Testis Histopathology Research Articles

Pre- and postoperative status of gonadotropins (FSH and LH) and inhibin-B in relation to testicular histopathology at orchiopexy in infant boys with unilateral undescended testes

In recent publications of boys with cryptorchidism, gonadotropins are higher and serum inhibin-B lower than normal. To some extent, serum values of inhibin-B reflect the state of germinative epithelium in cryptorchid testes. The aim of the present study was to evaluate the impact of unilateral orchiopexy on levels of gonadotropins and inhibin-B and correlate the hormone findings to the histopathology of the unilateral undescended testis. 50 boys (mean age: 1 year and 2 months) operated for unilateral cryptorchidism had blood samples for serum luteinizing hormone (LH), follicle-stimulating hormone (FSH) and inhibin-B taken preoperatively and 3 months to 2 years postoperatively. Testicular biopsies were performed at orchiopexy. The total germ cell number per transverse tubule and presence of adult dark spermatogonia were estimated. Preoperatively, 8 patients had impaired inhibin-B levels. In contrast with the expected normal physiological decline, 16 patients had an absolute rise in serum inhibin-B level postoperatively. The 4 patients who normalized the preoperative impaired serum level of inhibin-B all had low germ cell number in the testis at time of operation. Nine patients had preoperatively elevated serum levels of both LH 0.5-2.3 IU/l (mean: 1.0 IU/l) and FSH 1.3-2.2 IU/l (mean: 1.6 IU/l). Eight of these patients normalized both LH and FSH serum values postoperatively. None of the 4 boys with impaired inhibin-B level that did not normalize after surgery had elevated gonadotropins. Orchiopexy in unilateral cryptorchidism had a clear impact on the serum level of inhibin-B and gonadotropins of 32% and 16%, respectively.

Black tea extract ameliorates indomethacin induced changes in testicular histopathology of albino rats

Context: Reactive oxygen species and lipid peroxidation play a role in the pathogenesis induced by the non-steroidal antiinflammatory drug indomethacin. Aims: This study was aimed to assess the simultaneous effect of black tea extract (BTE) on indomethacin induced alteration in testicular pathology. Materials and Methods: Adult rats were divided into four groups (n = 6/group); Group I (control); Group II (indomethacin, 5 mg/kg b.wt.; i.p.); Group III (BTE, 2.5 g tea leaf/dL of water, i.e., 2.5% of aqueous BTE, orally) and Group IV (indomethacin + BTE). Serum vitamin E, sperm count, motility, and histopathology of testes were evaluated. Statistical Analysis: Statistical comparisons were performed using the one-way ANOVA, followed by post-hoc t-test. Results: Indomethacin induced rats showed a significant decrease in testicular weight, sperm count, sperm motility, and serum vitamin E concentrations. Histopathology of the testes revealed tortuous seminiferous tubules, loss of spermatogenesis process, marked decrease in the number of interstitial cells of Leydig and been replaced by many foci of congestion, edema, necrosis, and interstitial fibrosis. Rats simultaneously treated with BTE and indomethacin showed improvement of testicular weight, sperm count, sperm motility, and serum vitamin E concentrations when compared to indomethacin alone treated rats. Similarly, histopathology of rats treated simultaneously with indomethacin and BTE showed near normal testicular architecture when compared to indomethacin alone treated rats. Conclusion: The result suggests that BTEs might have potential beneficial effect to combat against indomethacin induced testicular damage in rats. Key words: Black tea extract, indomethacin, testicular damage, vitamin E

Diabetes mellitus induced impairment of male reproductive functions: a review.

Diabetes mellitus (DM) represents one of the greatest threats to human health all over the world. The incidence of DM is rising rapidly also including children and young persons of reproductive age. Diabetes has been associated with reproductive impairment in both men and women. Diabetes may affect male reproductive functions at multiple levels as a result of its effects on the endocrine control of spermatogenesis, steroidogenesis, sperm maturation, impairment of penile erection and ejaculation. A large number of studies both on diabetic men and experimental diabetic animals have been published on the impact of DM on male reproductive functions during the past few years but many of them have conflicting results. The present review summarizes the research finding of a large number of research papers on the reproductive functions especially on hypothalmo-pituitary-gonadal axis, spermatogenesis, histopathology of testis, synthesis and secretion of testosterone, sperm quality, ejaculatory function and fertility both in diabetic men and experimental diabetic animals.

Protective effects of pomegranate (Punica granatum) juice on testes against carbon tetrachloride intoxication in rats.

BackgroundPomegranate fruit has been extensively used as a natural medicine in many cultures. The present study was aimed at evaluating the protective effects of pomegranate (Punica granatum) juice against carbon tetrachloride (CCl4)-induced oxidative stress and testes injury in adult Wistar rats.MethodsTwenty eight Wistar albino male rats were divided equally into 4 groups for the assessment of protective potential of pomegranate juice. Rats of group I (control) received only vehicles and had free access to food and water. Rats of groups II and IV were treated with CCl4 (2 ml/kg bwt) via the intraperitoneal route once a week for ten weeks. The pomegranate juice was supplemented via drinking water 2 weeks before and concurrent with CCl4 treatment to group IV. Group III was supplemented with pomegranate juice for twelve weeks. The protective effects of pomegranate on serum sex hormones, oxidative markers, activities of antioxidant enzymes and histopathology of testes were determined in CCl4-induced reproductive toxicity in rats.ResultsPomegranate juice showed significant elevation in testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) those depleted by the injection of CCl4. Activity levels of endogenous testesticular antioxidant enzymes; superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and glutathione reductase (GR) and glutathione (GSH) contents were increased while lipid peroxidation (LPO) and nitric oxide (NO) were decreased with pomegranate juice. Moreover, degeneration of germ and Leydig cells along with deformities in spermatogenesis induced after CCl4 injections were restored with the treatment of pomegranate juice.ConclusionThe results clearly demonstrated that pomegranate juice augments the antioxidant defense mechanism against carbon tetrachloride-induced reproductive toxicity and provides evidence that it may have a therapeutic role in free radical mediated diseases.

Diagnosis of Testicular Choriocarcinoma: A Case Study

Testicular cancer, although relatively rare, is the most common malignancy in men at the age of 15 to 35 years. Germ cell tumor (GCT) is the most common testicular tumor (90%-95%) and peak age of incidence is between 20 years to 50 years. Choriocarcinoma is very rare in male as a pure testicular tumor (<1%) but may be seen as a component of mixed GCT. These tumors characteristically secrete hCG (human chorionic gonadotrophin) into the serum, which use as an important serum tumor marker for these tumors. A 30 years old male presented to us with the complaints of hard feeling of the left testis for 6 months which was initiated with mild pain but the size of the testis was unchanged. On examination there was an indurated area (2cm X 2cm) at lower part of the left testis and epididymis felt separately. He had no history crypto-orchidism, orchitis and scrotal trauma. Ultrasonogram showed a mixed echoic mass lesion (13 X 10mm) at infero-medial aspect left testis with an epididymal cyst. On laboratory investigation his ?-hCG and AFP level were 306 MIU/L(high) & 6.3 IU/L respectively. Contrast enhanced CT scan of the whole abdomen revealed no abnormality except enlarged lymph node (> 1 CM) in right lower lung. Fine needle aspiration cytology (FNAC) showed features of chronic orchitis. We explored his left testis because of high ?-hCG through inguinal approach and suspected testicular tissue was sent for frozen section biopsy which also revealed inconclusive findings. On the basis of his high ?-hCG, we performed left radical orchidectomy. Histopathology of the left testis showed features of Choriocarcinoma, epididymis and spermatic cord were normal. According to TNM classification, AJCC (American Joint Committee on Cancer) staging and international germ cell consensus prognostic classification it was T3N0MISI, stage IIIa and intermediate prognosis group respectively. Postorchidectomy ?-hCG dropped to 7.3 MIU/ML. Now he is on systemic chemotherapy BEP(bleomycin, etoposide, cisplatin). Choriocarcinoma, though is a rare malignancy, it may affect young men in the prime of life and is the most aggressive histologic variant of germ cell tumor. But it has a good prognosis if diagnosed early and treated accurately. Serum ?-hCG level plays most important role in diagnosis, in monitoring therapy and follow-up of patients with choriocarcinoma. DOI: http://dx.doi.org/10.3329/bmj.v40i2.18514 Bangladesh Medical Journal 2011 Vol.40(2): 60-62

The Role of Fermented Milk Containing Probiotic, Dandelion as Prebiotic or their Combination on Serum Metabolites, Enzymes, Testosterone and Testicular Histopathology of Arsenic-Intoxicated Male Rats

This study aimed at investigating the ameliorative effects of probiotic and/or dandelion aqueous extract to reducing the risk of arsenic (As) intoxication on male rats. Fifty rats were randomly allotted into five groups, group 1(C-) given regular diet and water daily for 56 days, group 2 (C+) given sodium arsenate in drinking water, group 3 (PRO) given sodium arsenate in addition to probiotic, group 4 (PRE) given dandelion aqueous extract plus sodium arsenate (prebiotic) and group 5 (SYN) given sodium arsenate plus probiotic/dandelion extract (synbiotic). At the experiment conclusion rats were sacrificed and blood and testes were collected and taken for analysis and histopathological study, respectively. Glutathione-S-transferase (GST), Alanine aminotransaminase (ALT) and Aspartate aminotransaminase (AST) activities and creatinine, triglycerides (TG) and testosterone(T) concentration were determined and testes histopathology was studied. Creatinine, AST and TG were lower (P

Assessment of protective and anti-oxidant properties of Tribulus terrestris fruits against testicular toxicity in rats.

Aims:This study was carried out to assess the protective and anti-oxidant activities of the methanolic extract of Tribulus terrestris fruits (METT) against sodium valproate (SVP)-induced testicular toxicity in rats.Materials and Methods:Fifty mature male rats were randomly divided into five equal groups (n = 10). Group 1 was used normal (negative) control, and the other four groups were intoxicated with SVP (500 mg/kg–1, orally) during the last week of the experiment. Group 2 was kept intoxicated (positive) control, and Groups 3, 4 and 5 were orally pre-treated with METT in daily doses 2.5, 5.0, and 10.0 mg/kg–1 for 60 days, respectively. Weights of sexual organs, serum testosterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels, semen picture, testicular anti-oxidant capacity and histopathology of testes were the parameters used in this study.Results:Oral pre-treatment with METT significantly increased weights of testes and seminal vesicles; serum testosterone, FSH and LH levels and sperm motility, count and viability in SVP-intoxicated rats. METT enhanced the activity of testicular anti-oxidant enzymes and partially alleviated degenerative changes induced by SVP in testes.Conclusion:The pre-treatment with METT has protective and anti-oxidant effects in SVP-intoxicated rats. Mechanisms of this protective effect against testicular toxicity may be due to the increased release of testosterone, FSH and LH and the enhanced tissue anti-oxidant capacity. These results affirm the traditional use of T. terrestris fruits as an aphrodisiac for treating male sexual impotency and erectile dysfunction in patients. The study recommends that T. terrestris fruits may be beneficial for male patients suffering from infertility.

Oral, short-term exposure to titanium dioxide nanoparticles in Sprague-Dawley rat: focus on reproductive and endocrine systems and spleen

The study explored possible reproductive and endocrine effects of short-term (5 days) oral exposure to anatase TiO2 nanoparticles (0, 1, 2 mg/kg body weight per day) in rat. Nanoparticles were characterised by scanning electron microscopy (SEM) and transmission electron microscopy, and their presence in spleen, a target organ for bioaccumulation, was investigated by single-particle inductively coupled plasma mass spectrometry and SEM/energy-dispersive X-ray. Analyses included serum hormone levels (testosterone, 17-β-estradiol and triiodothyronine) and histopathology of thyroid, adrenals, ovary, uterus, testis and spleen. Increased total Ti tissue levels were found in spleen and ovaries. Sex-related histological alterations were observed at both dose levels in thyroid, adrenal medulla, adrenal cortex (females) and ovarian granulosa, without general toxicity. Altered thyroid function was indicated by reduced T3 (males). Testosterone levels increased in high-dose males and decreased in females. In the spleen of treated animals TiO2 aggregates and increased white pulp (high-dose females) were detected, even though Ti tissue levels remained low reflecting the low doses and the short exposure time. Our findings prompt to comprehensively assess endocrine and reproductive effects in the safety evaluation of nanomaterials.

Protective effects of Lactuca sativa ethanolic extract on carbon tetrachloride induced oxidative damage in rats

ObjectiveTo study the protective effects of the ethanolic extract of lettuce (Lactuca sativa L. var. longifolia) leaves against the toxicity caused by carbon tetrachloride (CCl4) in reproductive system of rats. MethodsLettuce leaves were dried and extracted with ethanol (plant: solvent, 1:10, w/v). The extract was filtered and evaporated to yield dried lettuce extract. Animals were divided into seven groups and treated with CCl4 and different concentrations of lettuce extract. At the end of the experimental period, the animals were sacrificed and blood was collected and centrifuged for serum separation. Body weights, testis size, histopathology of testis and liver, catalase (CAT) activity, superoxide dismutase (SOD) activity, peroxidase (POD) activity, reduced glutathione (GSH), glutathione peroxidase activity (GSH-Px), thiobarbituric acid reactive substances (TBARS), nitrite level, and serum hormones were determined. ResultsOxidative stress induced by CCl4 (2 mL/kg body weight) in rat decreases the increase in body weight and relative testis weight. It also markedly increases the level of TBARS and nitrites along with corresponding decrease in reduced glutathione and various antioxidant enzymes in testis (i.e., CAT, POD, SOD and GSH-Px). Serum level of testosterone, luteinizing hormone and follicle stimulating hormone was decreased while estradiol and prolactin were increased during CCl4 treatment. Histopathology of CCl4-treated rats indicated the partial degeneration of germ and leydig cells along with deformities in spermatogenesis. Supplementation of lettuce extract (100, 150, 200 mg/kg body weight orally) once a week for 10 weeks results in decrease of TBARS and nitrite, while increase in antioxidant enzymes; CAT, POD, SOD, GSH-Px and GSH contents. Serum level of testosterone, luteinizing hormone, follicle stimulating hormone, estradiol, prolactin, histology, body weight and relative testis weight was also concomitantly restored to near normal level by lettuce extract supplementation to CCl4-intoxicated rat. ConclusionsThe results clearly demonstrate that lettuce extract treatment augments the antioxidants defense mechanism against CCl4-induced toxicity and provides evidence that it may have a therapeutic role in free radical mediated diseases.

Long-term effects of 900 MHz radiofrequency radiation emitted from mobile phone on testicular tissue and epididymal semen quality

The purpose of this study is to bridge this gap by investigating effects of long term 900 MHz mobile phone exposure on reproductive organs of male rats. The study was carried out on 14 adult Wistar Albino rats by dividing them randomly into two groups (n: 7) as sham group and exposure group. Rats were exposed to 900 MHz radiofrequency (RF) radiation emitted from a GSM signal generator. Point, 1 g and 10 g specific absorption rate (SAR) levels of testis and prostate were found as 0.0623 W/kg, 0.0445 W/kg and 0.0373 W/kg, respectively. The rats in the exposure group were subject to RF radiation 3 h per day (7 d a week) for one year. For the sham group, the same procedure was applied, except the generator was turned off. At the end of the study, epididymal sperm concentration, progressive sperm motility, abnormal sperm rate, all-genital organs weights and testis histopathology were evaluated. Any differences were not observed in sperm motility and concentration (p > 0.05). However, the morphologically normal spermatozoa rates were found higher in the exposure group (p < 0.05). Although histological examination showed similarity in the seminiferous tubules diameters in both groups, tunica albuginea thickness and the Johnsen testicular biopsy score were found lower in the exposure group (p < 0.05, p < 0.0001). In conclusion, we claim that long-term exposure of 900 MHz RF radiation alter some reproductive parameters. However, more supporting evidence and research is definitely needed on this topic.

Chronic exposure to MDMA (ecstasy)induces DNA damage, impairs functional antioxidant cellular defenses, enhances the lipid peroxidation process and alters testes histopathology in male rat.

3,4-Methylenedioxymethamphetamine (MDMA or ecstasy) is consumed mainly by young population. For this reason, it is especially relevant to take into consideration the effects on the reproductive system. The influence of MDMA on the fertility and reproduction of the male rat was assessed in this study. Material and methods: MDMA was administered orally at 0 mg/kg (control), 10 and 30 mg/kg to male rats for 15,30,45 consecutive days followed by 15 days withdrawal. Hormonal, biochemical, histological and testicular were evaluated in the rats. The present study aimed to investigate if daily oral administration of ecstasy at low doses(10mg) for 45 days has any deleterious effects on reproductive functions of male rats. Animals were randomly divided into four groups of ten rats each, assigned as control rats, or(0mg ecstasy), rats treated with 10mg ecstasy for, (15,30,45) days, rats treated with 30mg/kg body weight ecstasy for(,15,30,45)days by oral gavage. The third group(45 days) was followed by 15 withdrawal period(W15). Results: The activities of superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase in testicular homogenate were decreased while the levels of lipid peroxidation increased significantly in the treated rats as compared with the corresponding group of control animals. In group 30mg, only, arachidonic acid was significantly elevated in the testicular homogenate while linoleic acid was decresed when compared to control. Testis DNA fragmentation was observed in 30mg group, but not 10.mg. It is concluded that low doses of ecstasy exposure(10 mg/Kg) had moderate detrimental effects on reproductive organ system and more severe effects are likely to be observed at higher dose levels. These results indicate that ecstasy is directly toxic to primary Leydig cells, and that the decreased percentage of normal cells and the increased level of DNA damage in ecstasy -exposed Leydig cells may be responsible for decreased testosterone secretion. The results suggested that graded doses of ecstasy elicit depletion of antioxidant defence system and induce oxidative stress in testis of rats. In conclusion: the adverse effect of ecstasy on male reproduction may be due to induction of oxidative stress.

The Relation between Adult Dark Spermatogonia and Other Parameters of Fertility Potential in Cryptorchid Testes

The fertility potential of boys with cryptorchidism may be related to the number of adult dark spermatogonia per tubular transverse section in testicular biopsies taken at orchiopexy. Placental-like alkaline phosphatase positive gonocytes in testes within year 1 of life indicate preserved ability for germ cell transformation. We related these parameters to the total number of tubular germ cells and other factors associated with fertility potential. The study comprised 89 boys 0.7 to 3 years old (median age 1.8) who underwent bilateral testicular biopsy at bilateral orchiopexy and provided blood samples for gonadotropins and inhibin B. Of 76 boys with adult dark spermatogonia 44 (58%) had a normal mean number of spermatogonia per tubular transverse section compared to 2 of 13 (15%) without adult dark spermatogonia (p <0.05). In the 30 boys with good fertility potential, including a normal mean number of tubular germ cells, and normal gonadotropins and inhibin B, the mean number of adult dark tubular germ cells was 0.081 vs 0.031 in the 38 with low fertility potential, including impaired tubular germ cells and/or low inhibin B but no reactive increase in gonadotropins (p <0.05). In the 21 patients with increased gonadotropins the mean number of adult dark spermatogonia per tubular transverse section was 0.063. Of the 20 boys with normal mean adult dark spermatogonia per tubular transverse section 12 (60%) had good fertility potential, including a normal mean number of tubular germ cells, normal gonadotropins and normal inhibin B, compared to only 18 of 69 (26%) with an impaired mean number of adult dark spermatogonia per tubular transverse section (p <0.05). Of 46 boys with a normal mean number of tubular germ cells 26 (57%) had placental-like alkaline phosphatase positive cells compared to 14 of 43 (33%) with a decreased mean number of tubular germ cells (p <0.05). The number of placental-like alkaline phosphatase positive gonocytes and adult dark spermatogonia per tubular transverse section are important parameters related to the fertility potential of boys with cryptorchid testes.

The Inhibin B Response to a Motilin Receptor Agonist in Male Rats

In a repeat oral dose toxicity study, all of 16 male rats given 100 mg/kg/day GSK1322888 sustained testicular injury after 4 weeks of treatment; the findings were not reversible after 12 weeks off-dose. The current study was conducted to further characterize testicular toxicity and to explore the possible relationship between onset of lesions, and changes in circulating hormone levels. Male Sprague Dawley rats were orally administered 30 or 100 mg/kg/day GSK1322888 for 2 weeks with a 4-week off-dose period. Blood was collected via tail vein twice during the treatment period (days 4 and 11) and three times during the off-dose period (days 28, 36, and 42) for measurement of serum testosterone, dihydrotestosterone, and Inhibin B, luteinizing hormone, and follicle stimulating hormone concentrations. A histopathologic examination of testes was performed at the end of the treatment and off-dose periods. At 100 mg/kg/day, microscopic findings of the testis (degeneration of the germinal epithelium) were evident for 9 of 10 male rats on day 14 and all 10 rats at the end of the 4-week recovery period. There was no testicular toxicity observed at 30 mg/kg/day. During all stages of evaluation, there was no apparent difference among control and treated animals in hormone concentrations. There was poor correlation between changes in serum levels of Inhibin B and testis histopathology. Based on these observations, the utility of Inhibin B as a hormonal marker for germ cell toxicity is limited.

The Inhibin B Response in Male Rats Treated with Two Drug Candidates

Serum Inhibin B was measured in two studies of known testis-toxic drug candidates. Study 1 was for a compound for Hepatitis C, and utilized a 10-week dosing period, followed by mating and necropsy of half of each group, and then a 12-week recovery period for the remaining animals. At the postmating necropsy, 6 of 15 high-dose males had testis lesions; Inhibin B was significantly reduced in all animals in that group. The mid-dose group had no lesions but significantly reduced serum Inhibin B. At recovery, 9 of 15 high-dose males showed damage in testes; serum Inhibin B levels were not different from controls. Inhibin B appeared to both overreport and underreport testis damage in Study 1. Study 2 was an acute pathogenesis study for an antibacterial compound, using control and two dose levels and multiple time points (days 5, 8, 15, 22, and then untreated until day 71). At each time point blood was sampled from all remaining rats and five/group were killed for histologic evaluation. The low-dose group had minimal to moderate lesions, while serum Inhibin B was never changed. The high-dose animals progressed quickly from minimal lesions to being broadly and moderately affected; serum Inhibin B levels were reduced at days 8 and 15 only. In Study 2, Inhibin B appeared less sensitive than histology, except at the extremes of testis damage, when Inhibin B was routinely low. We conclude that in these two studies there was a poor correlation between changes in serum levels of Inhibin B and testis histopathology.

Efficiency of barley bran and oat bran in ameliorating blood lipid profile and the adverse histological changes in hypercholesterolemic male rats.

The efficiency of oat bran and barley bran in lowering the induced hyperlipidemia and hypercholesterolemia in blood of male Albino rats (Rattus rattus) was studied. Twenty rats were divided into four groups each consisted of five rats and fed the specified test diets for eight weeks. The first group (G1) is the negative group which was fed basal diet, the second group (G2) was fed 1.0% cholesterol, was the third group (G3) fed 1.0% cholesterol and 10% oats bran, and the fourth group (G4) was fed 1.0% cholesterol and 10% barley bran. Feeding rats on 1% cholesterol significantly increased serum total cholesterol, low density lipoprotein, and very low density lipoprotein and triglyceride and decreased serum high density lipoprotein. Furthermore, enzyme activity of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase was increased, and lipid peroxide was increased, whereas catalase and glutathione-S-transferase were decreased. Kidney functions parameters in the cholesterol supplemented group were elevated compared with the negative control. In addition, histological alteration in kidney, liver, heart, and testes was observed, compared with the negative control. Hypercholesterolemic rats supplemented with oat bran and barley bran showed significant decrease in lipid parameters, significant increase in high density lipoprotein-cholesterol, improved antioxidant enzyme, and improved histopathology of kidney, liver, heart, and testes. In conclusion, both oat bran and barley bran had protective effects against induced hyperlipidemia and improved histological alterations. Oat bran appeared more efficient than barley bran in lowering the lipid profile levels in hypercholesterolemic rats.

Male and Female Fertility Assessment in the Cynomolgus Monkey Following Administration of ABT‐874, a Human Anti‐IL‐12/23p40 Monoclonal Antibody

ABT-874 is an anti-IL-12/23 monoclonal antibody that binds to the p40 subunit of human IL-12 and IL-23. As part of its preclinical safety assessment, studies were conducted to asses its potential effects on the reproductive system in male and female cynomolgus monkeys. Sexually mature male cynomolgus monkeys (n = 6/group) were administered once weekly subcutaneous doses of 0, 5, 25, or 100 mg/kg ABT-874 for 13 weeks. Four monkeys/group were necropsied at the end of the 13-week dosing period and two monkeys/group were necropsied following an 8-week recovery period. Endpoints assessed in these males included sperm parameters such as sperm count and morphology, male reproductive hormones, and testes histopathology. Sexually mature female cynomolgus monkeys (n = 6/group) were administered subcutaneous doses of 0, 5, 25, or 100 mg/kg/week ABT-874 for two menstrual cycles, and recovery was subsequently assessed in each of these animals over two menstrual cycles. Endpoints assessed in these females included menses and reproductive hormone levels. In both the male and female fertility studies, there were no unscheduled deaths and there was no evidence of toxicity. In male monkeys, there were no ABT-874-related effects on sperm count or motility, histopathology of the testes or effects on testosterone and inhibin B levels. In addition, menstrual cycle length, progesterone, 17ß-estradiol, and luteinizing hormone levels in female monkeys were comparable among control and ABT-874-treated groups. These results demonstrate that ABT-874 had no adverse effects on reproductive hormones or fertility parameters in male or female cynomolgus monkeys.

Novel molecular targets associated with testicular dysgenesis induced by gestational exposure to diethylhexyl phthalate in the rat: a role for estradiol

Significant research has been focused on phthalate-induced alterations in male reproductive development. Studies on rodents have prompted the notion that a syndrome exists in the human male which includes phenotypic alterations such as hypospadias, cryptorchidism, poor semen quality, and even testicular cancer. Each phenotype in this 'testicular dysgenesis syndrome' is predicated on reduction in testosterone production by the fetal Leydig cell. We sought to examine the relationship between dysgenesis and steroidogenic capacity in the fetal rat testis more stringently by incorporating lower exposures than those typically used, conducting a comprehensive, non-targeted quantitative evaluation of the fetal testis proteome, and relating alterations in individual proteins to the capacity of the fetal Leydig cell to produce testosterone, and histopathology of the fetal testis. Pregnant dams were dosed orally from gestation day (GD) 13-19 with 0, 10, or 100 mg diethylhexyl phthalate (DEHP)/kg body weight per day. Each endpoint was represented by 16l. Clustering of Leydig cells occurred before any significant decrease in the capacity of the GD19 Leydig cell to produce testosterone. At 100 mg DEHP/kg, testosterone production was reduced significantly, Leydig cell clusters became quite large, and additional dysgenetic changes were observed in the fetal testis. Of 23 proteins whose expression was altered significantly at both DEHP exposure levels, seven were found to be correlated with and predictive of the quantified endpoints. None of these proteins have been previously implicated with DEHP exposure. Notably, pathway analysis revealed that these seven proteins fit a pathway network in which each is regulated directly or indirectly by estradiol.

Histopathological and biological studies of the effect of cadmium on Rhinella arenarum gonads

This study was to determine the lethal dose 50 (LD50) of CdCl2 in adult Rhinella arenarum and analyzed the effect of two sublethal doses (0.5 and 5mg/kg) of the xenobiotic in gonads. The 48h LD50 were 50.0 and 49.8mg/kg for males and females respectively. Alterations in the ovary were evidenced by nuclear pleomorphism and cytoplasmic vacuolization of the oocytes at the early stages of development with the highest dose and an increase in the population of atretic oocytes. In the interstitial tissue we noticed congestion, edema and fibroblast proliferation. The nuclear maturation of the oocytes was affected by the xenobiotic in a dose- and time-dependent manner. In males, treatment with 5mg/kg of cadmium (Cd) caused a decrease in the concentration, viability and straight progressive motility of sperm while there was an increase in immotile sperm. Testis histopathology revealed dilated seminiferous tubules, disappearance of cysts, tissue disorganization and leukocyte infiltration. Numerous germ cells showed hydropic tumefaction or signs of focal necrosis. The Cd content in animals intoxicated gonads with the highest sublethal dose was significantly higher than in the control. Results indicate that R. arenarum gonads are target for the xenobiotic, compromising the formation of gametes competent for fertilization, the effective CdCl2 dose being 5mg/kg.

Acrylamide-mediated subacute testicular and genotoxicity, is it reversible?

Background and aim Humans may be susceptible to acrylamide poisoning that may induce genotoxicity and testicular toxicity. Studies on recovery from acrylamide-induced reproductive toxicity are scarce. This study aimed to evaluate the natural recovery of testicular and genotoxicity caused by subacute exposure to acrylamide in rats. Materials and methods Thirty-six male Sprague–Dawley rats were divided into six acrylamide-treated groups and one control group. They were dosed orally once a day with acrylamide at 45 mg/kg/day for 5 days and then held for different recovery periods (3, 5, 10, 15, 25, and 55 days). The parameters examined were sperm count and morphology, hormonal assay, histopathology, comet assay, and apoptosis detection in testis. Statistical analysis was carried out by one-way analysis of variance using the SPSS software (significance was considered at P<0.05). Results Sperm abnormalities (detached heads and intersegmentation) detected were decreased markedly after 55 days of recovery. Transforming growth factor-β1 level was significantly increased following 10 days of recovery and then reverted to control levels. Abnormalities in the testis were detected between 3 and 25 days of recovery. None of these abnormalities was observed after 55 days of recovery besides a reduction in the luminal sperm reserve of the epididymis. Significant DNA damage was also induced by arylamide in blood leukocytes and reached its maximum after 3 days of recovery (60%). A gradual reduction in cell damage and tail moment occurred until 15 days of recovery (1%). Conclusion This study showed that oral administration of acrylamide in rats at a dose of 45 mg/kg for 5 consecutive days induced systemic effects as well as reproductive toxicity. In general, these effects were reversible, although the extent of the recovery during the 55-day period studied ranged from complete to partial.

Bilateral Undescended Testes Classified According to Preoperative and Postoperative Status of Gonadotropins and Inhibin B in Relation to Testicular Histopathology at Bilateral Orchiopexy in Infant Boys

In recent series of boys with cryptorchidism gonadotropin levels have been higher and serum inhibin B levels have been lower than normal. To some extent the serum values of inhibin B reflect the state of germinative epithelium in cryptorchid testes. We evaluated whether blood samples of gonadotropins and inhibin B as well as histopathology could be used to classify undescended testes. A total of 69 boys (median age 2 years) who underwent surgery for bilateral cryptorchidism had blood samples taken preoperatively and 3 months to 2.1 years postoperatively. Testicular biopsies were performed bilaterally at orchiopexy. The average germ cell number per tubular transverse tubule was measured. Group 1 included 17 patients with increased follicle-stimulating hormone levels. Serum follicle-stimulating hormone and luteinizing hormone decreased significantly after surgery. In 77% of patients (13 of 17) follicle-stimulating hormone levels were normalized. Of these boys 35% (6 of 17) had a low postoperative serum inhibin B. Group 2 consisted of 27 patients with a decreased germ cell number and/or low preoperative inhibin B, but not increased serum follicle-stimulating hormone or luteinizing hormone. There were no significant postoperative changes in follicle-stimulating hormone and luteinizing hormone. Of these boys 22% (6 of 27) had a low serum inhibin B postoperatively. In group 3 there were 25 patients with a normal germ cell number, normal preoperative serum inhibin B and normal gonadotropins. There were no significant changes in luteinizing hormone and follicle-stimulating hormone postoperatively. Only 1 boy in this group had a low postoperative serum inhibin B. Patients with increased gonadotropin levels may have testicular dysgenesis and some may benefit from early surgery. Patients with normal gonadotropin levels and a decreased germ cell number have transient hypothalamus-pituitary-gonadal hypofunction and a poor fertility prognosis. These patients may benefit from gonadotropin treatment after orchiopexy. Patients with normal gonadotropins, inhibin B and germ cell number have a good fertility prognosis after surgery.