PubMed Health⌕ Search

Biomedical subjects

C V Vorhees

Publications and source records attributed to C V Vorhees.

At least 19 recordsLinked to original sources
PubMed1992

Preliminary evidence for methamphetamine-induced behavioral and ocular effects in rat offspring following exposure during early organogenesis.

Gravid Sprague-Dawley CD (VAF) rats received 50 mg/kg (d,l)-methamphetamine (MA) HCl (expressed as free base, N = 15) or distilled water (N = 6) by SC injection x 2/day in a 3 ml/kg volume on embryonic (E) days 7-12. Control rats were pair-fed to MA-exposed dams on days E7-18. No control dams failed to deliver; however, of 15 MA-exposed dams 4 did not deliver (2 died and 2 had completely resorbed litters). One additional MA litter had all the offspring die shortly after birth. There was no difference between groups on offspring postnatal (P) body weight. The offspring exposed prenatally to MA had significantly lower olfactory orientation scores (P9, 11, 13) to their home cage scent. In a test of early activity (P10, 12, 14) the MA-exposed progeny were marginally less active than controls. MA-exposed offspring exhibited hyperreactivity and marginally shortened response latency on a test of acoustic startle (P27). Motor activity showed no differential response in MA treated or control offspring to MA (P63) or fluoxetine challenge (P70). However, the MA offspring were more active than controls with respect to central and side activity during the second week of testing. No group differences were found for performance in a straight swimming channel or on the number of errors committed or latency to escape in a complex (Cincinnati) water maze (P84). Prenatal exposure to MA also induced eye defects (i.e., anophthalmia, microphthalmia and folded retina) in 16.7% of the progeny. However, MA did not effect hippocampal or neostriatal monoamine levels when measured on P28.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1991

Comparison of the behavioral teratogenic potential of phenytoin, mephenytoin, ethotoin, and hydantoin in rats.

Pregnant Sprague-Dawley CD rats were orally administered either phenytoin (PHT, 200 mg/kg), mephenytoin (MPH, 100 mg/kg), ethotoin (ETH, 600 mg/kg), hydantoin (HYD, 1,200 mg/kg) or vehicle (propylene glycol) on days 7-18 of gestation. Mean (+/- S.E.) maternal serum concentrations of PHT, MPH, and ETH 1 hour after dosing on gestational day 18 were 16.0 +/- 3.3, 10.7 +/- 3.0, and 65.2 +/- 10.45, respectively, and free fractions were 16%, 18%, and 11% respectively. The free fraction for PHT is similar, but was lower for both MPH and ETH than that seen in humans. Preweaning mortality for PHT, MPH, ETH, HYD, and controls was 25%, 6.3%, 12.5%, 2.0% and 0.8%, respectively. The MPH and ETH-exposed animals weighed approximately 6.6% less than controls throughout the study; the other groups did not differ significantly. PHT offspring showed increased early locomotor activity. Only PHT-exposed animals (27%) exhibited abnormal circling behavior after weaning. PHT-circlers accounted for higher levels of activity in an open-field test and for longer straight channel swimming times. PHT-circlers and noncirclers differed from one another and controls on performance of a complex (Cincinnati) maze and on the development of the air-righting reflex. Offspring prenatally exposed to MPH showed an early delay in air-righting. ETH and HYD offspring were not consistently different from controls in behavior. The data suggest the following ordinal relationship among the drugs for behavioral teratogenesis: PHT much greater than MPH greater than ETH congruent to HYD congruent to CON. The effects of PHT are consistent with previous findings. Data on the other drugs suggest that other hydantoins do not possess the behavioral teratogenic efficacy of PHT and that PHT may be unique in its effects on CNS development.

Animals↗
PubMed1991

Lack of teratogenicity of trans-2-ene-valproic acid compared to valproic acid in rats.

The teratogenicity of trans-2-ene-valproic acid (300 and 400 mg/kg) was compared with that of valproic acid (VPA; 300 mg/kg) and controls (corn oil) administered by gavage to Sprague-Dawley CD rats on embryonic (E) days 7-18. At the 300 mg/kg dose, trans-2-ene-VPA produced no change in maternal weight, number of implantations, proportion of resorptions, proportion of malformations, or fetal weight. By contrast, the same dose of VPA (300 mg/kg) reduced maternal weight during gestation, increased malformations (12.0% vs. 0.7% in controls), and reduced fetal body weight by 25.1%. An even higher dose of trans-2-ene-VPA (400 mg/kg) produced a reduction in maternal body weight during treatment and reduced fetal body weight (by 7.9%), but did not increase resorptions or malformations in the fetuses. On day E18, maternal serum drug concentrations of VPA were higher in the VPA-treated group compared with those of trans-2-ene-VPA in the trans-2-ene-VPA-treated groups at 1 hr posttreatment. At 6 hr posttreatment the reverse was seen. trans-2-ene-VPA may be absorbed more rapidly and distributed differently than VPA. Overall, the data support the view that trans-2-ene-VPA at equal or higher doses than VPA is not teratogenic in rats.

Animals↗
PubMed1991

A teratologic evaluation of continuous-wave, daily ultrasound exposure in unanesthetized pregnant rats.

Pregnant Sprague-Dawley rats were trained to remain immobile when placed in water in an ultrasound exposure tank and exposed to 0, 0.1, 2.0, or 30.0 W/cm2 ISPTA (spatial peak, temporal average), 3.0-MHz continuous wave (cw) ultrasound on embryonic (E) days 4-19 for approximately 15 min/day. On E20 fetuses were removed; weighed; examined for external, skeletal, and visceral malformations; and uteri were examined for resorptions. Analyses revealed no increase in pre-implantation loss and no effects on maternal body weight, food, or water consumption. No increase in skeletal or visceral malformations was found, in fact exposed groups had a lower incidence of defects than controls. A significant increase in resorptions in the lowest exposure group (0.1 W/cm2) was obtained, but the effect was isolated, non-dose dependent and not credible as a treatment-related effect. No reduction in fetal weight was obtained, in fact the lowest (0.1-W/cm2) and middle (2.0-W/cm2) exposure level groups weighed slightly more than controls. The immobility procedure succeeded in avoiding anesthetization or forced restraint of the dams, thereby eliminating these factors as potential confounders. The results demonstrated that in unanesthetized, unrestrained rats in utero exposure to incident intensities of ultrasound of up to 30.0 W/cm2 cw ultrasound (or estimated internal exposures of 4-21 W/cm2, depending on body orientation to the incident beam) produced no evidence of embryotoxicity based on fetal necropsy data.

Analysis of Variance↗
PubMed1990

Teratogenicity of carbamazepine in rats.

The teratogenicity of carbamazepine (CBZ) was investigated in Sprague-Dawley CD rats at doses of 0, 200, 400, and 600 mg/kg administered by gavage in corn oil on days 7-18 of gestation in a dosage volume of 2 ml/kg. The CBZ-600 dose was maternally toxic in that dams in this group weighed 30.6% less than controls by E20. This group had significantly increased resorptions, reduced live fetal weight (51.6% less than controls), and increased skeletal and visceral abnormalities. The CBZ-400 dose also significantly reduced maternal weight gain during gestation to 26.6% less than controls by E20. No significant increase in resorptions occurred in this group; live fetuses weighted 42.9% less than controls and showed an increase in visceral, but not skeletal, abnormalities. The CBZ-200 dose did not significantly affect maternal weight gain or increase resorptions or fetal abnormalities but did reduce fetal body weight (20.3% less than controls). Maternal serum total CBZ concentrations 1 hr after the final dose were 22.9, 27.9, and 34.4 micrograms/ml for the 200, 400, and 600 mg/kg groups, respectively. These levels were little changed 6 h post-treatment. CBZ was 65-70% serum protein bound across dose groups. Human therapeutic levels of CBZ are 4-12 micrograms/ml and the drug is typically 80% serum protein bound. This suggests that abnormalities in rats occur at concentrations well above the human therapeutic range. However, a no-effect level was not found for fetal body weight. Further experiments will be required to determine how much lower doses will need to be in order to find a no-effect level for fetal body weight. Nevertheless, the present data suggest that CBZ is not potent at inducing malformations in rats.

Animals↗
PubMed1990

Prenatal phenytoin exposure decreases neuronal membrane order in rat offspring hippocampus.

Pregnant Sprague-Dawley CD rats were administered 0 or 200 mg/kg of phenytoin by gavage on days 7-18 of gestation, with controls pair-fed to the phenytoin exposed dams. At birth, litter sizes were standardized to 10, balancing for sex, and were reared by their biological dams until either day 3 or 28. At each of these ages half of the litters from each group were used to determine synaptic plasma membrane order in selected brain regions (cerebellum, cortex, hippocampus) by fluorescence polarization using the probe 1,6-diphenyl-1,3,5-hexatriene (DPH). No significant differences in membrane anisotropy were noted in 3-day-old phenytoin offspring, but a reduction in anisotropy in 28-day-old phenytoin offspring hippocampal regions was observed. The effect was specific in that no changes were found in the cerebellum or cortex at this age. The magnitude of the change corresponded to an approximately 3-5 degrees C increase in temperature and to changes produced by other known membrane disordering agents, such as ethanol. The data, together with previous findings of memory impairments in phenytoin offspring, support an association between the hippocampal membrane disordering effect and functional impairments produced by prenatal phenytoin exposure.

Aging↗
PubMed1990

Effects of exposure period and nutrition on the developmental neurotoxicity of anticonvulsants in rats: short and long-term effects.

The results of three experiments on the functional neuroteratogenicity of anticonvulsants in rats are presented. Two of the experiments have been reported previously and are reviewed here, while the third experiment is presented here for the first time. The first experiment examined prenatal phenytoin (200 mg/kg), trimethadione (250 mg/kg), and phenobarbital (80 mg/kg) for critical period effects by exposing separate groups of rats to the drugs or to vehicle on embryonic (E) days 7-10, 11-14, or 15-18. Phenytoin produced effects in the E11-14 offspring, but few effects in the E15-18 offspring, and almost no effects in the E7-10 offspring. Phenytoin's E11-14 effects in the offspring were increased pivoting, delayed swimming ontogeny, hyperactivity, impaired water maze learning, and impaired passive avoidance retention. The second experiment looked for phenytoin's long-term effects. Phenytoin-exposed offspring administered 200 mg/kg on E7-18 exhibited numerous postnatal dysfunctions, including water maze learning deficits that persisted to beyond 501 days of age. The learning deficits were neither increased nor decreased in severity at this age compared to those seen in littermates tested at 50 days of age. The third experiment assessed the role of manganese in counteracting phenytoin-induced postnatal dysfunction and the possible confounding effects of maternal undernutrition associated with the drug's administration. The typical pattern of phenytoin-induced behavioral effects was observed in rat offspring. The results demonstrated that undernutrition was not a confound, since pair-feeding and pair-watering controls did not diminish the phenytoin-induced dysfunction in the offspring. Also, administration of a manganese supplementation (200 ppm in the drinking water) during gestation did not significantly alter the pattern of phenytoin-induced postnatal effects.

Animal Nutritional Physiological Phenomena↗
PubMed1989

Branched chain amino acids improve complex maze learning in rat offspring prenatally exposed to hyperphenylalaninemia: implications for maternal phenylketonuria.

Maternal phenylketonuria results in a high incidence of children born who are mentally retarded. It has been suggested that blood-brain-barrier transport of phenylalanine may be reduced by competitive inhibition of transporter uptake by supplemental administration of other large neutral amino acids. We hypothesized that large neutral amino acids might also be effective at improving the outcome of fetuses exposed to hyperphenylalaninemia in utero. If correct, sparing of embryonic CNS development might be possible. Pregnant rats were given a hyperphenylalaninemic diet alone or the same diet supplemented with a combination of valine, isoleucine, and leucine. As adults, the progeny exposed in utero to hyperphenylalaninemia showed characteristic learning deficits in a complex maze, while those exposed in utero to hyperphenylalaninemia combined with valine, isoleucine, and leucine showed no deficits in maze acquisition. The valine, isoleucine, and leucine supplement may show promise as a treatment for intrauterinely acquired mental deficiency associated with maternal phenylketonuria.

Amino Acids, Branched-Chain↗
PubMed1988

Effects of short-term prenatal alcohol exposure on neuronal membrane order in rats.

Long-Evans rat dams were treated with ethanol (4 g/kg, twice daily) by gavage on gestational days 10-14. This dosage schedule has been shown to produce significant behavioral and ponderal teratogenicity. Pair-fed dams were gavaged with isocaloric amounts of sucrose. All offspring were reared by untreated, surrogate dams. Pups were sacrificed on days 3 and 28, and whole brain neuronal plasma membranes were prepared for analysis by a fluorescence polarization technique using 1,6-diphenyl-1,3,5-hexatriene as the membrane probe. On day 3, steady-state anisotropy was significantly decreased in the ethanol-treated pups. Arrhenius plots revealed that this difference was associated with a change on both membrane entropy and enthalpy. By day 28, the differences between groups disappeared. These data would be consistent with the view that the brief gestational ethanol exposure delays neuronal maturation.

Animals↗
PubMed1987

Teratogenicity and developmental toxicity of valproic acid in rats.

The teratogenicity and developmental toxicity of valproic acid (VPA) was investigated in Sprague-Dawley CD rats at doses of 0, 150, 200, 300, 400, and 600 mg/kg administered by gavage on days 7-18 of gestation. The VPA-600 dose was maternally toxic, causing death in two of four dams. This dose produced 100% embryonic resorption. The VPA-400 dose was maternally toxic in as much as maternal weight gain was reduced, but no deaths occurred. At this dose five of fifteen litters were completely resorbed, and 52% of all embryos were resorbed. Among survivors, 49% were malformed (68% having skeletal defects and 41% visceral defects). Fetal weight was reduced by 43% in this group. Most of the defects were ectrodactyly, hydronephrosis, cardiovascular defects, hypoplastic bladder, rib and vertebral defects, and other defects of the limbs and tail. The VPA-300 dose (nine litters) produced fewer defects, larger fetuses, and no increase in resorptions. The defects at this dose were primarily cariovascular, rib, and vertebral. The VPA-200 dose (12 litters) produced no reduction in fetal weight, no increase in resorptions, and few defects. The defects noted were hydronephrosis, cardiovascular abnormalities, and rib defects, primarily wavy ribs. Additional litters were prepared using doses of 150 and 200 mg/kg and were allowed to deliver and grow until 70 days. These doses produced no reduction in maternal weight gain, no reduction in litter size, birth weight, or sex ratio of the offspring. These doses produced no reduction in offspring weight to day 70, no increase in mortality, and only rare cases (two offspring of each dose) of tail defects.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗
PubMed1987

Fetal hydantoin syndrome in rats: dose-effect relationships of prenatal phenytoin on postnatal development and behavior.

Sprague-Dawley rats were gavaged once daily on days 7-18 of gestation with, 100, 150, or 200 mg/kg of phenytoin. Only the highest dose of phenytoin decreased maternal weight during gestation or increased offspring mortality up to weaning. Offspring were evaluated for activity prior to weaning (pivoting and photocell) and afterwards (figure 8, open-field, and hole-board), dynamic righting development, maze learning (Biel maze), and visual discrimination (Y maze), and for startle reaction to both auditory and tactile stimuli. The highest dose of phenytoin produced increased activity on all tests of activity, delayed dynamic righting development, impaired Biel maze and Y-maze learning, and inhibited tactile startle responses. The two lower doses of phenytoin generally showed a dose-effect relationship with values on most measures intermediate between values for controls and for the highest-dose group. Dose-effect relationships were most evident on measures of early activity (both tests), dynamic righting, and Biel maze learning, whereas only trends were evident on measures of later activity, Y maze, and startle. A dose-related rotational defect was found in a minority of phenytoin offspring, and although these individuals contributed to the behavioral abnormalities observed, they in no instance accounted for the overall pattern of effects seen in the phenytoin offspring. Maternal plasma phenytoin levels at the end of treatment were dose-related. Offspring showed no effects on postnatal growth, total brain weight, or brain protein content as adults. The data support the view that phenytoin is a potent behavioral teratogen at doses well below those causing any evidence of gross teratogenicity or embryotoxicity.

Animals↗
PubMed1987

Behavioral teratogenicity of valproic acid: selective effects on behavior after prenatal exposure to rats.

Pregnant Sprague-Dawley rats were treated with 0, 150 or 200 mg/kg valproic acid by gavage (VPA) on days 7-18 of gestation. These doses produced no maternal toxicity, reproductive effects or effects on offspring growth and survival. Maternal plasma VPA peak levels averaged 99 and 134 micrograms/ml 1 h after the last treatment, values approximating human therapeutic levels. VPA offspring tested after weaning exhibited reduced open-field central, but not peripheral, activity and reduced hole-board horizontal, but not vertical, activity. No activity differences were found in a figure-8 test or a preweaning activity test. The VPA offspring also showed lengthened straight channel swimming times, increased swimming maze errors, but only among the females, while producing no differences in maze times. VPA offspring exhibited reduced spontaneous alternation frequency and reduced startle responding to both auditory and tactile (air-puff) stimuli. The effects of VPA were dose dependent in some cases (straight channel swimming and water maze errors), or the effect was seen only in the high-dose group (open-field, hole-board, spontaneous alternation, startle). The conclusion was reached that prenatal VPA is behaviorally teratogenic in rats at relevant maternal blood concentrations and at non-malforming doses.

Animals↗