Search

Despite increased prescription of sertraline during pregnancy, little is known about its action on reproductive development. Therefore, this study aimed to investigate the impact that stress, associated or not with sertraline, causes on the reproductive development of male rats. Pregnant Wistar rats were divided into 4 groups (n = 16/group): CO—received filtered water; SE—received 20 mg/kg sertraline; ST—submitted to restraint stress and received filtered water; SS—submitted to restraint stress and received sertraline. The treatment was carried out from gestational days (GDs) 13–20. The animals were euthanized on GD 20 (n = 8/group), postnatal day (PND) 45 (n = 8/group), and PND 110 (n = 8/group). The testes and epididymis were analyzed histologically, and immunohistochemistry was performed on the testes by proliferating cell nuclear antigen (PCNA) and the Wilms tumor protein (Wt1). Sperm quality was also analyzed on PND 110. The evolution of body weight, anogenital distance (AGD), and puberty installation day were also verified. Statistical analysis: 2-way ANOVA or Kruskal-Wallis test (p ≤ .05). Fetal testes presented a large number of acidophilic cells in the sertraline-exposed groups. The SS group also showed a decrease in the nuclear volume of Leydig cells. This same group showed low expression of PCNA and Wt1, decreased weight of the testes and epididymis, lower AGD, and delayed puberty installation. The adulthood groups exposed to sertraline presented alterations in sperm morphology and motility. The results demonstrated that prenatal exposure to sertraline compromises the development of the rat reproductive system.

Made available in DSpace on 2020-12-12T02:36:00Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-07-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) 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. Department of Morphology Institute of Biosciences São Paulo State University - UNESP Graduate Program in Cell and Structural Biology Institute of Biology State University of Campinas – UNICAMP Department of Morphology Physiology and Basic Pathology School of Dentistry of Ribeirão Preto University of São Paulo – USP Reproductive Toxicity Branch Toxicity Assessment Division National Health and Environmental Effects Research Laboratory Office of Research and Development US Environmental Protection Agency Department of Morphology Institute of Biosciences São Paulo State University - UNESP FAPESP: 2014/15566-2 CNPq: 308842/2013-8 CNPq: 312118/2017-1

Made available in DSpace on 2020-12-12T02:46:16Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-01-01 Sibutramine is a non-selective serotonin-norepinephrine reuptake inhibitor orally administered for weight loss. In a previous study, we showed pharmacological mechanisms involved in the reduction of sperm quality and fertility of rats exposed for 30 days to this anorexigen in the light phase of the light-dark (l/d) cycle. It is already known that rodents are nightlife animals, with higher metabolic activity during the dark phase than in the light phase of the light-dark (l/d) cycle. Thus, the present study aimed to investigate whether the deleterious effects on reproductive parameters after sibutramine administration would be enhanced after a shorter period of exposure during the dark phase of the l/d cycle. For this, adult male Wistar rats were treated with sibutramine (10 mg/kg/d) or vehicle for 15 days during the dark phase of the l/d cycle. Sibutramine treatment decreased final body and reproductive organ weights, as well as serum testosterone levels. Sperm transit time through the epididymis was accelerated, and sperm concentration and motility were diminished in the sibutramine-exposed rats. The decrease in sperm concentration was also verified in the epididymal histological sections. In conclusion, the deleterious effects of sibutramine on reproductive parameters of male rats were enhanced when the exposure occurred in the dark phase of the l/d cycle, even after a short exposure duration. Our results reinforce the impact of timing on drug therapeutic action. Department of Structural and Functional Biology Institute of Biosciences UNESP - São Paulo State University Department of Morphology Stomatology and Physiology USP – University of São Paulo Department of Structural and Functional Biology Institute of Biosciences UNESP - São Paulo State University

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.

Made available in DSpace on 2022-05-01T09:30:56Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-11-15 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) 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. Graduate Program in General and Applied Biology São Paulo State University (UNESP) Institute of Biosciences Laboratory of Reproductive and Developmental Biology and Toxicology Department of Structural and Functional Biology Institute of Biosciences São Paulo State University (UNESP) Graduate Program in General and Applied Biology São Paulo State University (UNESP) Institute of Biosciences Laboratory of Reproductive and Developmental Biology and Toxicology Department of Structural and Functional Biology Institute of Biosciences São Paulo State University (UNESP) CNPq: 312118/2017-1

Made available in DSpace on 2018-12-11T17:14:37Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-11-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Excessive fetal glucocorticoid exposure has been linked to increased susceptibility to hypertension and cardiac diseases in the adult life, a process called fetal programming. The cardiac contribution to the hypertensive phenotype of glucocorticoid-programmed progeny is less known, therefore, we investigated in vitro cardiac functional parameters from rats exposed in utero to betamethasone. Pregnant Wistar rats received vehicle (VEH) or betamethasone (BET, 0.1 mg/kg, i.m.) at gestational days 12, 13, 18 and 19. Male and female offspring were killed at post-natal day 30 and the right atrium (RA) was isolated to in vitro evaluation of drug-induced chronotropic responses. Additionally, whole hearts were retrograde-perfused in a Langendorff apparatus and infarct size in response to in vitro ischemia/reperfusion (I/R) protocol was evaluated. Male and female progeny from BET-exposed pregnant rats had reduced birth weight, a hallmark of fetal programming. Male BET-progeny had increased basal RA rate, impaired chronotropic responses to noradrenaline and adenosine, and increased myocardial damage to I/R. Though a 12-fold reduction in the negative chronotropic responses to adenosine, the effects of non-metabolisable adenosine receptor agonists 5′-(N-ethylcarboxamido)adenosine or 2-Chloro-adenosine were not different between VEH- and BET-exposed male rats. BET-exposed female offspring presented no cardiac dysfunction. Prenatal BET exposure engenders male-specific impairment of sinoatrial node function and on myocardial ischemia tolerance resulting, at least in part, from an increased adenosine metabolism in the heart. In light of the importance of adenosine in the cardiac physiology our results suggest a link between reduced adenosinergic signaling and the cardiac dysfunctions observed in glucocorticoid-induced fetal programming. Department of Pharmacology São Paulo State University (UNESP) Institute of Biosciences, Campus of Botucatu, Distrito de Rubião Junior s/n° Department of Physiology São Paulo State University (UNESP) Institute of Biosciences, Campus of Botucatu, Distrito de Rubião Junior s/n° Department of Morphology São Paulo State University (UNESP) Institute of Biosciences, Campus of Botucatu, Distrito de Rubião Junior s/n° Instituto de Ciências da Saúde Federal University of Mato Grosso Department of Pharmacology São Paulo State University (UNESP) Institute of Biosciences, Campus of Botucatu, Distrito de Rubião Junior s/n° Department of Physiology São Paulo State University (UNESP) Institute of Biosciences, Campus of Botucatu, Distrito de Rubião Junior s/n° Department of Morphology São Paulo State University (UNESP) Institute of Biosciences, Campus of Botucatu, Distrito de Rubião Junior s/n° FAPESP: 08/50423-7 FAPESP: 2012/25350-1 CNPq: 308842/2013-8

Made available in DSpace on 2018-12-11T17:03:44Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-02-01 Betamethasone is the drug of choice for antenatal treatment, promoting fetal lung maturation, decreasing the incidence of respiratory distress syndrome and neonatal mortality. Previous studies reported that prenatal treatment with this drug reduced testosterone levels, sperm quality and fertility in adult rats. We aimed to further evaluate the reproductive consequences of prenatal betamethasone exposure in male rats. Pregnant Wistar rats (n = 13/group) were separated into two groups: control (vehicle) and betamethasone- treated (0.1 mg/kg IM) and rats were injected on gestational days 12, 13, 18 and 19. Body weight, sexual behavior, reproductive organ weights, serum hormone levels, accessory glands contractility, sperm parameters, and fertility after in utero artificial insemination were evaluated. Our results showed that prenatal betamethasone exposure provoked a significant reduction in body weight at PND 01 and, at adulthood, decrease in FSH levels, sperm motility and production. Furthermore, seminal vesicle weight was decreased while testicular and ventral prostate weights were increased. Serum LH levels and the percentage of abnormal sperm were significantly increased. Although sexual behavior was not altered, a significant reduction in fertility in the adult rats exposed prenatally to betamethasone was noted. We concluded that prenatal betamethasone exposure leads to long-term reproductive impairment in male rats. These results may have important implications for humans, considering the use of this glucocorticoid in pregnant women. Departments of Morphology Institute of Biosciences of Botucatu UNESP—Univ Estadual Paulista, Distrito de Rubião Junior s/n° Departments of Pharmacology Institute of Biosciences of Botucatu UNESP—Univ Estadual Paulista, Distrito de Rubião Junior s/n° Departments of Morphology Institute of Biosciences of Botucatu UNESP—Univ Estadual Paulista, Distrito de Rubião Junior s/n° Departments of Pharmacology Institute of Biosciences of Botucatu UNESP—Univ Estadual Paulista, Distrito de Rubião Junior s/n°

Lorcaserin is an anti-obesity drug whose weight loss effect results from 5-hydroxytryptamin (5-HT)To investigate the effects of lorcaserin in different in vitro and in vivo experimental models of ejaculation in rats.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.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.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-HTDue to its reported clinical safety, repurposing lorcaserin for the treatment of delayed ejaculation may be suggested.The pro-ejaculatory effect of lorcaserin administration and the role of 5-HTOur results demonstrate that the clinically approved 5-HT

The reported cumulative prevalence of hyponatremia (sodium135 mmol/L) in bronchiolitis is 28%. However, sodium level was never measured by direct potentiometry, the method recommended by the International Federation of Clinical Chemistry and Laboratory Medicine. Aim of this study was to assess the prevalence of hyponatremia, measured by direct potentiometry, in infants with moderate-severe bronchiolitis.A prospective cross-sectional study was conducted in infants ≥1month and ≤24months of age with bronchiolitis.160 consecutive infants were enrolled. Hyponatremia was observed in 91 (57%) patients and occurred more commonly in infants ≤6 months than in older infant (P 0.005).The first study on sodium level measured by the direct potentiometry in infants with bronchiolitis points out that the prevalence of hyponatremia is two-fold higher than so far reported.

Made available in DSpace on 2018-12-11T17:38:14Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-09-02 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) 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. Graduate Program in Cell and Structural Biology Institute of Biology State University of Campinas–UNICAMP Department of Morphology São Paulo State University (Unesp) Institute of Biosciences Department of Morphology Physiology and Basic Pathology School of Dentistry of Ribeirão Preto USP–University of São Paulo Department of Morphology São Paulo State University (Unesp) Institute of Biosciences FAPESP: #014/13659-3 CNPq: 308842/2013-8

Made available in DSpace on 2018-12-11T17:20:32Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-08-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) 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. Graduate Program in Cell and Structural Biology Institute of Biology State University of Campinas – UNICAMP Department of Morphology São Paulo State University (Unesp) Institute of Biosciences Department of Pathology São Paulo State University (Unesp) Medical School Department of Morphology Stomatology and Physiology School of Dentistry USP – University of São Paulo, Ribeirão Preto Department of Morphology São Paulo State University (Unesp) Institute of Biosciences Department of Pathology São Paulo State University (Unesp) Medical School FAPESP: #013/22495-1 FAPESP: #014/13659-3 CNPq: 308842/2013-8

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.

Made available in DSpace on 2018-12-11T17:37:36Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-08-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Therapy with betamethasone, a synthetic glucocorticoid, is used in cases of preterm birth risk, in order to promote fetal lung maturation, and decrease neonatal mortality and morbidity. However, late reproductive disorders related to the prenatal exposure to this compound have been reported by our Laboratory, in both male and female rats. Thus, the present study aimed to evaluate the impact of betamethasone on postnatal reproductive development, during pre-puberty, of male offspring exposed in utero to this synthetic glucocorticoid. For this purpose, pregnant Wistar rats were allocated into two groups: Control, treated with saline, and the group treated with betamethasone at 0.1 mg/kg/day. Control and betamethasone groups were treated with intramuscular injection on gestational days 12, 13, 18 and 19, critical days of prenatal reproductive development. The treatment is associated with reduced body and organ weights, disorders in initial reproductive parameters of pre-pubertal male offspring exposed in utero to betamethasone, such as reduction of anogenital distance, alterations in histomorphometric parameters and immunostaining pattern of androgen and estrogen receptors on testicles and epididymides. Our results suggest that prenatal exposure to betamethasone potentially causes reproductive reprogramming and impairs male postnatal reproductive development. This data raise concerns about the use of betamethasone for human antenatal therapy. Department of Morphology São Paulo State University (UNESP) Institute of Biosciences Department of Morphology São Paulo State University (UNESP) Institute of Biosciences FAPESP: 2012/25350-1 FAPESP: 2017/02764-9 CNPq: 308842/2013-8 CNPq: 312118/2017-1

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.

Made available in DSpace on 2018-12-11T17:34:21Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-09-29 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) The acute promyelocytic leukemia (APL) is a rare disease, affecting 0.1/100,000 individuals globally. Despite significant advances in APL therapy, some patients still experience relapsed disease. Currently, arsenic trioxide (As2O3) was found to be effective in relapsed APL treatment and considered as standard treatment for these cases. However, it has been shown that exposure to As2O3 may exert adverse effects on the male reproductive system since this substance might also induce apoptosis of other important cell types including stem cells. Studies demonstrated that treatment with this metallic substance decreased plasma levels of testosterone and interfered with sperm parameters such as concentration, motility, and viability. In addition, As2O3 was found to produce significant damage to spermatocytes, which may be associated with testicular toxicity and consequent inhibition of spermatogenesis. The aim of this study was to determine subchronic treatment effects of As2O3 on sperm and testicular morphology, androgen receptor (AR) immunoreactivity in testes and epididymis, in addition to evaluation of fertility parameters in adult male mice. Thirty adult Swiss mice were divided into three experimental groups: control; received distilled water (vehicle) while treated received 0.3 or 3 mg/kg/day As2O3 subcutaneously, for 5 days per week, followed by 2 days of interruption, for 5 weeks. Results showed that As2O3 (1) decreased spermatozoa number, (2) produced seminiferous epithelium degeneration and exfoliation of germ cells tubule lumen (3) altered nucleus/cytoplasm proportion of Leydig cells and (4) reduced AR immunoreactivity in both Leydig and epithelial epididymal cells. Further, fetal viability tests demonstrated an increase in post-implantation loss in females that were mated with As2O3- treated males. Data indicate that As2O3 exposure altered the spermatogenic process and subsequently fetal viability. Department of Structural and Functional Biology Institute of Biology University of Campinas (UNICAMP) Department of Morphology Institute of Biosciences Univ Estadual Paulista (UNESP) Department of Morphology Institute of Biosciences Univ Estadual Paulista (UNESP) FAPESP: FAPESP 2012/14342-8

Made available in DSpace on 2018-12-11T17:11:56Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-08-01 Prenatal betamethasone (BM) exposure in rats negatively impacts sperm quality and male fertility. Studies have shown that BM can cause multi-generational effects on the pituitary-adrenal-axis of rats. The objective of this study was to assess the reproductive development and fertility of male rats (F2) whose fathers (F1) were exposed to BM (0.1 mg/kg) on gestational days 12, 13, 18 and 19. In F2 rats, there was a significant reduction in body weights of the BM-treated group at PND 1 as well as delayed onset of puberty, and decreases in FSH levels, Leydig cell volume, sperm number and motility, seminal vesicle contractility and ejaculated volume. Furthermore, increased serum LH levels, sperm DNA damage and abnormal morphology were observed, resulting in reduced fertility. In conclusion, prenatal BM-treatment leads to intergenerational long-term reproductive impairment in male rats, raising concern regarding the widespread use of BM in preterm births. Department of Morphology Institute of Biosciences of Botucatu UNESP – São Paulo State University, Distrito de Rubião Junior s/nº Department of Pharmacology Institute of Biosciences of Botucatu UNESP – São Paulo State University, Distrito de Rubião Junior s/nº Department of Pathology Botucatu Medical School UNESP – São Paulo State University, Distrito de Rubião Junior s/n° Laboratory for Reproductive Toxicology INRS-Institut Armand-Frappier University of Quebec, 531 Boulevard des Prairies Department of Morphology Institute of Biosciences of Botucatu UNESP – São Paulo State University, Distrito de Rubião Junior s/nº Department of Pharmacology Institute of Biosciences of Botucatu UNESP – São Paulo State University, Distrito de Rubião Junior s/nº Department of Pathology Botucatu Medical School UNESP – São Paulo State University, Distrito de Rubião Junior s/n°

Made available in DSpace on 2018-12-11T17:31:21Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-02-01 Leptin is a protein secreted by the adipocytes, which serves as a link between fat and brain. Its main action is to decrease appetite and increase energy expenditure, but it is also involved in the control of different neuroendocrine systems, including gonadal axis. Although the effects of leptin deficiency on reproduction are well recognized, the effect of excess leptin on male reproductive function is not clear. The aim of this study was to evaluate fertility and sperm parameters of male rats exposed to exogenous leptin. A group of adult male rats received exogenous leptin intraperitoneally (30 μg/kg/day) for 42 days, and a control group received only the vehicle during the same period. After the treatment, animals were evaluated for sperm count, sperm motility, and fertility after intrauterine artificial insemination. There was no statistically significant difference between the groups related to sperm production, sperm concentration, and sperm motility. However, fertility evaluation after artificial insemination showed a quantitative decrease in the uterus plus fetuses weight, number of implantation sites, and number of live fetuses. The fertility potential showed a reduction of about 40%, whereas the preimplantation loss rate increased more than 2-fold in leptin-treated animals. In conclusion, leptin administration to nonobese male rats impairs ability of treated animals to generate offspring, since the occurrence of implantation was diminished. So leptin can impair sperm quality, affecting the reproductive capacity. Laboratory of Reproductive and Developmental Biology and Toxicology Department of Morphology Institute of Biosciences UNESP Univ Estadual Paulista Pró-Reitoria de Pesquisa e Pós-Graduação Central de Laboratórios de Ciências e Tecnologia Ambiental Laboratório de Toxicologia Experimental Universidade Sagrado Coração, Rua Irmã Arminda 10-50 Laboratory of Reproductive and Developmental Biology and Toxicology Department of Morphology Institute of Biosciences UNESP Univ Estadual Paulista

Made available in DSpace on 2018-12-11T17:34:04Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-11-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) 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. Graduate Program in Cell and Structural Biology Institute of Biology State University of Campinas – UNICAMP Department of Morphology São Paulo State University (Unesp) Institute of Biosciences Graduate Program in Genetics São Paulo State University (Unesp) Institute of Biosciences Department of Morphology São Paulo State University (Unesp) Institute of Biosciences Graduate Program in Genetics São Paulo State University (Unesp) Institute of Biosciences FAPESP: #013/22495-1 FAPESP: #014/13659-3 CNPq: 308842/2013-8

Made available in DSpace on 2018-12-11T17:23:59Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-01-01 Oxidative stress is known as the leading factor responsible for varicocele-related infertility and for that reason, many antioxidant therapies have been proposed. Considering that, we evaluated the reproductive outcomes and fertility of varicocelized rats and the impact of chrysin within these parameters. The animals were allocated into three groups: sham (control), varicocele treated via gavage with 50 mg/kg/day of chrysin (V1), or vehicle (V2) for 56 days. Chrysin treatment prevented oxidative damage resulting from varicocele by decreasing testicular concentrations of malondialdehyde and sperm DNA fragmentation. It also improved histological aspect of the testis and maintained morphometric parameters similar to the sham group. Furthermore, there were no differences in body and reproductive organ weights, histopathological analysis of epididymis, sperm counts and morphology, testosterone levels, sexual behavior, and fertility parameters among experimental groups. Our results reinforce the idea that injuries provoked by experimental varicocele are related, at least in part, to oxidative stress. Moreover, varicocele showed bilateral deleterious effects without interfering with fertility. Chrysin administration significantly ameliorated sperm parameters, protecting the reproductive system against varicocele damages. For that reason, chrysin might be an alternative adjuvant therapy to improve sperm quality in men presenting this condition. Department of Morphology Institute of Biosciences São Paulo State University (UNESP) Graduate Program in Cell and Structural Biology University of Campinas (UNICAMP) Department of Clinical Analyses Toxicology and Food Sciences School of Pharmaceutical Sciences of Ribeirão Preto University of São Paulo Department of Morphology Institute of Biosciences São Paulo State University (UNESP)

Summary Here we investigated the hypothesis that normal levels of glucocorticoids, a class of adrenal steroid hormones, are required for normal testicular and epididymal functions. We examined the effects of the manipulation of glucocorticoid plasma levels by bilateral adrenalectomy (1, 2, 7 and 15 days) alone or in combination with daily treatment with the synthetic glucocorticoid dexamethasone (DEX; 5 μg/kg, i.p., 6 days) on the morphology of the testis and sperm parameters in rats. We showed that adrenalectomy led to a reduction in testicular sperm count and daily sperm production starting 2 days after surgery and a differential decrease in sperm count in the epididymis, according to the region and time post-adrenalectomy analysed. In parallel, testes from 7-day adrenalectomized (ADX) rats displayed a higher frequency of damaged seminiferous tubules and the presence of elongated spermatids retained in the basal epithelial compartment in stages IX–XVII, which is indicative of defective spermiation. The alkaline comet assay revealed a late effect of adrenalectomy on epididymal sperm DNA fragmentation, which was increased only 15 days after surgery. DEX treatment prevented the changes in testicular and epididymal sperm count observed in 7-day ADX rats, but failed to protect the testis from ADX-induced morphological abnormalities. Thus, our results indicated that glucocorticoids may be involved in events related to the maintenance of spermatogenesis and sperm maturation during adulthood. These findings provide new insights into the importance of adrenal steroids to male fertility.

Made available in DSpace on 2018-12-11T17:23:32Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-10-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) 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 10 mg/kg/day of rosuvastatin, 150 mg/day of ascorbic acid, or 150 mg/day of ascorbic acid associated with 3 or 10 mg/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. Graduate Program in Cell and Structural Biology Institute of Biology State University of Campinas—UNICAMP Department of Morphology São Paulo State University (Unesp) Institute of Biosciences Department of Clinical Analyses Toxicology and Food Sciences School of Pharmaceutical Sciences of Ribeirão Preto University of São Paulo—USP, Ribeirão Preto Department of Morphology São Paulo State University (Unesp) Institute of Biosciences FAPESP: #013/22495-1 CNPq: 308842/2013-8

Background: Anti-phosphatidylserine/prothrombin (aPS/PT) antibodies have begun to be considered potentional biomarkers for antiphospholipid syndrome (APS). This cohort study investigate the role of aPS/PT antibodies as a risk factor for severe APS by evaluating the association between those antibodies and clinical/laboratory profiles of APS. Methods: Plasma/serum samples from 197 APS patients, 100 healthy subjects and 106 patients with autoimmune diseases were collected. IgG/IgM aPS/PT antibodies were assayed using commercial ELISA kit. Results: Prevalences of IgG and IgM aPS/PT (p Conclusions: APS/PT antibodies were associated to severe thrombosis, severe pregnancy complications inducing prematurity, and vascular microangiopathy, all generally associated to high risk APS forms requiring strong therapy.

Made available in DSpace on 2018-12-11T17:00:54Z (GMT). No. of bitstreams: 0 Previous issue date: 2016-04-01 Cisplatin (CP) is used to treat a number of cancers, including testicular cancer. Studies indicate that CP-treatment can impair spermatogenesis in humans and rodents by germ cell DNA binding, through different modes of action. CP-paternal exposure resulted in adverse effects in F1 male offspring. In this study, F1 female offspring was assessed for reproductive development after CP-paternal exposure. Peri-pubertal male rats, treated with 1 mg/Kg/day of CP or vehicle for 3 weeks, were mated with unexposed females. F1 female offspring of CP-treated fathers showed a decrease in fetal ovary germ cells, in estrous cycle length and FSH levels, and an increase in the percentage of antral follicles in adults. Based on our previous results and the findings of the present work we concluded that CP-paternal exposure leads to adverse effects on rat male and female reproductive development, raising concern, in humans, for children born to men exposed to CP. Department of Morphology Institute of Biosciences of Botucatu UNESP-Univ Estadual Paulista Department of Anatomy Institute of Biosciences of Botucatu UNESP-Univ Estadual Paulista Department of Clinical Toxicological and Bromatological Analyses Faculty of Pharmaceutical Sciences of Ribeirão Preto USP-University of São Paulo Department of Morphology Institute of Biosciences of Botucatu UNESP-Univ Estadual Paulista Department of Anatomy Institute of Biosciences of Botucatu UNESP-Univ Estadual Paulista

Made available in DSpace on 2018-12-11T17:03:39Z (GMT). No. of bitstreams: 0 Previous issue date: 2016-08-01 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Antenatal betamethasone is used for accelerating fetal lung maturation for women at risk of preterm birth. Altered sperm parameters were reported in adult rats after intrauterine exposure to betamethasone. In this study, male rat offspring were assessed for reproductive development after dam exposure to betamethasone (0.1 mg/kg) or vehicle on Days 12, 13, 18 and 19 of pregnancy. The treatment resulted in reduction in the offspring body weight, delay in preputial separation, decreased seminal vesicle weight, testosterone levels and fertility, and increased testicular weight. In the testis, morphologically abnormal seminiferous tubules were observed, characterized by an irregular cell distribution with Sertoli cell that were displaced towards the tubular lumen. These cells expressed both Connexin 43 (Cx43) and Proliferative Nuclear Cell Antigen (PCNA). In conclusion, intrauterine betamethasone treatment appears to promote reproductive programming and impairment of rat sexual development and fertility due to, at least in part, unusual testicular disorders. Department of Morphology Institute of Biosciences Univ Estadual Paulista-UNESP, Distrito de Rubião Junior s/n Laboratory for Reproductive Toxicology INRS-Institut Armand-Frappier University of Quebec, 531 boulevard des Prairies Department of Morphology Institute of Biosciences Univ Estadual Paulista-UNESP, Distrito de Rubião Junior s/n CNPq: 308842/2013-8

This study was performed to determine whether developmental exposure (perinatal and juvenile) to the herbicide diuron exerted adverse effects on adult rat male reproductive system. Pregnant Sprague-Dawley rats received basal diet or diet containing diuron at 500 or 750 ppm from gestational day 12 (GD 12) until the end of lactation period (postnatal day 21, PND 21). After weaning male offspring received basal diet or diet containing diuron until PND 42 (peripubertal age). At PND 90, adult male rats from each experimental group were anesthetized and euthanized for evaluation of body and reproductive organ weights, sperm parameters, plasma testosterone levels, and testicular and epididymal histopathology. Male offspring exposed to diuron at 750 ppm displayed reduced body weight at PND 10, 21, 42, and 90 compared to controls. At PND 90, diuron treatment did not induce significant change in daily sperm production, sperm morphology and motility, and testosterone levels compared to controls. In conclusion, diuron at 750 ppm induced male offspring toxicity but these alterations were not permanent, as evidenced by absence of reproductive-system alterations in adult Sprague Dawley rats.

This study evaluated the effects of antiandrogen exposure during the prepubertal period on reproductive development and reproductive competence in adults. Male rats were divided into two groups: flutamide, receiving 25 mg/kg/day of flutamide by oral gavage and control, receiving vehicle daily. Dosing continued from PND 21 to 44, and animals were killed on PND 50 or PND 75-80. The epididymis, prostate, vas deferens and seminal vesicle weights were lower in Flutamide group on PND 50, while on PND 80 only seminal vesicle weight was reduced. Fertility assessed by IUI revealed a decrease in the fertility potential in the flutamide-treated adults. Flutamide accelerated sperm transit time through the epididymis, impairing sperm motility and storage. A quantitative analysis of the cauda sperm membrane proteome revealed a few significant changes in protein expression. Thus, exposure to flutamide during the prepubertal period compromises the function of the epididymis along with epididymal sperm quality at adulthood.

Jacaranda decurrens subsp. symmetrifoliolata FariasProença (Bignoniaceae) is a species widely used for their medicinal properties. At least to our known, no study has been conducted concerning its toxicological profile after gestational and lactational exposure.The present study was carried out to evaluate the effects of J. decurrens on development of the reproductive system in male rats.Pregnant rats were treated daily (gavage) with 250 or 500 mg/kg/day of aqueous extract of J. decurrens or vehicle, from day 12 of pregnancy to day 21 of lactation.Both doses of J. decurrens significantly anticipated (p 0.05) the age of testicular descent to the scrotum, a parameter indicative of puberty initiation. Furthermore, at puberty, there was a significant reduction (p 0.05) in testicular and epididymis weights in the offspring exposed to the higher dose of extract, without effect on sperm production and the histology of reproductive organs. On the other hand, at adulthood, the reproductive parameters analyzed did not differ among groups.J. decurrens, in this experimental model, interfered with the initial development of the reproductive system, but without lasting effects on sperm production in adulthood.

The symptoms of lumbar disc herniation, such as low back pain and sciatica, have been associated with local release of cytokines following the inflammatory process induced by the contact of the nucleus pulposus (NP) with the spinal nerve.Using an animal experimental model of intervertebral disc herniation and behavioral tests to evaluate mechanical (electronic von Frey test) and thermal (Hargreaves Plantar test) hyperalgesia in the hind paw of rats submitted to the surgical model, this study aimed to detect in normal intervertebral disc the cytokines known to be involved in the mechanisms of inflammatory hyperalgesia, to observe if previous exposure of the intervertebral disc tissue to specific antibodies could affect the pain behavior (mechanical and thermal hyperalgesia) induced by the NP, and to observe the influence of the time of contact of the NP with the fifth lumbar dorsal root ganglion (L5-DRG) in the mechanical and thermal hyperalgesia.The cytokines present at highest concentrations in the rat NP were TNF-α, IL-1β and CINC-1. Rats submitted to the disc herniation experimental model, in which a NP from the sacrococcygeal region is deposited over the right L5-DRG, showed increased mechanical and thermal hyperalgesia that lasted at least 7 weeks. When the autologous NP was treated with antibodies against the three cytokines found at highest concentrations in the NP (TNF-α, IL-1β and CINC-1), there was decrease in both mechanical and thermal hyperalgesia in different time points, suggesting that each cytokine may be important for the hyperalgesia in different steps of the inflammatory process. The surgical remotion of the NP from herniated rats 1 week after the implantation reduced the hyperalgesia to the level similar to the control group. This reduction in the hyperalgesia was also observed in the group that had the NP removed 3 weeks after the implantation, although the intensity of the hyperalgesia did not decreased totally. The removal of the NP after 5 weeks did not changed the hyperalgesia observed in the hind paw, which suggests that the longer the contact of the NP with the DRG, the greater is the possibility of development of chronic pain.Together our results indicate that specific cytokines released during the inflammatory process induced by the herniated intervertebral disc play fundamental role in the development of the two modalities of hyperalgesia (mechanical and thermal) and that the maintenance of this inflammation may be the most important point for the chronification of the pain.

Objective To evaluate the changes in the caput epididymis following cryptorchidism and orchidopexy. Design Experimental study in a research laboratory. Setting Reproductive biology research laboratory. Animal(s) Immature male and mature female mice (C57BL/6). Intervention(s) Experimental cryptorchidism and orchidopexy. Main Outcome Measure(s) Morphometric-stereologic analyses, serum testosterone dosage, immunohistochemical staining of the antigen TRA54 (testicular germ cells immunized to a rat monoclonal antibody), smooth muscle α-actin (SM α-actin) and SM myosin heavy chain, sperm transit time, and fertility parameters. Result(s) There was a significant reduction in the morphometric-stereologic parameters in the cryptorchidic mice. These parameters demonstrated significant recovery following orchidopexy. Staining for an androgen-dependent antigen, TRA54, was observed in all groups. SM α-actin and SM myosin heavy chain staining was significantly increased in the cryptorchidism group but stable in the orchidopexy group. Despite the recovery of daily sperm production in the testes, the sperm transit time in the epididymis and fertility parameters remained significantly reduced in the orchidopexy group. Conclusion(s) In cryptorchidic animals, there was an acceleration of sperm passage through the epididymal duct. Orchidopexy did not restore the normal passage time. Accordingly, there was a significant reduction in the fertility parameters in the cryptorchidic group that were not fully recovered following orchidopexy.

Sibutramine is a drug globally used for the treatment of obesity. The aim of this study was to investigate male reproductive disorders caused by sibutramine in adult rats. Wistar rats were treated for 28 consecutive days (gavage) with 10 mg/kg of sibutramine. Control animals received only vehicle (dimethylsulfoxide and saline). The rats were sacrificed for evaluation of body and reproductive organ weights, sperm parameters, hormone levels (luteinizing hormone, follicle-stimulating hormone, and testosterone), testicular and epididymal histopathology, sexual behavior, fertility and in vitro contractility of the epididymal duct. Sibutramine decreased (P.05) weights of the epididymis and ventral prostate, but not of other reproductive organs. The sperm number and transit time in the epididymal cauda were decreased (P.001), but the daily sperm production was not altered. Moreover, morphology and sperm motility, histopathology of the testes and epididymis, sexual behavior, fertility, and serum hormone levels were not altered by the treatment. Sibutramine increased the potency of norepinephrine and, per se, increased the mechanical activity of the epididymal duct in vitro. Thus, although sibutramine in these experimental conditions did not interfere with the reproductive process of rats, it provoked acceleration of the sperm transit time and a decrease in the sperm reserves in the epididymal cauda. This alteration is probably related to the sympathomimetic effect of this drug, as shown by the in vitro assays. In humans, use of this drug might present a threat for male fertility because sperm reserves in men are naturally lower than those in rats.

The potential adverse reproductive effects, with emphasis on the epididymis, of in utero and lactational exposure to 100 mg/kg/d di-n-butyl phthalate (DBP) in adult male rat offspring were investigated. The fetal testis histopathology was also determined. The selected endpoints included reproductive organ weights, sperm motility and morphology, sperm epididymal transit time, sperm quantity in the testis and epididymis, hormonal status, fetal testis and epididymal histopathology and stereology, and androgen receptor (AR), aquaporin 9 (AQP9), and Ki-67 immunoreactivities. Pregnant females were divided into two groups: control (C) and treated (T). The treated females received DBP (100 mg/kg/d, by gavage) from gestation day (GD) 12 to postnatal day (PND) 21, while control dams received the vehicle. Some pregnant dams were killed by decapitation on GD20, and testes from male fetuses were collected for histopathogy. Male rats from other dams were killed at PND 90. Fetal testes from treated group showed Leydig-cell clusters, presence of multinucleated germinative cells, and increase of the interstitial component. Testosterone levels and reproductive organ weights were similar between the treated and control adult groups. DBP treatment did not markedly affect relative proportions of epithelial, stromal, or luminal compartments in the epididymis; sperm counts in the testis and epididymis; sperm transit time; or sperm morphology and motility in adult rats. The AR and AQP9 immunoreactivities and proliferation index were similar for the two groups. These results showed that fetal testes were affected by DBP as evidenced by testicular histopathologic alterations, but reproductive parameters and epididymal structure/function were not significantly altered in the adult animals exposed to 100 mg/kg DBP in utero and during lactation.

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.

Selective chemical sympathectomy of the internal genital organs of prepubertal to mature male Wistar rats was performed by chronic treatment with low doses of guanethidine. Sympathetic denervation caused an increase in intratesticular progesterone levels in prepubertal and early pubertal rats in addition to a decrease in androstenedione and testosterone levels in prepubertal animals, thus indicating a decrease in the conversion of progesterone into androgen, probably by blocking the steroidogenic enzymatic pathway at the 17 alpha-hydroxylase/17, 20 desmolase level. A lower degree of testicular maturation, probably related to reduced androgen activity, was observed in prepubertal and early pubertal sympathectomized rats. Concentration of spermatozoa, on the other hand, was increased in the enlarged cauda epididymidis of late pubertal and mature denervated animals. This result is discussed in terms of the impairment of epididymal mechanisms of seminal emission, fluid resorption and spermatozoal disposal.

Summary 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 μg/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.

Parabens are used as preservatives in cosmetic, pharmaceutical, and food industries, and are frequently detected as contaminants in human fluids and tissues. The endocrine disrupting effects of parabens in female rodents include uterotrophic response, steroidogenesis impairment, and ovarian disturbances. The objective of this study was to determine the effects of maternal butyl paraben (BP) exposure on female sexual development. Pregnant Wistar rats were treated subcutaneously with either corn oil or BP at doses of 10, 100, or 200 mg/kg, from gestational day (GD) 12 until GD 20 for female foetal gonad evaluation, and from GD 12 until the end of lactation to evaluate sexual parameters on the female offspring. Immature female rats were also used in the uterotrophic assay to evaluate the possible estrogenic action of parabens. Our results revealed that, in this experimental protocol, BP did not show estrogenic activity at the doses used and did not impair sexual development and fertility capacity in the female rats, but impaired sexual behavior. We conclude that brain sexual development may be more sensitive to BP effects and we speculate that doses higher than 100 mg/kg (the male lowest observed adverse effect level (LOAEL) for rodent reproductive parameters) would be necessary to promote damages in the female reproduction, regarding the same protocol of exposure. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 776-788, 2017.

Made available in DSpace on 2018-12-11T17:22:59Z (GMT). No. of bitstreams: 0 Previous issue date: 2016-01-01 Arsenic trioxide (As2O3) has shown effectiveness in treatment of leukemia but is also associated with reproductive toxicity. Since remediation with N-acetylcysteine (NAC) may mitigate the adverse effects caused by exposure, we assessed the effects of As2O3 and its potential reversibility after exposure cessation or coadministration of NAC. Animals received 0.3 or 3.0 mg/Kg/day of As2O3 subcutaneously and 40 mM of NAC in tap water. As2O3 treatment impaired spermatogenesis and sperm motility and decreased seminal vesicle weight and testosterone serum levels; after suspension of treatment, these parameters remained altered. When NAC was administered, animals showed improvement in sperm parameters and seminal vesicle weight. In vitro epididymal contractility was increased in As2O3-treated animals. We concluded that As2O3 is toxic to the male mouse genital system by compromising sperm quality and quantity; these effects persisted even after suspension of the treatment. However, the coadministration of NAC ameliorates the harmful effects of the drug on the male genital system. Department of Morphology Institute of Biosciences Universidade Estadual Paulista (UNESP) Department of Pharmacology Institute of Biosciences Universidade Estadual Paulista (UNESP) Department of Clinical Analyses Toxicology and Food Sciences School of Pharmaceutical Sciences University of São Paulo (USP) Department of Morphology Stomatology and Physiology School of Dentistry University of São Paulo (USP) Department of Morphology Institute of Biosciences Universidade Estadual Paulista (UNESP) Department of Pharmacology Institute of Biosciences Universidade Estadual Paulista (UNESP)

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.

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.

Androgen exposure during sexual development induces alterations in steroidal target tissues. The objective of this study was to evaluate the uterine responsiveness to estradiol after perinatal androgenization. Pregnant Wistar rats were exposed to corn oil or testosterone propionate at 0.05, 0.1, or 0.2 mg/kg from gestational day 12 until postnatal day 21. Female offspring was challenged with estradiol (E

The objective of this work was to evaluate reproductive function in adult male rats exposed to ethanol since puberty. Male Wistar rats, 50 days old, received a liquid diet with 36% of the daily calories derived from ethanol or an isocaloric control diet for 55 days. The ethanol treatment impaired sexual behavior and only 22% of these rats reached ejaculation. The fertility of ethanol-treated animals was significantly reduced, mainly after natural mating. Serum testosterone levels, daily sperm production and sperm count in the epididymis were also significantly diminished after ethanol treatment, associated with an acceleration of the sperm transit time in the cauda epididymidis, decrease in sperm motility and increased percentage of abnormal shaped sperm cells. The results showed that chronic consumption of ethanol beginning at puberty impairs the reproductive function of adult male rats.

Previous work in our laboratory revealed that the pubertal period of reproductive development in the male rat was particularly vulnerable to gossypol exposure, with a higher frequency of round structures in the lumen of the cauda epididymidis in the treated rats. Herein, we utilized hemicastration and electron microscopy to confirm that the epididymis is a definitive target of gossypol. Although exposure to gossypol from weaning through puberty caused a significant decrease in daily sperm production, as well as in the concentration of sperm in the epididymis, serum testosterone levels and reproductive organ weights were not altered. In gossypol treated rats, sperm morphology was compromised severely, but the epithelium in testis and epididymis appeared morphologically normal. Ultrastructural examination revealed that round structures, present only in gossypol exposed males, represented: (1) principal cells exfoliated from the epididymal epithelium; (2) epididymal epithelial cell cytoplasm containing degenerating sperm; and (3) degenerating epithelial cells, consisting of vesicles and particles of different sizes, forms and densities. Taken together, the data confirm that gossypol targets the epididymis, disturbing both the structure and function of this organ, and presumably disrupts sperm maturation.

Studies of diabetes mellitus in the streptozotocin rat model suggest that sexual dysfunctions may result from diabetes-induced alterations of the neuroendocrine-reproductive tract axis. Our investigation was performed to better define the effects of short-term hyperglycaemia on rat epididymal sperm quantity, quality and transit time, using both natural mating and artificial in utero insemination protocols. Male rats were made diabetic with streptozotocin (sc, 40 mg/kg), whereas controls received vehicle. Sexual behaviour was tested after 15 days and sperm fertilizing ability was checked 22 days after the injection through natural mating and artificial in utero insemination. Other parameters such as daily sperm production, testosterone levels, as well as sperm morphology and motility were also investigated. Fifty per cent of the diabetic animals showed no copulatory behaviour during tests and the number of animals reaching ejaculation was smaller in the diabetic group when compared with the control group (33% vs. 83%). Diabetes resulted in decreased body and reproductive organ weights, as well as diminished sperm counts in the testis and epididymis, that were associated with diminution of plasmatic testosterone levels. After natural mating, there was a decrease in the fertility in the diabetic adult male rats (25.5%) compared with control animals (81.5%). However, distal cauda epididymal sperm from diabetic rats displayed normal fertilization ability (91.5%) using in utero insemination. There were no effects of hyperglycaemia on sperm transit time in the epididymis and on spermatogenesis. Our results indicate that diabetes mellitus produces reproductive dysfunction, but does not compromise sperm fertilizing ability in the cauda epididymis in this experimental model.

To assess the prevalence of fibromyalgia in primary Sjögren's syndrome and to evaluate the clinical differences between patients affected with both primary fibromyalgia and primary Sjögren's syndrome and those affected only with primary fibromyalgia.Clinical features of fibromyalgia were evaluated in 100 consecutive outpatients with primary Sjögren's syndrome and, as controls, in 90 patients with non-insulin-dependent diabetes mellitus, in 75 patients with primary fibromyalgia and in 30 healthy subjects.Fibromyalgia was recorded in 22% of patients with primary Sjögren's syndrome, in 12.2% with diabetes and in 3.3% of healthy controls. In the primary Sjögren's syndrome group the prevalence was significantly higher than in healthy controls (P0.01), but not significantly different than in diabetes. Moreover, primary Sjögren's syndrome with fibromyalgia and primary fibromyalgia patients did not differ with respect to the number of tender points, while the mean pain threshold was lower in the latter (P = 0.05). Purpura, hypergammaglobulinemia, rheumatoid factor, and a focus scoreor = 1 on lip biopsy were significantly more frequent in primary Sjögren's syndrome patients without than with fibromyalgia.As recently reported by other authors, our study confirms the moderate increase of fibromyalgia prevalence in primary Sjögren's syndrome. Typical fibromyalgic findings are quite similar to those of primary fibromyalgia, but surprisingly, primary Sjögren's syndrome patients with fibromyalgia show a less severe global involvement than those with primary Sjögren's syndrome alone.

To evaluate the relevance of anti-adalimumab (anti-ADA) antibodies (Abs) and their relationship with clinical/laboratory features in rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA).Fifty-eight patients affected with RA, AS and PsA were prospectively enrolled. Clinical/laboratory characteristics, disease activity, anti-ADA, anti-nuclear (ANA), anti-double strand (ds)DNA, anti-extractable nuclear antigens (anti-ENA) and anti-phospholipid Abs (aPL) were evaluated at baseline, 4, 12 and 24 weeks of adalimumab treatment.Anti-ADA Abs were observed in 11/58 (19%) patients; they were detected within the 4th week of therapy in 90.9% of the positive subjects. Anti-ADA positivity was associated with significantly lower mean adalimumab serum levels (P0.05). Treatment failure was observed in 20/58 (34.5%) patients and was significantly associated with anti-ADA Abs (P0.05). Mean adalimumab serum levels were significantly lower in patients with treatment failure than in the responders one, both in the whole cohort (P0.01) and in the group of anti-ADA positive patients (P0.01). Adverse events happened more often in anti-ADA positive then in anti-ADA negative patients (27.3% vs 14.9%).Anti-ADA abs could be considered an early marker associated to a poor clinical response to adalimumab treatment. Routine ANA/anti-ENA/aPL monitoring did not reveal as useful tools to predict the development of anti-ADA abs.

Bupropion is a dopamine (DA) and norepinephrine (NE) reuptake inhibitor used as smoking cessation and antidepressant drug with a lower incidence of male sexual dysfunction. We showed previously that sibutramine, a norepinephrine/serotonine reuptake inhibitor, reduced male rat fertility. As there are no studies evaluating the impact of bupropion treatment on spermatic parameters and male fertility, we evaluated the effects of bupropion treatment (15 and 30 mg kg(-1), 30 days) on sexual behavior, spermatic parameters and fertility of male Wistar rats and on the epididymal duct in vitro contractility. Bupropion 15 mg kg(-1) increased the serum luteinizing hormone level and the epididymal duct contractility, but the sperm quality was not affected. At 30 mg kg(-1) bupropion impaired sperm quality increasing the incidence of non-progressive sperm. The male sexual behavior and fertility were not modified at both bupropion doses. These results, in rats, suggest the importance of studies evaluating the effects of bupropion on the human male sperm quality.

Made available in DSpace on 2014-12-03T13:10:56Z (GMT). No. of bitstreams: 0 Previous issue date: 2014-01-01Bitstream added on 2014-12-03T13:22:53Z : No. of bitstreams: 1 WOS000333627500001.pdf: 4425569 bytes, checksum: de518044f50a2e8c8ff0d30fa8be2a1c (MD5) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Methylmercury, organic form of mercury, can increase the number of abnormal sperm and decrease sperm concentration and testosterone levels possibly due to the damage caused by reactive species to germ and Leydig cells. Mana-cubiu (Solanum sessiliflorum Dunal) is a native fruit from Amazon rich in iron, zinc, niacin, pectin, and citric acid, used in foods, beverages, and medicinal purposes, since it has been useful for treatment of various diseases caused by oxidative stress or nutritional deficiency. Therefore, this study evaluated the phytoremediation potential of this fruit on damages caused by exposure to MeHg on sperm quantity and quality and the histological aspect of the testis and epididymis. Wistar male rats (n = 20) were randomly allocated into four groups: Control group (received distilled water), MeHg group (140 mu g/Kg), Solanum group (1% of fruit Mana-cubiu on chow), and Solanum plus MeHg group (same treatment as MeHg and Solanum group). The organs were weighted, histopathology; sperm morphology and counts were obtained. The results showed reduction in body weight gain, testis weights, reduced sperm production, and increased histopathological abnormalities in the MeHg-treated group. However, treatment with Solanum plus MeHg revealed a protective effect of this fruit on damages caused by MeHg. Univ Estadual Paulista UNESP, Dept Morphol, Inst Biosci, BR-18618970 Botucatu, SP, Brazil Univ Sao Paulo, Dept Clin Anal Toxicol & Food Sci, Sch Pharmaceut Sci Ribeirao Preto, BR-14040903 Ribeirao Preto, SP, Brazil Univ Estadual Paulista UNESP, Dept Morphol, Inst Biosci, BR-18618970 Botucatu, SP, Brazil FAPESP: 13/05560-4

Submitted by Guilherme Lemeszenski (guilherme@nead.unesp.br) on 2013-08-22T18:52:38Z No. of bitstreams: 1 S0100-879X2000000900019.pdf: 119417 bytes, checksum: f4d24ade954f4e0925547b8e8e482c88 (MD5) Made available in DSpace on 2013-08-22T18:52:38Z (GMT). No. of bitstreams: 1 S0100-879X2000000900019.pdf: 119417 bytes, checksum: f4d24ade954f4e0925547b8e8e482c88 (MD5) Previous issue date: 2000-09-01 Made available in DSpace on 2013-09-30T19:44:01Z (GMT). No. of bitstreams: 2 S0100-879X2000000900019.pdf: 119417 bytes, checksum: f4d24ade954f4e0925547b8e8e482c88 (MD5) S0100-879X2000000900019.pdf.txt: 18902 bytes, checksum: 7a378e93196bf69eadfc0213ab2785d2 (MD5) Previous issue date: 2000-09-01 Submitted by Vitor Silverio Rodrigues (vitorsrodrigues@reitoria.unesp.br) on 2014-05-20T15:11:31Z No. of bitstreams: 2 S0100-879X2000000900019.pdf: 119417 bytes, checksum: f4d24ade954f4e0925547b8e8e482c88 (MD5) S0100-879X2000000900019.pdf.txt: 18902 bytes, checksum: 7a378e93196bf69eadfc0213ab2785d2 (MD5) Made available in DSpace on 2014-05-20T15:11:31Z (GMT). No. of bitstreams: 2 S0100-879X2000000900019.pdf: 119417 bytes, checksum: f4d24ade954f4e0925547b8e8e482c88 (MD5) S0100-879X2000000900019.pdf.txt: 18902 bytes, checksum: 7a378e93196bf69eadfc0213ab2785d2 (MD5) Previous issue date: 2000-09-01 In order to investigate whether prolonged stress interferes with the onset of sexual behavior at puberty and with fertility at adulthood, prepubertal male Wistar rats (40 days of age) were immobilized 6 h a day for 15 days (up to early puberty) or for 60 days (until sexual maturity). Pubertal stressed rats showed a two-fold increase in the latency for the first mount (probably due to repeated aversive experience in which a change of environment was always followed by immobilization) and a 2.5-fold increase in the frequency of thrusting (indicative of enhanced sexual performance). The apparently stimulatory effect of prolonged stress on the onset of sexual behavior is discussed in terms of increased testosterone level and interference with the complex interchanges between the neurotransmitters/neuropeptides involved in the central control of male sexual activity. Adult stressed animals were mated with normal females, which became pregnant but exhibited a more than two-fold increase in both pre-implantation and post-implantation loss, probably due to a smaller rate of fertilization and/or fertilization with damaged spermatozoa. Universidade de São Paulo Faculdade de Medicina de Ribeirão Preto Departamento de Fisiologia Universidade Estadual de São Paulo Instituto de Biociências Departamento de Morfologia Universidade de São Paulo Faculdade de Odontologia de Ribeirão Preto Departamento de Morfologia, Estomatologia e Fisiologia

In this paper we suggest the potential clinical usefulness of two projective tests (Rorschach and Object Relation Technique) and of a clinical interview focused on the pathway to suicide, life events, and major life difficulties to better define subtypes of patients attempting suicide. Thirty-three hospitalized subjects who had attempted suicide in the previous 6 months were examined using an in-depth assessment of the pathway to suicide. The aims of this study were: (1) to compare, within a clinical sample of suicidal attempters, the psychopathological, personality, and psychosocial characteristics of subjects with mood disorders alone, personality disorders and dysfunctional personality alone, and mood disorders with personality disorders and/or dysfunctional personality; and (2) to analyze the relationship between the method chosen and the clinical characteristics of the subgroups.

Dyslipidemias are frequently found in children due to obesity, bad eating habits and the lack of physical exercises. Rosuvastatin acts as an HMG-CoA reductase inhibitor, decreasing total cholesterol and triglycerides. This study aimed to investigate initial sexual development and morphological aspect of the testis and epididymis in juvenile rats exposed to rosuvastatin since pre-puberty. Three groups were formed with newly weaned rats: control, whose rats received saline solution 0.9%, rosuvastatin at doses of 3 or 10 mg/kg daily by gavage, since post-natal day 21 until puberty onset. In the rosuvastatin-treated groups, the results demonstrated a trend toward a decrease in testosterone concentration, but below the significance level, as well as delays in both the age of puberty onset and in epididymal development. There were also testicular alterations that might be related to delayed puberty and decrease of serum testosterone. In conclusion, rosuvastatin administration to juvenile rats not only delayed puberty onset and epididymal development, but also impaired testicular and epididymal morphology.

It is known that during sex differentiation, fetal androgens are critical determinants of the male phenotype. Although testosterone is necessary for normal development of male sexual behavior, perinatal androgen treatment can result in disruption of normal male sexual reproduction. Pregnant Wistar rats were administered either corn oil (vehicle) or testosterone propionate at 0.2 mg/kg from gestational day 12 until the end of lactation and the reproductive function of male offspring was evaluated at 90 (adulthood) and 270 (middle age) days of age. Perinatal androgenization in the rat provoked a reduction in sperm production and reserves in adulthood that did not affect fertility and did not persist at more advanced ages, as shown by the results at post-natal day 270. If perinatal androgenization promotes similar effects in humans of reproductive age, the results of the present work can impact male reproduction health, given the less efficient spermatogenesis and lower sperm reserves in the human epididymis, compared to rodents.