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

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

Low Corticosterone Response to Stress in a Perimenopausal Rat Model Is Associated with the Hypoactivation of PaMP Region of the Paraventricular Nucleus and Can Be Corrected by Exogenous Progesterone Supplementation.

INTRODUCTION: The transition to menopause is characterized by mood, behavioral and metabolic changes. However, little is known about the changes in adrenal response to stress. AIMS: The aim of the study was to evaluate, in an animal model of perimenopause induced by 4-vinylcyclohexene diepoxide (VCD), (1) the endocrine and neuronal stress system activity in response to acute restraint stress and (2) the effect of hormonal therapy in this response. METHODS: Prepubertal female Wistar rats received daily injections (s.c) of oil or VCD (160 mg/kg) for 15 days. On 56th-66th days after treatment onset, the groups to be stressed received s.c implants containing placebo (PL), 17ß-estradiol (E2), progesterone (P4), or E2P4. At 80 ± 5 days after VCD/oil injections, stress was applied for 30 min. Blood samples were collected immediately after and 60 min after the end of stress session from the tail tip followed by transcardial perfusion with PFA 4% for the assessment of c-Fos expression in the medial and posterior parvocellular (PaMP and PaPo) subdivisions of the paraventricular nucleus (PVN) and c-Fos/tyrosine hydroxylase in the locus coeruleus (LC) using immunohistochemistry. Control groups were not stressed nor received hormone therapy. RESULTS: While basal corticosterone levels were similar between VCD-periestropausal and control rats, the secretion in response to stress in the VCD group was lower. This effect was prevented by P4 therapy. Inversely, basal levels of P4 were lower in VCD-periestropausal rats than in the controls, and no differences were found in response to stress between the groups. As expected, 30-min restraint stress increased c-Fos immunoreactivity in all brain areas studied in both control and VCD-periestropausal rats. However, the c-Fos increase in the PaMP region was attenuated. In all areas examined, there were no significant differences in the number of c-Fos-positive neurons across hormonal therapies. DISCUSSION/CONCLUSION: This is the first study to demonstrate in a perimenopausal rat model that reproductive aging is accompanied by inadequate secretion of corticosterone in response to acute stress in association with the hypoactivation of the PaMP region of the PVN, while adrenal P4 response is preserved. Moreover, P4 therapy was shown to attenuate the effects of progressive ovarian failure on adrenal functioning during stress.

Developmental and Reproductive Outcomes in Male Rats Exposed to Triclosan: Two-Generation Study.

Triclosan (TCS) is a phenolic compound with broad-spectrum antimicrobial action that has been incorporated into a variety of personal care products and other industry segments such as toys, textiles, and plastics. Due to its widespread use, TCS and its derivatives have been detected in several environmental compartments, with potential bioaccumulation and persistence. Indeed, some studies have demonstrated that TCS may act as a potential endocrine disruptor for the reproductive system. In the current study, we are reporting on the results obtained for male rats after a two-generation reproduction toxicity study conducted with TCS. Female and male Wistar rats were treated daily by gavage with TCS at doses of 0.8, 2.4, and 8.0 mg/kg/day or corn oil (control group) over 10 weeks (F0) and over 14 weeks (F1) before mating and then throughout mating, until weaning F2 generations, respectively. TCS exposure decreased sperm viability and motility of F1 rats at the dose of 2.4 mg/kg. The effects of TCS on sperm quality may be related to the exposure window, which includes the programming of reproductive cells that occurs during fetal/neonatal development.

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

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

In utero and lactational exposure to triclocarban: reproductive effects on female rat offspring.

Triclocarban (TCC) is an antimicrobial compound widely used in personal care products such as soaps, toothpaste, and shampoo. This agent is incompletely removed by wastewater treatment and represents an environmental contaminant. Recent studies have shown that TCC is associated with some endocrine disruptions. The aim of the present study was to evaluate if TCC exposure during critical periods of development (gestation and lactation) could lead to adverse effects on reproductive and behavior parameters of female offspring. Pregnant female Wistar rats were divided into four groups (n = 8-11/group): Control; TCC 0.3 mg/kg (TCC 0.3); TCC 1.5 mg/kg; TCC 3.0 mg/kg (TCC 3.0); and treated daily by oral gavage from gestational day 0 to lactational day 21. The female pups (F1 generation) were weaned on post-natal day 21 and included in the study. No litter-mates were used for the same group. There was a decrease in estradiol levels in the TCC 0.3 and TCC 3.0 groups. Moreover, there was a decrease in progesterone levels and an increase in pre-implantation loss in the TCC 3.0 group in adulthood. It is suggested, in this study, that the decrease in progesterone biosynthesis could interfere with implantation process. The exposure window to TCC is an important factor, as we found alterations only in the offspring.

Identification of Suitable Reference Genes for Quantitative Gene Expression Analysis in Innervated and Denervated Adipose Tissue from Cafeteria Diet-Fed Rats.

Our previous studies show that cafeteria diet increases body adiposity, plasma insulin levels, and sympathetic activity to brown adipose tissue (BAT) and white adipose tissue (WAT) of Wistar rats, leading to rapid and progressive changes in the metabolic profile. The identification of suitable reference genes that are not affected by the experimental conditions is a critical step in accurate normalization of the reverse transcription quantitative real-time PCR (qRT-PCR), a commonly used assay to elucidate changes in the gene expression profile. In the present study, the effects of the cafeteria diet and sympathetic innervation on the gene expression of adrenoceptor beta 3 (Adrb3) from BAT and WAT were assessed using one of the most stable and one of the least stable genes as normalizers. Rats were fed the cafeteria diet and on the 17th day, interscapular BAT or retroperitoneal WAT was denervated and, 7 days after surgery, the contralateral innervated tissue was used as control. Ten reference genes were evaluated (18S, B2m, Actb, CypA, Gapdh, Hprt1, Rpl32, Tbp, Ubc, and Ywhaz) and ranked according to their stability using the following algorithms: geNorm, NormFinder, BestKeeper, and comparative delta threshold cycle (ΔC t ) method. According to the algorithms employed, the normalization of Adrb3 expression by the least stable genes produced opposite results compared with the most stable genes and literature data. In cafeteria and control diet-fed rats, the three most stable genes were Hprt1, Tbp, and Rpl32 for interscapular BAT and Tbp, B2m, and Hprt1 for retroperitoneal WAT, while the least stable genes were 18S, Actb, and Gapdh for both tissues.

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

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

Investigation of the potential effects of triclosan as an endocrine disruptor in female rats: Uterotrophic assay and two-generation study.

Triclosan (TCS) is a phenolic compound with antimicrobial action widely used in cosmetics and other personal care products and other industry segments. Its widespread use over the decades has made TCS one of the most commonly detected compounds in wastewater and effluent worldwide already being found in human urine, plasma and milk. In this study, the (anti)estrogenicity of TCS was evaluated in the uterotrophic assay in 18-day old female Wistar rats. In a second protocol, female rats were evaluated for the reproductive effects of TCS in a two-generation reproduction toxicity study. Female rats were daily treated by gavage with TCS at the doses of 0.8, 2.4 and 8.0 mg/kg/day or corn oil (control group) over 10 weeks (F0) and over 14 weeks (F1) prior to mating and then throughout mating, gestation and lactation until weaning of F1 and F2 generation respectively. TCS had no effect on the uterus weight in the uterotrophic assay. In the two-generation study, the TCS exposure compromised female sexual behavior, decreased maternal food consumption and increased pup grooming on TCS 2.4 group. The TCS chronic exposure also decreased the perimetrium thickness of F0 females from TCS 8.0 group and growing follicle number of TCS 2.4 females from F1 generation. Despite the some specific changes detected in the two-generation study, no impairment was observed in the uterotrophic assay and other important reproductive endpoints. In a weight of evidence evaluation, the results suggest that exposure to TCS at low doses did not act as an endocrine disruptor in the female rat reproductive system.

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

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

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

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

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

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

Reproductive parameters of female Wistar rats treated with methylphenidate during development.

Methylphenidate (MPH), a psychoactive agent that acts mainly by blocking the uptake of dopamine, is the main drug used to treat Attention Deficit Hyperactivity Disorder in children and adolescents. During development, important changes in brain architecture and plasticity occur, these changes, sensitive to exposure to stimulant drugs, are important in the control of GnRH secretion, influencing the release of sex hormones throughout the ovarian cycle. This study investigated the effects of repeated treatment with MPH during development on reproductive parameters of adult female rats. Wistar rats received MPH 2.5mg/kg, MPH 5.0mg/kg, or tap water (gavage) from postnatal day (PND) 21 to PND 60. From PND 75, one subgroup of females was selected for evaluation of estrous cycle, estradiol levels, weight of sexual organs, and histomorphological analysis of ovary follicles and uterus. In another subgroup, the sexual and maternal behaviors were evaluated at PND 90 and on lactational day 5, respectively. No significant alterations were observed in the MPH groups. This study demonstrated that repeated administration of MPH during the period corresponding to childhood to early adulthood does not interfere in the reproductive function of female rats in adulthood.

Sperm quality and fertility in rats after prenatal exposure to low doses of TCDD: A three-generation study.

Exposure to Tetrachlorodibenzo-p-dioxin (TCDD) in male rats promotes, decreased sperm concentration, alterations in motility and in sperm transit time. We evaluated the effect transgenerational of in utero exposure to low doses TCDD in the sperm quality. Pregnant rats (F0) were exposed to 0.1; 0.5 and 1.0µg of TCDD, on gestational day 15, coincides with the end of most organogenesis in the fetus. Adult male offspring (F1, F2 and F3 generation) were investigated for fertility after artificial insemination in utero. After collection of the uterus and ovaries, the numbers of corpora lutea and implants were determined. TCDD provoked alterations in sperm morphology and diminution in serum testosterone levels and sperm transit time in the cauda epididymis. The fertility significantly decreased in all the generations, at least at one dose. In conclusion, TCDD exposure decreases rat sperm quality and fertility in adult male offspring and this effects persist into the next generation.

In utero and lactational exposure to fipronil in female rats: Pregnancy outcomes and sexual development.

Fipronil, a phenylpyrazole insecticide, is used in agriculture, veterinary medicine, and public health. Because this insecticide is considered a potential endocrine disruptor, the aim of this study was to examine the influence of perinatal exposure to fipronil on neonatal female reproductive system development. Pregnant rats were exposed (via gavage) daily to fipronil (0.03, 0.3, or 3 mg/kg) from gestational day 15 to day 7 after birth, and effects on the reproductive functions assessed on postnatal day (PND) 22. No signs of maternal toxicity were observed during daily treatment with fipronil. Perinatal exposure to the highest dose of fipronil (3 mg/kg) delayed the age of vaginal opening (VO) and first estrus without markedly affecting the anogenital distance (AGD). Further, exposure to 0.3 mg/kg fipronil produced a significantly shorter estrus cycle and reduced number of cycles during the period of evaluation. However, the other reproductive parameters analyzed, including fertility, hormone levels, sexual behavior, and histology of ovaries and uterus, displayed no marked alterations. In this experimental model, fipronil interfered with development of neonatal female reproductive system as evidenced by delay in VO and estrus cycle alterations without apparent significant effects on fertility. Further studies are needed to identify the mechanisms of action associated with the observed female reproductive system changes.

The transition to reproductive senescence is characterized by increase in A6 and AVPV neuron activity with attenuation of noradrenaline content.

During the course of life, cyclic females face a state of midlife transition that occurs in a fully functioning neurological system, and results in reproductive senescence. The authors' hypothesis was that changes in the activity noradrenergic neurons may be one of the factors involved in this phenomenon. The aim of this study was to investigate the activity of the neurons in the anteroventral periventricular nucleus (AVPV) and locus coeruleus (LC), to analyze their role in determining reproductive senescence. Adult female Wistar rats in the diestrus phase (4months/cyclic) and old females (18-20months/acyclic) in persistent diestrus, were decapitated or perfused at three different time intervals (10, 14 and 18h) throughout the day. In acyclic rats, the gonadotropin-releasing hormone (GnRH) and noradrenaline (NE) content were reduced; Fos-related antigen (FRA) in AVPV and Fos-related antigen/Tyrosine hydroxylase (FRA/TH) in LC showed immunolabeling of a higher number of neurons in these animals. The 3-methoxy-4-hydroxyphenylglycol/noradrenaline (MHPG/NE) ratio was higher and plasma LH was lower in the acyclic rats. Furthermore, the estradiol level was higher, and the progesterone level was lower after 14h of persistent diestrus. These findings suggested that during the periestropause, there was a higher level of POA/AVPV and NE neuronal activity in the LC of acyclic rats, associated with a lower capacity of synthesis and storage of neurotransmitters and neurohormones contributed to changes in the temporal pattern of neuroendocrine signaling, thereby compromising the accuracy of inhibitory and stimulatory effects, causing irregularity in the estrous cycle and determining reproductive senescence.

In utero and lactational exposure to fluoxetine delays puberty onset in female rats offspring.

Depression is one of the most prevalent disorders in the world and may occur during pregnancy and postpartum periods. Fluoxetine (FLX) has been widely prescribed for use during depression in pregnancy and lactation. This study aimed to investigate if in utero and lactational exposure to FLX could compromise reproductive parameters in female offspring. Wistar rats received, by daily gavage, FLX 5mg/kg or 0.3ml of water (control group) from the first gestational day until weaning (21 days). Assessments in the female offspring included: body weight, anogenital distance, vaginal opening, first estrus, estrous cycle, reproductive organs weight, uterine morphometric analyses, ovarian follicle and corpora lutea counting, estradiol plasmatic concentration, sexual behavior, maternal behavior and fertility test. Exposure to FLX delayed the puberty onset in female pups. The present study demonstrated that developmental exposure to FLX can deregulate the neuroendocrine hormonal control of female offspring during prepubertal and pubertal periods.

The Coadministration of N-Acetylcysteine Ameliorates the Effects of Arsenic Trioxide on the Male Mouse Genital System.

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.

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

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

Activity of neurons in the preoptic area and their participation in reproductive senescence: Preliminary findings.

Alterations in the hypothalamic-pituitary-gonadal axis in females determine the transition from regular to irregular reproductive cycles, with loss of fertility. Stimulation of noradrenergic neurons of the anteroventral periventricular neurons (AVPV) is essential for regular reproductive cycles. Therefore, we examined the activity of neurons of the AVPV and measure the noradrenaline (NE) of acyclic rats, in constant estrus, and compared it with that of cyclic rats in estrus. Female cyclic (4-5 months) and acyclic (17-18 months) rats were euthanized at 10, 14, and 18 h in estrus. Brains were processed for immunoreactivity to antigens related to Fos (FRA) in AVPV, and the NE was determined by HPLC-ED. Plasma concentrations of LH, FSH, E2 and P4 were determined. In the acyclic animals, plasma LH was higher but the FSH was lower. There was decreasing P4 at different times, while the E2 was constant and lower in acyclic rats. FRA-ir expression in AVPV neurons of acyclic rats as well as turnover of NE was higher when compared with cyclic group. The preliminary findings showed increased activity in AVPV neurons in aging contribute to changes in the temporal pattern of neuroendocrine signaling, compromising the accuracy of inhibitory and stimulatory effects, causing irregularity in the estrous cycle and determining reproductive senescence.

Effects of repeated administration of methylphenidate on reproductive parameters in male rats.

Methylphenidate (MPH) is a psychostimulant drug which acts by blocking the dopamine and norepinephrine transporters and is the main drug used to treat attention deficit hyperactivity disorder in children and adolescents. During puberty, changes in neurotransmitter systems (including dopaminergic system) are engaged on the release of gonadal hormones and the development of cephalic structures responsible for reproductive function. This study investigated the effects of repeated treatment with methylphenidate during development on reproductive parameters of adult male rats. Wistar rats received MPH 2.5 mg/kg, MPH 5.0 mg/kg, or distilled water (gavage) from postnatal day (PND) 21 to PND 60. At PND 100, an increase in percentage of abnormal tail morphology sperm in MPH 2.5 and increase in testicular interstitial tissue volume in MPH groups as well as in the number of type A spermatogonia in MPH 5.0 group were observed. This study demonstrated that repeated administration of methylphenidate during periods corresponding childhood to early adulthood interfered on testicular function in rats at adult life.