Effects of three male reproductive toxicants on rat cauda epididymal sperm motion.

The sensitivity of the CellSoft computer-assisted sperm analysis (CASA) system to detect changes in rat sperm motion was evaluated. CASA motion endpoints were measured in cauda epididymal sperm from Long-Evans rats treated with each of three known male reproductive toxicants reported to affect the epididymis and epididymal sperm motility: alpha-chlorohydrin, ornidazole, and trimethylphosphate. Significant changes in endpoints describing sperm swimming vigor (curvilinear velocity and straight-line velocity) and pattern (linearity and amplitude of lateral head displacement) were observed for rats dosed with each agent when evaluations included mean values and other statistical parameters (i.e., percentiles and distributional shape). alpha-Chlorohydrin (ACH) treatment (10 mg/kg/day; 8 days) resulted in reductions in the mean percentage of motile sperm, curvilinear velocity (VCL), straight-line velocity (VSL), lateral head displacement (ALH), and linearity (LIN). Treatment with ornidazole (ONZ) (200 mg/kg/day/14 days) reduced the percentage of motile sperm. Mean VCL, VSL, and ALH were reduced by 400 mg ONZ/kg/day treatment. Trimethylphosphate (TMP) treatment led to (a) a reduction in the 75th and 90th percentiles for ALH (100 mg TMP/kg/day; 5 days) (P < or = 0.04), (b) a reduction in VCL, VSL, and ALH (250 mg TMP/kg/day), (c) a reduction in the percentage of motile cells and in the 10th and 25th percentiles for VSL (600 mg TMP/kg/day), and (d) increases in the 90th percentile for VSL, in the mean, 75th, and 90th percentiles for VCL, and in the 75th and 90th percentiles for ALH (600 mg TMP/kg/day). The general utility of these analytic approaches in reproductive toxicology studies was demonstrated in the observations of effects at or below dose levels previously reported.

Teratogenic effects of trichloroacetonitrile in the Long-Evans rat.

Trichloroacetonitrile (TCAN) is among a number of contaminants found in drinking water produced by reactions of chlorine with background organic material. Long-Evans rats were intubated with TCAN (0, 1, 7.5, 15, 35, 55 mg/kg) in a tricaprylin vehicle on gestation days 6-18. The highest dose tested (55 mg/kg) was lethal in 21% of the dams and produced 100% resorptions in two-thirds of the survivors. Only one maternal death was seen at the next-lower dose; however, fetal weight and viability were decreased in a dose-related manner. The percentage of embryolethality was 13.9% at the lowest dose and 78.4% at the high dose, with resorption of entire litters seen at 7.5 mg/kg and above. At all doses, cardiovascular (interventricular septal defect, levocardia, common carotid, and right-sided aortic arch and ductus arteriosus) and urogenital (hypoplastic, missing, misplaced and fused kidneys, and hypoplastic uterine horns) malformations were seen in the offspring. Frequency of these malformations was dose related, ranging from 8% to 35% at the 1.0- and 35-mg/kg doses, respectively. The incidence of total soft tissue malformations was statistically significant at 15 and 35 mg/kg. There were no significant treatment-related changes in the incidence of skeletal malformations. The no-effect dose was established by statistical analysis to be 1.0 mg/kg/day.

Diazepam-induced cleft palate in the mouse and lack of correlation with the H-2 locus.

Cleft palate frequencies were studied in AJ and SW mice following either 1- or 2-day dosing schedules with the anxiolytic drug diazepam (DAZ). In all cases, mice were food and water deprived for 24 and 48 hours in the 1- and 2-day dosing schedules, respectively. High cleft palate frequencies in control mice of both strains resulting from 48-hour food and water deprivation (on days 13.5 and 14.5 of gestation) were reduced in mice deprived for 24 hours, indicating a stress related effect. Two-day dosing with DAZ (400 mg/kg) produced a net increase in cleft palate frequency in SW (33%) and AJ (18%) mice. Mice treated only on day 13.5 had reduced control and DAZ cleft palate frequencies, neither of which were significant. Clefting was significant but reduced following 1-day dosing on day 13/20 of gestation (13 days 20 hours) in SW mice (18%), whereas no clefting was seen in the AJ strain. This strain difference was shown not to be related to differences in developmental timing. Production of cleft palate seen in AJ mice after 2 days of dosing may be indicative of an interaction of DAZ with the stresses resulting from food and water deprivation. Genes of the major histocompatibility locus, H-2, have been shown to regulate cleft palate formation following glucocorticoid and phenytoin administration to mice. Despite pharmacological similarities between DAZ and phenytoin, comparison of cleft palate frequencies following administration of DAZ to various strains of mice of different H-2 haplotypes indicated that genes associated with the H-2 locus do not regulate DAZ-induced cleft palate in these strains.

Evaluation of the teratogenic effects of Tri-ortho-cresyl phosphate in the Long-Evans hooded rat.

The developmental toxicity of tri-ortho-cresyl phosphate (TOCP) was evaluated in Long-Evans rats. Pregnant rats were treated with 87.5, 175, and 350 mg/kg/day TOCP throughout organogenesis from gestation Days 6 through 18 (Day of sperm = Day 0). The highest dose tested (350 mg/kg) was lethal in 28% of the dams; no maternal deaths or toxicity were observed in the 87.5 or 175 mg/kg dose groups. There were no significant differences noted among the experimental and control groups for preimplantation loss or resorption. Fetal weights for both sexes in the TOCP groups were significantly greater than in the control group; however, no difference among the TOCP groups was observed. Malformation rates were too low to warrant statistical analysis. Numerous soft tissue and skeletal variations were observed in both control and TOCP-treated groups; there were no significant differences in the frequency of variations among the dose groups. The results of this study indicate that TOCP is not teratogenic in the Long-Evans rat.

Differential analgetic actions of amphetamine enantiomers in the mouse: a drug-drug interaction study.

A series of agents were tested for their ability to interact with the analgetic actions of either d-amphetamine (d-AMP) or l-amphetamine (l-AMP), or morphine in rats using the hot plate procedure. The analgetic action of l-AMP was potentiated by morphine and slightly antagonized by naloxone; it was antagonized by clonidine, alpha-MT, yohimbine, fluoxetine and metergoline, but enhanced by PCPA. The analgetic action of morphine was antagonized by both naloxone and PCPA. The analgetic actions of l-AMP and morphine appear to involve different biogenic amine systems.

Analgesic activities of amphetamine isomers.

The analgesic activity of single doses of d- and l-amphetamine was tested in mice using four systems: 65 degrees C hot plate, 55 degrees C hot plate, tail flick, and acetic acid-induced writhing. Although both isomers had some activity, the l-isomer was generally more potent and had a greater duration of activity.

Effects of repetitive doses of lithium in fluid-deprived rats.

Repetitive daily dosage (2.0 mEq/kg) of LiCl to rats maintained on a restricted fluid intake system resulted in cyclical increases and decreases in volume consumed on about a 10 day interval. At a higher dose (4.0 mEq/kg) a similar treatment led to death of the animals in 10 days. Both doses were associated with polyuria and weight loss.

The effects of single doses of alkali metal cations on deprivation-induced fluid consumption by rats.

The adult, male rat, trained to consume daily fluid intake in a deprivation-induced situation, was used to examine the effects of single doses of the monovalent alkali metal cations. Dosages of LiCl (0.25 - 5.0 mEq/kg, i.p.) showed a biphasic action with a threshold at 0.5 mEq/kg and a maximum dipsogenic action of 1 - mEq/kg. In contrast, single doses of NaCl (1.0 - 7.5 mEq/kg, i.p.) showed a continuing dipsogenic effect over the entire dose range. Single doses of KCl (0.25 - 5.0 mEq/kg, i.p.) or RbCl (0.5 - 5.0 mEq/kg, i.p.) had no effect on fluid consumption, while CsCl (0.5 - 2.1 mEq/kg, i.p.) caused decrements in fluid consumption with no clear dose-response relationship.