Cytotoxic and cell transforming effects of the insecticide, lindane (gamma-hexachlorocyclohexane) on BALB/c 3T3 cells

The present study was designed to elucidate the correlation between findings from reproductive performance testing and those from histopathological examination of the testis and sperm analysis in rats given a benzodiazepine derivative, nitrazepam, for 2 and 4 weeks. The mechanisms of toxicological action of nitrazepam on the male reproductive organs were also investigated. Nitrazepam was given orally to Sprague-Dawley male rats (6-week-old) at a daily dose of 80 mg/kg for 2 weeks or at daily doses of 20, 40 or 80 mg/kg for 4 weeks. Treated males were mated to examine reproductive performance with untreated females after each dosing period, and after 4 and 9 week of recovery periods. Necropsy was performed for histopathological examination of the testis and epididymis and for sperm analysis after each dosing period and the final mating trial (total of 11 weeks recovery). In the findings from reproductive performance testing, significant decrease in the fertility index was observed in the 80 mg/kg group even after 2 weeks dosing and thereafter until 4 weeks recovery, though the mating index did not significantly differ from that of controls through the experiment. In the histopathological examination and sperm analysis, testicular signs of toxicity, decrease in number of sperm heads in the testis and increase in number of sperm with abnormal heads in the seminiferous tubules were noted in the 80 mg/kg group after 2 weeks dosing and in the 40 and 80 mg/kg groups after 4 weeks dosing. Concentrations of plasma testosterone and content of testis testosterone in nitrazepam-treated groups were not significantly different from those of controls. Plasma FSH concentration was significantly elevated in the 80 mg/kg group through the experiment, although significant elevation of plasma LH was observed only after 2 weeks dosing. These results indicate that histopathological examination is the most reliable approach to detect male reproductive adverse effects induced by nitrazepam rather than using parameters from mating trials. The four-week-dosing period is appropriate for their detection. Hypospermatogenesis induced by nitrazepam is suggested to be caused by direct action of nitrazepam on germ cells and/or Sertoli cells rather than by indirect action through inhibition of testosterone secretion.     

Effects of antifertility drugs on epididymal protein secretion, acquisition of sperm surface proteins and fertility in male rats

The possibility that alpha-chlorohydrin, 6-chloro-6-deoxyglucose (6CDG) and cyproterone acetate (CPA) might affect epididymal protein secretion or acquisition of sperm surface proteins as the cause of their antifertility action in male rats was investigated. Daily administration of 9 mg/kg alpha-chlorohydrin for 7--14 days and 24 mg/kg 6CDG for 14--21 days induced sterility in male rats and imparied the capacity of the cauda epididymal spermatozoa to initiate motility. Treatment with CPA (30 mg/kg/day) for 21--28 days, however, was found to have no effect on fertility and initiation of sperm motility, although the epididymis of the treated animals underwent a loss in weight. The antifertility effects of alpha-chlorohydrin or 6CDG did not seem to be attributed to an interference with epididymal protein secretion. The cauda epididymal fluids of the alpha-chlorohydrin, 6CDG and CPA treated animals have similar protein patterns compared to those of the control animals. However, when the surface proteins of the spermatozoa were labelled with radioactive iodine, the sperm surface proteins alpha-chlorohydrin and 6CDG treated animals were found to differ from those of the control animals. Two peaks (MW 32 000 and 70 000) and one peak (70 000) were significantly reduced in the alpha-chlorohydrin treated and 6CDG treated animals, respectively. Additional bands appeared on the surface of the treated (infertile) animals. In contrast, CPA treatment did not affect the surface protein pattern of the epididymal spermatozoa. It was concluded that the antifertility affects of alpha-chlorohydrin and 6CDG are not due to an interference with epididymal secretion of specific proteins but to an intervention of the subsequent acquisition of these proteins by epididymal spermatozoa. This results in a decrease in the capacity of the epididymal sperm to initiate motility and hence a loss of fertilizing capacity.     

Male fertility in rats treated with etretinate for 4 weeks

The toxicity of Etretinate, a retinoid compound, on the male reproductive system was studied in male rats. The drug was administered for four weeks at the dose levels of 0 (control: Vehicle, Peanut oil), 5 and 25 mg/kg/day. The animals were then allowed to mate, and their male reproductive functions and organs were examined in detail. No significant changes due to toxicity were observed in male reproductive functions and organs in the 5 mg/kg/day group after the 4-week treatment. In contrast, males in the 25 mg/kg/day group showed drug-related changes in their reproductive performance (decrease of mating ability and fertility rate), testosterone blood level, sperm head counts, sperm viability and number in the caudal epididymis, organ weight and in the histopathology of their reproductive organs (atrophy of seminiferous tubules, necrosis of spermatocytes and spermatids, vacuolation of nuclei of spermatocytes and spermatids). Even though Etretinate belong to the retinoid group of compounds, the changes seen in the 25 mg/kg/day group were almost the same as those observed in Vitamin A-deficient animals. In conclusion, there is a correlation between changes due to toxicity observed for parameters of male fertility and for histopathological evaluation of the testis of rats that receiving high dose, treatment with Etretinate for 4 weeks.     

In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-rho-dioxin: effects on development of the male and female reproductive system of the mouse

To evaluate effects of in utero and lactational 2,3,7,8-tetrachlorodibenzo-rho-dioxin (TCDD) exposure on male and female reproductive system development of the mouse, the offspring of pregnant ICR mice administered 0, 15, 30, or 60 microg TCDD/kg on Gestation Day (GD) 14 were examined at the postweanling, pubertal, young adult, and adult stages of development. Dam and offspring body weights and prenatal and postnatal mortality were unaffected by TCDD exposure. The most sensitive endpoints in male offspring were decreased ventral prostate, coagulating gland, and thymus weights, accelerated eye opening, and hydronephrosis. Decreases in pituitary gland weight and epididymal sperm numbers were also found in TCDD-exposed male offspring. Testis, epididymis, and dorsolateral prostate weights, anogenital distance, latencies to testis descent and to preputial separation, and serum testosterone concentrations were unaffected. At the highest maternal TCDD dose uterus weights were decreased in female offspring evaluated during estrus and diestrus. No morphologic changes in the external genitalia of female offspring were found, nor were there alterations in ovary or pituitary gland weights. Cross-species comparisons showed that the mouse was not as sensitive to TCDD-induced developmental reproductive toxicity as the rat and hamster. Many endpoints affected by TCDD in rat and hamster offspring were either not affected or were less sensitive in mouse offspring. Endpoints of androgenic status were not affected in the mouse, decreases in accessory sex organ weights were restricted to fewer organs in the mouse, and decreases in daily sperm production were not found in the mouse. The only developmental reproductive endpoint observed in all three species was a reduction in epididymal sperm numbers.     

The effects of coital lubricants on sperm motility in vitro

Infertility affects approximately 15% of couples, and in about one-third the primary cause is a male factor. Patients undergoing infertility investigations frequently experience sexual dysfunction, which often is due to inadequate vaginal lubrication. This can lead to increased use of coital lubricants. The effects of such lubricants on sperm motility have not been widely studied, although sperm motility is one of the best prognostic indicators of fertilization. Using a prospective longitudinal control-based study, we analysed the effect of adding four lubricants: KY jelly, baby oil, olive oil and saliva on sperm motion in 16 samples from patients undergoing infertility investigations. Sperm samples were prepared by density gradient centrifugation prior to mixing with lubricants. Motility parameters were determined using computer-assisted semen analysis after 5, 15 and 30 min. All lubricants except baby oil significantly decreased percentage progressive motility, progressive velocity, curvilinear velocity and lateral head displacement at 12.5% concentration. At a lower concentration of 6.25%, both olive oil and saliva still significantly reduced progressive motility parameters, while KY jelly diminished head movement parameters. Hence, even at these very low concentrations, coital lubricants impair sperm motility and thus may adversely affect fertility.     

The effect of proliferative status and clonogen content on the response of mouse jejunal crypts to split-dose irradiation

As a component to the risk assessment process for para-nonylphenol (NP; CASRN 84852-15-3), a 90-day study was conducted in rats following U.S. EPA TSCA guidelines and Good Laboratory Practice regulations. NP was administered to four groups of rats at dietary concentrations of 0, 200, 650, or 2000 ppm which corresponded to approximate dietary intakes of 0, 15, 50, or 150 mg/kg/day, respectively. There were 25 rats/sex/group in the control and high-dose groups and 15 rats/sex/group in the low- and middose groups. Ten of the 25 rats/sex in the control and high-dose groups were designated as recovery animals and were maintained on control diets for 4 weeks after completion of the 90-day exposure period to assess the reversibility of any effects which might be observed. To evaluate for the possible weak estrogen-like activity that has been reported for NP in a number of screening assays, estrous cyclicity was monitored using vaginal cytology during Week 8 of the study, and sperm count, motility, and morphology were evaluated at termination. In-life effects from NP exposure were limited to small decreases in body weight and food consumption in the 2000-ppm dose group. Postmortem measurements at Week 14 indicated a dose-related kidney weight increase in males and a decrease in renal hyaline globules/droplets in males from the high-dose group. The kidney weights showed complete recovery following the 4-week postdosing recovery period. Due to the small magnitude of the changes (i.e., all weights were within or near laboratory historical control values) and the lack of correlating clinical or histopathological changes, the kidney weight alterations were not considered toxicologically significant. The biological significance of reduced hyaline in the kidneys of male rats from the high-dose group is uncertain. Renal tubular hyaline is associated with the rat-specific protein, alpha-2u-globulin, and, therefore, this finding was not considered toxicologically relevant to humans. No other effects attributable to NP were observed. No changes were observed for estrous cycling, sperm evaluations, or effects on endocrine organs. NP, therefore, did not manifest any estrogen-like activity as measured in these parameters at dietary concentrations as high as 2000 ppm, the maximum dose administered in this study. Based on the minor findings for the 2000-ppm dose group, the NOAEL (no-observed-adverse-effect level) for NP in this study is considered to be 650 ppm in the diet, corresponding to an approximate intake of 50 mg/kg/day.     

Developmental exposure of male germ cells to 5-azacytidine results in abnormal preimplantation development in rats

Methylation of cytosine residues in mammalian DNA is established during gametogenesis and embryogenesis; it plays an important role in gene regulation and normal embryonic development and has also been implicated in genomic imprinting. In the present study, we evaluated whether paternal administration of 5-azacytidine, a drug that is incorporated into DNA and blocks DNA methylation, could alter male germ cell development and function. A drug that does not block methylation, 6-azacytidine, served as a control. Adult male Sprague-Dawley rats (n = 4-8 per group) were treated i.p., three times per week for 4 and 11 wk, with saline or 2.5 (low dosage) or 5.0 (high dosage) mg/kg of 5-azacytidine and 6-azacytidine. After each of the treatment periods, males were mated to determine effects on fertility and embryo development. Although neither 6-azacytidine nor 4 wk of 5-azacytidine treatment affected male reproductive organ weights or sperm counts, 11 wk of 5-azacytidine resulted in dose-dependent reductions in testis and epididymal weights and sperm counts. Both dosages of 5-azacytidine resulted in significant increases in preimplantation loss, and the high dosage of 5-azacytidine caused a decrease in fertility. Examination of embryos on Day 2 of gestation revealed a striking dose-dependent increase in the average number of abnormal embryos per litter sired by the males treated with 5-azacytidine (saline, 0.33 +/- 0.24; low dosage, 2.64 +/- 0.92; high dosage, 10.09 +/- 0.95). In summary, paternal administration of 5-azacytidine interfered with normal male germ cell development and resulted in alterations in fertilization and early embryo development. We suggest that 5-azacytidine-induced alterations in germ cell DNA methylation patterns may be one of the underlying mechanisms, since similar dosages of the analogue 6-azacytidine had no effect on male reproduction and progeny outcome.     

Development of an outcome measure to document pain relief for home hospice patients: a collaboration between nursing education and practice

Epididymal glycosidases play a role in sperm maturation by modifying sperm surface glycoproteins. To study the effects of ethanol on epididymal sperm maturation, ethanol (3 g/kg body weight as 25%, v/v) was administered to a group of rats by gastric-intubation twice daily for 30 days. In another group, rats were also treated with alcohol for 30 days but were then withdrawn from treatment for 30 days to assess the reversibility of ethanol-induced effects. Ethanol-induced changes in epididymal tissue and sperm glycosidases, cauda epididymal sperm motility and the fertility of rats were assessed. Ethanol treatment caused a marked decrease in the specific activities of glycosidases in both tissues and spermatozoa from epididymal segments. Cauda epididymal sperm motility and the fertility of ethanol-treated rats were significantly impaired compared to control rats fed an isocaloric diet. These changes are likely to be the consequence of direct and indirect effects of ethanol mediated through subnormal testosterone and dihydrotestosterone. Most of these changes were found to be reversible. The present study suggests that impaired activity of sperm glycosidases may be one of the factors responsible for defective sperm motility and fertilizing potential in ethanol-treated rats.     

Preliminary screening for the potential of drinking water disinfection byproducts to alter male reproduction

There is increasing epidemiologic interest in the role drinking water disinfection byproducts (DBPs) may play in adverse reproductive outcomes such as inability to conceive, spontaneous abortion, and low birth weight. Although dozens of DBPs already have been identified, only a few studies have attempted to determine whether DBPs alter male reproductive parameters such as testicular and epididymal histology, testicular and epididymal sperm numbers, and epididymal sperm morphology and motility in laboratory animals. In these studies, alterations in epididymal sperm motility seemed to be predictive of more generalized toxicity of the male reproductive system. Because there is a need to prioritize DBPs for thorough reproductive and developmental toxicity testing, preliminary screening for the potential of DBPs to alter reproductive function seems warranted. Here, we elected to examine only cauda epididymal sperm motion parameters and testicular and epididymal histopathology. The effects of exposure to two commonly occurring DBPs, bromodichloromethane (BDCM) and chloral hydrate (CH), via drinking water were evaluated in F344 rats at an interim (52 week) necropsy during cancer bioassay studies. Exposure to 22 and 39 mg/kg BDCM and 55 and 188 mg/kg CH did not produce any systemic toxicity. Histopathologic evaluation revealed no gross lesions in the reproductive organs, and no tumors were detected in any tissues. In contrast, exposure to 39 mg/kg BDCM significantly decreased the mean straight-line, average path, and curvilinear velocities of sperm recovered from the cauda epididymidis. This BDCM exposure shifted the average path velocity distribution to a lower modal velocity range. Exposure to 188 mg/kg CH significantly decreased both the percentage of motile and progressively motile sperm. This CH exposure shifted the straight-line velocity distribution to a lower modal velocity range. These are the first reproductive toxicity data from exposure to BDCM and CH. The observed effects on sperm motion occurred in the absence of carcinogenesis. Because the effects of BDCM on sperm motility occurred at a lower exposure than that of other DBPs that compromise sperm motility, a thorough reproductive evaluation now is underway.     

Antispermatogenic effects of ethyl methanesulfonate and benzo[a]pyrene in PD4 Lakeview hamsters

Mammalian sperm seems to provide an excellent cell type for monitoring mutagenic and other toxicological damage to the germinal tissue. Studies with mice indicated that most agents known for their mutagenic activity in vivo produced marked elevations in sperm abnormalities. To determine whether this response is typical of other species, groups of inbred Lakeview hamsters were exposed to ethyl methane-sulfonate (EMS) and benzo[a]pyrene (BP) in five daily subacute ip doses ranging from 5 to 125 mg/kg and 2 to 50 mg/kg, respectively. Percentage of abnormal sperm, testis weight, and body weight were monitored at wk 1, 4, and 10 after treatment. EMS exposures increased the frequency of sperm abnormalities and reduced sperm numbers and testis weights. Body weights were also affected. BP exposures did not induce sperm abnormalities; however, there were marked reductions in sperm number and testis weight. These findings are in agreement with results of EMS studies in the mouse; however, BP exposure did induce sperm abnormalities in the mouse.     

Adaptation to ozone in rats and its association with ascorbic acid in the lung

The present study evaluated the modulatory role of central corticotropin-releasing factor (CRF) systems in the mediation of the effects of acute exposure to the brain cannabinoid receptor agonist HU-210 [3-(1,1-dimethylheptyl)-(-)-11-hydroxy-delta 8-tetrahydrocannabinol] on defensive withdrawal behavior in male rats. The apparatus used for the defensive withdrawal test consisted of a small chamber, set on one side of a one-square meter open field. The actions of the potent CRF antagonist [D-Phe12,Nle21,38,C alpha MeLeu37]CRF (D-Phe CRF12-41) were examined on defensive behavior under both novel and familiar conditions. The acute i.c.v. administration of D-Phe CRF12-41 (0.2-5 micrograms/injection) antagonized the defensive behavior response to stressing conditions such as novelty or swim stress in field-habituated animals. The acute i.p. administration of HU-210 (4, 20 and 100 micrograms/kg) produced a clear dose-dependent stress-like effects in field-habituated animals, as reflected in the HU-210-induced increase in both the emergence latency and the mean time spent in the small chamber. The i.c.v. administration of 5 micrograms of D-Phe CRF12-41, 5 min before the administration of the cannabinoid prevented the stressing actions of HU-210 (20 micrograms/kg, but not 100 micrograms/kg). Acute administration of HU-210 also induced a dose-dependent increase in plasma corticosterone levels which was not antagonized by pretreatment with 5 micrograms of D-Phe CRF12-41. The present study suggests a role of central CRF systems in the mediation of the anxiogenic effects of brain cannabinoid receptor agonists. This finding is consistent with a direct hypothalamic effect of cannabinoids on the activation of the pituitary-adrenal axis.     

Importance of metabolism in pharmacological studies: possible in vitro predictability

Groups of 20 male and 20 female Sprague-Dawley rats were administered undiluted Aquacoat ECD ethylcellulose aqueous dispersion by oral gavage at doses of 903, 2709 or 4515 mg/kg body weight/day (dry weight basis) for 90 days. Control animals received water at the same dosage volume as the high-dose group. Body weights and food consumption were recorded weekly. Blood was collected prior to study termination for haematology and clinical chemistry measurements. Survivors underwent complete necropsies on days 91 94. Selected organs were weighed and histologically examined. The only treatment-related clinical sign observed was pale faeces which was noted among males and females receiving 2709 and 4515 mg/kg/day Aquacoat ECD. No statistically significant differences in body weights, body weight gains, food consumption and organ weights were noted among males and females when compared with controls. No treatment-related effects in haematology parameters were noted. Significantly decreased total protein and globulin levels and increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in male rats receiving 2709 and 4515 mg Aquacoat ECD/kg/day were considered to be treatment related. No gross or microscopic lesions were attributed to Aquacoat ECD treatment. Under the conditions of this study, the no-observed-adverse-effect level (NOAEL) for female rats is in excess of 4515 mg/kg/day: the NOAEL for male rats is 903 mg/kg/day.     

Effects of recombinant human interleukin 6 (rhIL-6) in marmosets (Callithrix jacchus). 1. General toxicity and hematological changes

The physiological and toxicological properties of recombinant human interleukin 6 (rhIL-6) were assessed in marmoset monkeys (Callithrix jacchus). Two experimental series were performed with daily subcutaneous administration: (a) 5 or 1000 micrograms rhIL-6/kg per day for three weeks and (b) 25, 100 or 500 micrograms rhIL-6/kg per day for 3 months. RhIL-6 was well tolerated and did not induce fever or any other non-specific signs of toxicity. The main findings were: (1) A two- to threefold increase in platelet counts at 2-4 weeks, which decreased following further continuous rhIL-6 administration; (2) increase in total white blood cells between 1 and 4 weeks of administration, including an absolute increase in granulocytes (including band forms) and basophils. A change in the number of monocytes was not detected; (3) an increase in total red blood cells, which peaked at 4 weeks, sustained elevation of red cell distribution width and a slight decrease in hemoglobin between week 1 and 4, concurrent with a distinct decrease in mean corpuscular hemoglobin at 4 weeks. This effect persisted for 9 weeks in the 100 micrograms/kg and 500 micrograms/kg groups; (4) decrease in plasma AST activity and increase in plasma protein concentration after 2 weeks of treatment; (5) no clinical or biochemical signs of renal glomerular dysfunction; (6) RhIL-6 after s.c. administration was detectable in the plasma, peak levels (mean values +/- SD) of 9.4 +/- 6.3 and 72.4 +/- 7.7 ng/ml were measured after a single dose of 100 or 1000 micrograms/kg; (7) antibodies against rhIL-6 developed within 2 weeks, increased during administration and neutralized the biological effect of rhIL-6 progressively from 4 to 9 weeks. In conclusion, aside from a mild anemia, rhIL-6 was well tolerated in marmosets and had a profound and sustained effect on thrombopoiesis. Due to the formation of neutralizing antibodies, the chronic biological effect of rhIL-6 is lost in marmosets and studies beyond 4 weeks are rendered less meaningful. The analyses of antibody formation, induction of acute phase proteins, histological changes and alterations on lymphocyte receptors will be reported in two following publications.     

Interferon-gamma differentially regulates antigen-processing functions in distinct endocytic compartments of macrophages with constitutive expression of class II major histocompatibility complex molecules

Treatment of pregnant female Sprague-Dawley rats on Gestational Day 15 with a single oral dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (0.5, 1.0, or 2.0 micrograms/kg) or indole-3-carbinol (I3C, 1.0 or 100 mg/kg), an aryl hydrocarbon (Ah) receptor agonist which is found in cruciferous vegetables, resulted in reproductive abnormalities in the male offspring (three to five litters in each treatment group). Anogenital distance and crown to rump length were altered by both compounds; however, the timing of the effects (Day 1 or 5) was variable and the responses were not necessarily dose-dependent. In 62-day-old offspring, seminal vesicle (24 to 26%), prostate (32 to 44%), testicular parenchymal (14%), and epididymal weight (19%) were decreased by one or more doses of TCDD. In contrast, I3C at one or more doses decreased daily sperm production/g testicular parenchyma (13 to 20%) and daily sperm production/testis (22%). Total number of sperum in the epididymis was significantly decreased (30 to 33%) in rats perinatally exposed to TCDD and this was due to a decreased (49 to 51%) number of sperm in the tail of the epididymis. Perinatal exposure to I3C did not affect any of these parameters. TCDD did not affect epididymal transit time of sperm through the complete epididymis at any of the doses (0.5 to 2.0 micrograms/kg). However, at the two highest doses (1.0 and 2.0 micrograms/kg), TCDD increased epididymal transit rate of sperm through the tail of the epididymis by 33 and 37%, respectively. In contrast, primarily due to decreased transit rate (39%) of sperm through the head plus body of the epididymis. I3C (1 mg/kg) significantly increased total epididymal transit time by 31%. In conclusion, perinatal exposure of pregnant rats to I3C, an Ah receptor agonist similar to TCDD, causes reproductive abnormalities in male rat offspring; however, I3C and TCDD elicited both common and different responses.     

Effects of lysozyme dimer on humoral response to sheep erythrocytes in non-treated and cyclophosphamide-immunosuppressed mice

The effects of lysozyme dimer on humoral response to sheep erythrocytes (SRBC) and restoration of the response impaired by a single cyclophosphamide dose (200 mg/kg) were tested on mice. The effect of lysozyme dimer on the humoral response to SRBC in non-treated with cyclophosphamide mice was determined in relation to doses (0.2, 2, 20 or 200 micrograms/kg) and the time of the drug administration with respect to the antigen before or after SRBC immunization. Moreover, the effect of lysozyme dimer on the humoral response in cyclophosphamide-treated mice was studied depending on the dose applied and time of exposure to the drug in relation to SRBC. It has been found that lysozyme dimer potentiates the humoral response to SRBC in mice, resulting in an increased number of splenocytes producing haemolytic antibodies (PFC) and the total and 2-mercaptoethanol resistant level of anti-SRBC antibodies. A single exposure to lysozyme dimer gave the strongest stimulating action on SRBC when the doses of 2 or 20 micrograms/kg were administered 2 h prior to the antigen. The potentiating effect of the drug was reduced when it was administered 24 h before the antigen and also when single doses were as high as 200 micrograms/kg and as low as 2 micrograms/kg. Exposure to four doses of lysozyme dimer at 24 h intervals was more activating than a single injection. A strong potentiating effect on the specific response to SRBC was noted after four injections of lysozyme dimer at doses from 0.2 to 20 micrograms/kg. The effect of the drug did not depend on the time of exposure to the antigen. It has also been found that lysozyme dimer significantly reduces the suppressive effect of a high cyclophosphamide dose (200 mg/kg) on the humoral response of SRBC-immunized mice. The protective action of lysozyme dimer was dose- and time-dependent. The strongest protection was observed after three doses of 20 micrograms/kg administered prior to pharmacological immunosuppression. Reduction in the dose to 2 micrograms/kg and shorter treatment resulted in reduced protective effects. We have also found that the protective action of three doses of lysozyme dimer (2 or 20 micrograms/kg each) administered between cyclophosphamide injection and the antigen, or after antigen administration is weaker than such a treatment prior to cyclophosphamide immunosuppression.     

Greatly improved sperm motility from vas deferens sperm retrieval: a case for accessory gland related subfertility in spinal cord injured man. Case report

When sperm motility from vibratory or electroejaculates of spinal cord injured men reveals consistently poor motility (< 10%), one should consider accessory gland factors as a potential cause. Herein, we report the case of a 22 year old paraplegic male who consistently had motility of 1-2% on electroejaculates. He was evaluated in the office with vas deferens sperm retrieval, which revealed a 0.4 ml volume, 9 million/ml density, and 67% motility. We suggest that this significant percent motility differential can only be explained by an accessory gland factor impacting negatively upon this individual's fertility. We propose vas deferens sperm retrieval as a potentially diagnostic and therapeutic procedure in similar cases.     

Effect of cyclosporine on fertility in male rats

The effect of cyclosporine (CsA) on fertility has assumed greater importance with the increasing numbers of pediatric transplantations being performed all over the world. Conflicting reports on the effects of CsA on sex hormones are available. This experimental animal study was designed to examine the effect of CsA on testicular weight, sperm counts, seminiferous tubular diameter (STD), testicular morphology, DNA flowcytometry, sex hormone levels, and fertility in male rats. Those rats who received CsA (20 mg/kg per day) showed significant reductions in testicular weight (P < 0.05), sperm count (P < 0.01), Johnsen score (P < 0.05), STD (P < 0.01), serum testosterone levels (P < 0.05), haploid cell population (P < 0. 001) in the testis, and fertility (P < 0.001) compared to those receiving CsA 10 mg/kg per day and control rats. These findings will have an important bearing for children receiving cyclosporine for long periods to guide the physician in optimally adjusting long-term treatment.     

Effects of p,p'-DDE on male reproductive organs in peripubertal Wistar rats following a single intraperitoneal injection

The effects of p,p'-DDE on male reproductive organs were investigated in detail in peripubertal Wistar rats following a single intraperitoneal injection. 220 mg/kg of p,p'-DDE (1/4 of LD50) were injected once into prepubertal and postpubertal Wistar rats and its effects were observed until 20 weeks of age. Weights of the body and reproductive organs in p,p'-DDE-injected rats were similar to those in control rats, who were injected with corn oil only. Sperm profile parameters such as spermatid number within the testis, sperm number within the epididymis, sperm motility and its morphology were not different between the prepubertal or postpubertal p,p'-DDE-exposed group and the control group. Like-wise, the histopathological examination at stage VII of the seminiferous epithelium cycle, when the germ cells are sensitive to testosterone, was similar in all three groups during the observation period. Serum levels of testosterone also showed no significant changes by exposure to p,p'-DDE under the conditions of this study. From these results, the antiandrogenic or estrogenic activity attributed to p,p'-DDE was not confirmed in male reproductive organs and no impairment of sperm profile was observed. This study confirmed that the reproductive functions of matured animals are scarcely affected by p,p'-DDE exposure during the peripubertal period and revealed that they might be relatively resistant to exogenous endocrine-disrupting chemicals. p,p'-DDE may threaten the hormonal equilibrium required for normal gonadal development during the organogenesis period, at an earlier stage of life. Further studies are necessary to fully reveal all the effects of p,p'-DDE on male reproductive organs and sperm profile.     

Fundamental and clinical evaluation of cefozopran in low birth weight infants and neonates

We conducted fundamental and clinical evaluations of a cephem antibiotic, cefozopran (SCE-2787, CZOP), in infants with low birth weights and mature infants. (1) Blood concentrations CZOP was intravenously given in bolus dose of 20 mg/kg to the newborn. The blood antibiotic concentrations were 69.7 micrograms/ml at 30 minutes after administration and the elimination half life was 2.99 hours in mature infants aged 1 to 3 days. They were 38.7 micrograms/ml and 2.85 hours in those aged 4 to 7 days, and 40.8 micrograms/ml and 3.81 hours in those aged 8 days or elder, respectively. In infants with lower birth weights aged 4 to 7 days the blood antibiotic concentrations were 48.6 micrograms/ml at 30 minutes after i.v. administration and the elimination half life was 3.77 hours. The blood antibiotic concentrations at 30 minutes after intravenous doses of 10, 20 and 50 mg/kg in mature infants aged 8 days or elder were 21.1, 40.8 and 153.6 micrograms/ml (value at 60 minutes) and the elimination half lives were 2.24, 3.81 and 3.07 hours, respectively. Administration of CZOP at doses of 20 and 40 mg/kg by intravenous drip infusion over 30 minutes gave the blood drug concentrations of 48.0 and 103.2 micrograms/ml at the end of the infusion and the half lives were 2.60 and 3.33 hours, respectively. (2) Urinary excretion The urinary excretion rates after i.v. bolus doses of 10, 20 and 40 mg/kg were 28.4 to 58.6% of dose. The urinary excretion rate after i.v. drip infusion of 40 mg/kg over 30 minutes was 49.0% of dose. (3) Transfer into cereblospinal fluid The transfer of the antibiotic into cereblospinal fluid in patients with serous meningitis was 4.1 to 15.5 micrograms/ml at 1 hours after administration. (4) Clinical results The clinical efficacy was judged "good" or "excellent" in 2 of the 3 patients with septicemia and in all of the 10 patients with suspected septicemia. It was judged "excellent" in all of the 9 patients with pneumonia, 3 with urinary tract infections and 3 with intrauterine infections. Prophylactic use of the antibiotic was effective in all of the 12 patients. Of the patients in whom bacteriological evaluation was successful, 7 of the 10 causative organisms were confirmed to be eradicated. No adverse drug reactions of signs and symptoms were recognized. Fourteen abnormal alterations of the laboratory test values such as elevation of gamma-GTP and that of GPT were recognized in 8 patients (16.7%). None of them were particularly serious. These results indicate that CZOP is a drug useful for treatment and prevention of infections in infants with lower birth weights as well as in mature infants.     

Effects of 2-ethylhexanoic acid on reproduction and postnatal development in Wistar rats

Reproductive toxicity of 2-ethylhexanoic acid (2-EHA) was studied in Wistar rats. The animals (24 animals per sex per group) were given 2-EHA as a sodium salt in drinking water at daily doses of 100, 300, or 600 mg/kg. Control animals received plain water. Male rats were exposed to 2-EHA for 10 weeks and females for 2 weeks prior to mating, both sexes during the mating period and females during the entire gestation and lactation period. 2-EHA caused a slight but dose-dependent decrease in fertility; time to mating increased at 300 and 600 mg/kg and even total infertility ensued. 2-EHA slightly decreased sperm quality in males. The spermatozoa were significantly less motile at 100 and 600 mg/kg and abnormal sperm occurred more frequently at the two highest dose levels. The average litter size was reduced by 16% in the dose group receiving 600 mg/kg. The birth weights of the pups were unaffected but the body weight gain was transiently slower during lactation at 600 mg/kg. Several pups appeared abnormal (kinky tail, lethargic, slightly paralyzed legs) and the physical development assessed by several landmarks (opening of eyes, eruption of teeth, hair growth) and reflexes (grip reflex, cliff avoidance) was delayed at 300 and 600 mg/kg. In another experiment, a single dose of 600 mg/kg 2-EHA was given to pregnant females by gavage on Gestational Day 4, 5, 6, or 7 and the number of implantations were counted on Gestational Day 10. Administration on Day 6 decreased the number of implantations and caused resorptions.(ABSTRACT TRUNCATED AT 250 WORDS)