphology and motility, mitochondrial activity, acrosome integrity, DNA integrity by Comet assay, lipid peroxidation as well as fertility potential were analyzed in all groups. Apoptotic spermatids were also evaluated by caspase-3 immunohistochemistry. In the cimetidine-treated animals, reduced serum testosterone levels, weak 17ß-HSD6 levels and impaired spermiogenesis were observed. Low sperm motility and mitochondrial activity were associated with high percentage of sperm tail abnormalities, and the percentage of spermatozoa with damaged acrosome and DNA fragmentation increased. MDA levels were normal in all groups, indicating that the cimetidine-induced changes are associated to androgenic failure. In conclusion, despite the fertility potential of rats was unaffected by the treatment, the sperm quality was significantly impaired. Therefore, considering a possible sperm-mediated transgenerational inheritance, the long term offspring health needs to be investigated. The administration of vitamin B12 to male rats prevents the androgenic failure and counteracts the damage inflicted by cimetidine upon sperm quality, indicating that this vitamin may be used as a therapeutic agent to maintain the androgenic status and the sperm quality in patients exposed to androgen disrupters.

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The progression of diabetes mellitus leads to several complications including overproduction of reactive oxygen species and reproductive alterations. As resveratrol (RES) is a powerful anti-oxidant and an anti-apoptotic compound, we hypothesized that side effects of type-1 diabetes (DM1) on male reproduction could be reduced by the RES treatment. Eighty-four prepubertal male rats were distributed into seven groups: sham-control (SC), RES-treated (R), resveratrol-vehicle-treated (RV), diabetic (D), diabetic-insulin-treated (DI), diabetic-RES-treated (DR), diabetic-insulin and RES-treated (DIR). DM1 was induced by a single intraperitoneal streptozotocin (STZ) injection (65 mg/kg) on the 30th day postpartum (dpp). Animals of DR, DIR and R groups received 150 mg/day of RES by gavage for 43 consecutive days (from the 33 to 75 dpp). DI and DIR rats received subcutaneous injections of insulin (1 U/100 g b.w./day) from 5th day after the DM1 induction. The blood glucose level was monitored. At 75 dpp, the euthanasia was performed for morphometric and biometric testicular analyses, spermatic evaluation and hormonal doses. In the D group, the blood glucose level was higher than in the DR, DI and DIR groups. Besides morphometric testicular measurements, testosterone and estradiol doses were lower in D group than in DR and DIR groups; LH dose was also lower than in DR. The preputial separation age was delayed in diabetes-induced groups. The DR and DIR groups showed an improvement in sperm mitochondrial activity, epididymal sperm counts and the frequency of morphologically normal sperms. RES treatment improved glycaemic level, sperm quantitative and qualitative parameters and the hormonal profile in DM1-induced rats and seems to be a good reproductive protector.

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