Toxicity In Reproductive Organs Research Articles

Effects of glyphosate-based herbicide-contaminated diets on reproductive organ toxicity and hypothalamic-pituitary-ovarian axis hormones in weaned piglets.

At present, glyphosate (GLP) is the most produced and used herbicide in the world. With the large-scale use of glyphosate-based herbicides (GBHs), their toxic effects on animals and plants have increasingly become a concern. Based on the Codex Alimentarius Commission (CODEX) dose (20mgkg-1) and the dose set by the government (40mgkg-1), four experimental groups in which Roundup® (R) herbicide was added to the feed of weaned piglets at GLP concentrations of 0, 10, 20, and 40mgkg-1 were designed. The results showed that R had no significant effect on the vulvar size or index of reproductive organs but that it could affect the tissue morphology and ultrastructure of the uterus and ovary. With the increase in GLP concentration, the activities of antioxidant enzymes [SOD (P<0.05) and GPx (P=0.002)] in the uterus showed significant increases. Compared with the control group, the content of hydrogen peroxide (H2O2) in the treatment groups increased significantly (P<0.05), the malondialdehyde (MDA) content in the 10mgkg-1 treatment group was significantly higher than that in the control group. We measured hypothalamic-pituitary-ovarian axis (HPOA) hormones and also found that GLP significantly increased luteinizing hormone-releasing hormone (LHRH), gonadotropin-releasing hormone (GnRH) and testosterone (T) content (P<0.05) and decreased follicle-stimulating hormone (FSH) content (P<0.05). In summary, although R does not affect the vulvar size or reproductive organ index of weaned piglets, it changes the morphology and ultrastructure of the uterus and ovaries, interferes with the synthesis and secretion of HPOA hormones, and causes changes in the balance of the antioxidant system of uterus. This study provided a theoretical basis for preventing reproductive system harm caused by GBHs.

Taurine ameliorates 5-flourouracil-induced intestinal mucositis, hepatorenal and reproductive organ damage in Wistar rats: A biochemical and histological study.

5-Fluorouracil is one of the most commonly used anticancer drugs for the treatment of various types of cancer but has potential adverse effects such as intestinal mucositis, renal, hepatic, and reproductive organ toxicity. Attention has been given to approaches to reduce the side effects and improve the therapeutic effectiveness of chemotherapeutic drugs. In this study, we have investigated the protective effect of taurine (Tau) on 5-fluorouracil (5-FU) induced adverse effects in Wistar rats. Animals were divided into four groups with six animals (n = 6) in each group. Group I received vehicle only and served as control group. Groups II, III, and IV animals were given oral gavage of 5-FU at 50 mg/kg body weight for 4 days. Tau was given to the animals of groups III and IV 30 min prior to 5-FU administration. We observed marked elevation in the myeloperoxidase (MPO) activity after 5-FU administration, which was reversed by Tau pretreatment. Histological observation of liver, kidney, intestine, testis, and prostate revealed that 5-FU administration resulted in anomalies like distortion of normal cellular architecture, infiltration of inflammatory cells, and loss of cellular integrity. These histopathological changes were markedly suppressed by Tau treatment. In conclusion, biochemical and histological findings of this study suggest that Tau has strong preventive potential against complications of anticancer drug 5-FU and hence Tau may play an important role in combinational chemotherapy to enhance the therapeutic efficacy of anticancer drugs.

Histopathological and ultra structural effects of nanoparticles on rat testis following 90days (Chronic study) of repeated oral administration.

BackgroundNanoparticles (Ag NPs) have recently received much attention for their possible applications in biotechnology and biomedical. However, little is known about the toxicity in reproductive organs of animal model following exposure to nanoparticles.ObjectiveThis study therefore, tried to examine the effects of nanoparticles with a diameter range of 5-20 nm on the histology of the testis of wistar rats and correlate it with Transmission Electron Microscopy results.Materials and methodsSixteen wistar rats were randomly divided into two groups of 8 rats each. Each group received the following via gavage technique for 90 days: Control Group (Group-1)-tap water; Experimental group (Group 2) - nanoparticles (20ug/kg/day). After ninety days (chronic study), rats were sacrificed and testis tissues was processed for histology and transmission electron microscopic study.ResultsThere was significant difference between the observations of group-1 and group 2. The changes observed in the testis were disarray of the spermatogenic cells and disorientation of the testis. These changes were observed to have been disappearing from normal histological features. Detailed structural damages were observed with TEM analysis, such as depletion of germ cells, germinal cells necrosis, especially in spermatogonia and Leydig cells had an abnormal fibroblast-like appearance, abnormal space between neighboring sertoli cells, mitochondria, lost cristae and vacuolated (none energized) with those animals exposed to nanoparticles.ConclusionIt seems that nanoparticles have acute and significant effects on spermatogenesis and number of spermatogenic cells. More experimental investigations are necessary to elucidate better conclusion regarding the safety of nanoparticles on male reproduction system.

Chlorpyrifos induced toxicity in reproductive organs of female Wistar rats

Chlorpyrifos (CPF) is an organophosphate (OP) insecticide extensively used in agricultural and domestic settings. Healthy adult female albino rats were divided into three groups of six rats in each. Two groups were dosed orally with CPF in vegetable oil (0.1 and 2.5mg/kg/day) and third group was given vegetable oil for 8weeks. Non-significant changes were observed for body weight and feed intake. A disruption in estrous cyclicity was observed with a prolonged metestrous. Erythrocyte osmotic fragility and lipid peroxidation levels increased significantly. Mammary gland whole mounts revealed a significant (P<0.05–0.0001) increase in the ductal thickness, number of branches, alveolar and terminal end bud number and terminal end bud diameter. A significant increase in ovarian surface epithelium height, follicular diameter and follicular atresia was observed in treated rats (P<0.05–0.0001). A similar significant increase in the uterine surface epithelium height, endometrial gland epithelium height and myometrium thickness in higher dose group was recorded (P<0.05–0.0001). Luminal epithelium height and endometrial gland diameter was increased significantly in both the treated groups (P<0.05–0.0001). The results indicate that sub-chronic exposure of CPF causes oxidative stress and negative effects on the reproductive organs of female rats, which may be a pointer towards beginning of cancer incidence.

Oral Propylparaben Administration to Juvenile Male Wistar Rats Did Not Induce Toxicity in Reproductive Organs

Parabens are in widespread use as preservatives in drugs. In the late 1990 s, concerns were raised about their capacity to disrupt endocrine function based on in vitro data and in vivo uterotrophic tests. Studies in juvenile male rats provided conflicting results on pospubertal sperm production. In an exploratory pharmacokinetic study, Wistar male rats received a single dose of propylparaben (PP) at 3, 10, 100, or 1000 mg/kg, orally on postnatal day (PND) 31. Plasma PP concentrations were quantifiable up 8h after dosing with a mean T max value of 15 min. Distribution was 4.8 l/kg, the plasma elimination half-life was 47 min, and clearance was 4.20 (l/h)/kg at 10mg/kg. A sulfoconjugated metabolite was detected. In the juvenile toxicology study, PP was orally administered by gavage to 20 Wistar male rats at doses of 3, 10, 100, or 1000 mg/kg/day in 1% hydroxyethylcellulose for 8 weeks starting on PND21. A first subgroup of 10 males/dose was necropsied immediately after the 8-week exposure period; a second subgroup of 10 males/dose was necropsied after a 26-week washout period. Blood samples were taken from additional satellite animals after dosing on PND21 and PND77 for toxicokinetic analysis. There was no evidence of an effect of PP on the weight of the male reproductive organs, epididymal sperm parameters, hormone levels, or histopathology. The dose of 1000 mg/kg/day was the no-observed adverse effect level, corresponding to a maximum plasma concentration of 12,030 ng/ml and exposure to 47 760 ng · h/ml (AUC0-8 h) at the end of the treatment.

Developmental toxicity in reproductive organs

Developmental toxicity in reproductive organs

Hypothyroidism protects di(n-butyl) phthalate-induced reproductive organs damage in Sprague-Dawley male rats

This study examined the deleterious effects of di(n-butyl) phthalate (DBP) on the male reproductive organs in hypothyroid rats. Hypothyroidism was induced in prepubertal male rats (28 days of age) by an intraperitonial (i.p.) injection of 10 mg/kg/day propylthiouracil (PTU) for 30 days. DBP (100 and 500 mg/kg/day) was administered by oral gavages to the intact or hypothyroid rats for 30 days. The body weight of the PTU-treated rats was significantly lower than the control group. The total triiodothyronine (T3) and thyroxine (T4) serum level was lower, and the thyroid-stimulating hormone (TSH) level was higher in the hypothyroid rats than in the control rats. The DBP treatment rats showed significantly lower testes, epididymides, seminal vesicles, and ventral prostate weights than the untreated rats. The hypothyroid rats had significantly higher thyroid weights and lower adrenal glands weights than the control rats. The histomorphological examination showed diffused Leydig cells hyperplasias and germ cells loss in the DBP (500 mg/kg)-treated rats, whereas these effects were mild in the DBP-treated hypothyroid rats. The serum levels of monobutyl phthalate (MBP) were significantly lower in PTU-induced hypothyroid rats than in the DBP-treated rats. This data suggests that the hypothyroid status might offer some protection from male reproductive organ toxicity caused by a disturbance in the metabolic activation of the parent compound, DBP.

CYP2E1-Catalyzed Oxidation Contributes to the Sperm Toxicity of 1-Bromopropane in Mice1

1-bromopropane (1-BrP) induces dose- and time-dependent reproductive organ toxicity and reduced sperm motility in rodents. The contribution of cytochrome P4502E1 (CYP2E1) to both 1-BrP metabolism and the induction of male reproductive toxicity was investigated using wild-type (WT) and Cyp2e1-/- mice. In gas uptake inhalation studies, the elimination half-life of [1,2,3-(13)C]-1-BrP was longer in Cyp2e1-/- mice relative to WT (3.2 vs. 1.3 h). Urinary metabolites were identified by 13C nuclear magnetic resonance. The mercapturic acid of 1-bromo-2-hydroxypropane (2OHBrP) was the major urinary metabolite in WT mice, and products of conjugation of 1-BrP with glutathione (GSH) were insignificant. The ratio of GSH conjugation to 2-hydroxylation increased 5-fold in Cyp2e1-/- mice relative to WT. After 1-BrP exposure, hepatic GSH was decreased by 76% in WT mice vs. 47% in Cyp2e1-/- mice. Despite a 170% increase in 1-BrP exposure in Cyp2e1-/- vs. WT mice, sperm motility in exposed Cyp2e1-/- mice did not change relative to unexposed matched controls. This suggests that metabolites produced through CYP2E1-mediated oxidation may be responsible for 1-BrP-induced sperm toxicity. Both 1-BrP and 2OHBrP inhibited the motility of sperm obtained from WT mice in vitro. However, only 2OHBrP reduced the motility of sperm obtained from Cyp2e1-/- mice in vitro, suggesting that conversion of parent compound to 2OHBrP within the spermatozoa may contribute, at least in part, to reduced motility. Overall, these data suggest that metabolism of 1-BrP is mediated in part by CYP2E1, and activation of 1BrP via this enzyme may contribute to the male reproductive toxicity of this chemical.

Growth suppression of Leydig TM3 cells mediated by aryl hydrocarbon receptor

Exposure to 2,3,7,8-tetrachlorodibenzo- p-dioxin induces developmental toxicity in reproductive organs. To elucidate the function of AhR, we generated stable transformants of TM3 cells overexpressing wild-type aryl hydrocarbon receptor (AhR) or its mutants which carried mutations in nuclear localization signal or nuclear export signal. In the presence of 3-methylcholanthrene (MC), proliferation of the cells transfected with wild-type AhR was completely suppressed, whereas cells expressing AhR mutants proliferated in a manner equivalent to control TM3 cells, suggesting AhR-dependent growth inhibition. The suppression was associated with up-regulation of cyclin-dependent kinase inhibitor p21 Cip1, which was abolished by pretreatment with actinomycin D. A p38 MAPK specific inhibitor, SB203580, blocked the increase of p21 Cip1 mRNA in response to MC. Treatment with indigo, another AhR ligand, failed to increase of p21 Cip1 mRNA, although up-regulation of mRNA for CYP1A1 was observed. These data suggest AhR in Leydig cells mediates growth inhibition by inducing p21 Cip1.

Di-n-butyl Phthalate is Toxic to the Male Reproductive System and Its Toxicity is Enhanced by Thioacetamide Induced Liver Injury

The modifying effects of liver injury on male reproductive organ toxicity of di-n-butyl phthalate (DBP) were studied using male F344 rats. Seventy-two male animals, aged 10 weeks at the commencement, were divided into 8 groups of 9 rats each. Groups 1 to 4 were given 200 mg/kg bw of thioacetamide (TAA) intraperitoneally 3 times / week, while Groups 5 to 8 were injected with the PBS vehicle only. From 1 week after the start, groups 1 and 5, 2 and 6, and 3 and 7 were given daily 500, 125, 31.25 mg/kg bw of DBP, respectively (23 times) for 4 weeks, while groups 4 and 8 served as vehicle controls. As the result of our treatment, liver injury was induced in the animals, and the liver injury was confirmed by histopathological findings and serum transaminase levels at sacrifice. Enhancement of rat male reproductive organ toxicity of DBP under liver injury status was also seen. The relative organ weights of prostate, bilateral seminal vesicles, bilateral epididymides and bilateral testes, and the sperm number and motility rate were decreased. Also the sperm abnormality rate was increased under liver injury. Furthermore histopathological abnormality of the testis, such as absence of germ cells and the presence of Sertoli cells only was seen in the rats treated with TAA and high dose of DBP, however neither the serum nor testicular testosterone levels varied in the present study. The sperm number and relative weight of bilateral epididymides were decreased by TAA treatment only, unrelated to DBP treatment. These facts suggest that liver injury can not only enhance the rat male reproductive organ toxicity of DBP, but also induce such toxicity by itself.