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W Slikker

Publications and source records attributed to W Slikker.

At least 181 records · Page 10Linked to original sources

The effect of dietary fortification on blood ethanol concentrations, caloric consumption, and weight gain during ethanol consumption in mice.

The objectives of this study were to determine the effects of dietary fortification on caloric consumption, weight gain, and blood ethanol concentration (BEC) in mice consuming ethanol-containing liquid diets. These diets have been used previously in this laboratory for ethanol fetotoxicity studies. To achieve these objectives, mice were adapted to a commonly used liquid mouse diet and randomly allocated to one of two experimental groups. One group received the liquid diet containing 4.1% (w/v) ethanol. The second group received the 4.1% w/v ethanol diet fortified with protein, carbohydrates, fats, vitamins, and minerals. Animals in both groups were monitored for weight changes and caloric intake. On days 5 and 12 of exposure (day 0- initial day), animals were sampled for BEC at 3-hour time intervals throughout a 24-hour period. All animals not previously sampled for BEC were also monitored every 3 hours for dietary intake. The animals receiving the fortified diet had a greater caloric consumption and weight gain during the 13 days of treatment than did the nonfortified diet animals. Blood ethanol levels determined on both sample days were significantly lower in the fortified diet group than in the nonfortified group. BEC values in both groups were significantly correlated with ethanol consumption during the previous 6-hour period. In conclusion, dietary modification could significantly alter the outcome of ethanol toxicity studies both by direct effects on growth and caloric/nutrient intake and by altering blood ethanol levels achieved during exposure.

Alcohol Drinking↗

Comparison of the transplacental pharmacokinetics of cortisol and triamcinolone acetonide in the rhesus monkey.

The late gestational age rhesus monkey was used to study the transplacental pharmacokinetics of radiolabeled triamcinolone acetonide (TAC) and cortisol. Tritiated-TAC and [14C]cortisol were administered simultaneously via the maternal radial vein were administered simultaneously via the maternal radial vein and blood samples were serially drawn from catheters implanted in both the maternal femoral artery and fetal umbilical vein and artery. High-performance liquid chromatography of the processed blood samples revealed that from 93 to 100% of the 3H in the fetal circulation was parent TAC, whereas only 14 to 49% of the 14C was cortisol during the 40-min period after dose administration. Fetal tissue samples taken at 3 hr after dose administration showed that 75 to 96% of the 3H present was TAC, whereas no cortisol was observed. TAC demonstrated dose-independent kinetics. Samples collected from the umbilical vein of the in situ placenta after fetectomy revealed that cortisol was extensively converted to cortisone by the placenta, whereas TAC was refractory to placental metabolism. This placental conversion of cortisol to cortisone and the further metabolism and conjugation of cortisol by the fetoplacental unit resulted in a fetal to maternal plasma cortisol ratio of 0.2. In contrast, the lack of placental or fetoplacental metabolism of TAC resulted in a fetal to maternal plasma TAC ratio of 0.6.

Animals↗

Placental transfer and metabolism of 17 alpha-ethynylestradiol-17 beta and estradiol-17 beta in the rhesus monkey.

The synthetic estrogen component of many oral contraceptives, 17 alpha-ethynylestradiol-17 beta (EE2) and the naturally occurring estrogen, estradiol-17 beta (E2) were studied in four pregnant rhesus monkeys (71% term: 108-121 days gestational age). Under ketamine anesthesia, catheters were implanted in the maternal femoral artery and fetal interplacental artery. After simultaneous i.v. administration of [3H]EE2-[14C]E2 to the maternal animal, serial blood samples were drawn from both mother and fetus. The estrogens and metabolites were identified and quantified by the comigration of radioactivity with reference standards in several high-performance liquid chromatography systems and subsequent selective enzyme hydrolysis of the conjugates. Only estrone (E1), E1 sulfate, EE2 and EE2-3 sulfate were observed in the fetal circulation, whereas the major radiolabeled compounds in the maternal circulation consisted of the above plus E2, E1 glucuronide and EE2-3 glucuronide. In order to determine whether the placenta could convert E2 to its metabolite E1, the placentas of three term rhesus monkeys were perfused in situ via the umbilical artery with 120 ml (15 ml/min) of Hanks' balanced salt solution (pH 7.4) containing [3H]E2. High-performance liquid chromatographic analysis of umbilical vein samples revealed that 96% of the E2 was metabolized to E1. These studies indicate that the placenta can metabolize the potent naturally occurring estrogen E2 to the less potent E1. In contrast, the synthetic estrogen EE2 does not undergo this placental metabolic conversion and thus enters the fetal circulation as the parent compound.

Animals↗

Steroid D-ring glucuronides: characterization of a new class of cholestatic agents in the rat.

Estriol-17 beta(beta-D-glucuronide) (E317G), estriol-16 alpha(beta-D-glucuronide) (E316G) and testosterone-17 beta(beta-D-glucuronide) (TG) produced an immediate, reversible and dose-dependent inhibition of bile flow after their i.v. administration in the rat. Within 15 to 30 min of their administration, bile flow was inhibited by 50% at doses of 13.2, 20.0 and 31.6 mumol/kg of E317G, TG and E316G, respectively. A plot of the logarithm of the dose of each agent vs. the maximal percentage of inhibition of bile flow yielded straight lines which were parallel. E317G, TG and E316G were 0.68, 0.40 and 0.29 times as potent, respectively, as estradiol-17 beta(beta-D-glucuronide), a previously identified cholestatic steroid glucuronide. Maximal inhibition of bile acid secretory rate was similar to that of bile flow for all three agents. Calculation of the bile acid vs. bile flow regression lines indicated substantial inhibition of bile acid independent flow by E317G and TG but only slight inhibition by E316G. In contrast, estriol-3(beta-D-glucuronide) at doses of 11 and 33 mumol/kg increased bile flow. After an i.v. dose (44 mumol/kg) of [3H]E316G, 53% of the dose was recovered in the bile in 3 hr. Unchanged [3H]E316G and a minor metabolite tentatively identified as [3H]estriol-3-sulfate-16 alpha(beta-D-glucuronide) were the predominant compounds recovered in the bile. These data present evidence for a new class of cholestatic compounds, the steroid D-ring glucuronides, and suggest a means by which endogenous or exogenous steroids may produce hepatobiliary dysfunction.

Animals↗

Transplacental pharmacokinetics and metabolism of diethylstilbestrol and 17 beta-estradiol in the pregnant rhesus monkey.

Experiments were performed to describe and compare the transplacental pharmacokinetics of the teratogen and transplacental carcinogen, diethylstilbestrol [4,4'-dihydroxy-alpha,alpha'-diethyl-trans, cis-stilbene (DES)], and the endogenous estrogen, 17 beta-estradiol (E2). Timed mated pregnant rhesus monkeys (119-137 days gestation) were anesthetized, and catheters were implanted in the maternal femoral artery and the interplacental fetal artery and vein using an extraamniotic technique. Single doses of either radiolabeled DES or E2 were administered via the maternal radial vein. Maternal plasma levels of labeled compound decreased rapidly after dose administration. Fetal plasma levels of radioactivity derived from either DES or E2 increased rapidly and then plateaued higher than maternal levels 1--2 h after dose administration. High pressure liquid chromatography of maternal and fetal plasma samples revealed both parent and conjugated metabolites of DES and E2. The principal metabolite of DES (DES monglucuronide) was radiolabeled and given to either the mother or the fetus iv. There was no significant cross-over of this metabolite in either direction. It is concluded that DES crosses the primate placenta in an unconjugated form and that, based on total radioactivity, placental transfer is similar to that of E2. The extensive fetoplacental metabolism of DES appears to be responsible for the greater half-life of this agent and its metabolites in the fetal circulation compared with the maternal circulation.

Animals↗

Characterization of cholestasis induced by estradiol-17 beta-D-glucuronide in the rat.

Estradiol-17 beta-D-glucuronide induced an immediate, profound and reversible inhibition of bile flow after its i.v. administration in the rat. The degree of cholestasis was dose-dependent in the range of 8.5 to 21 mumol/kg i.v. A dose of 11 mumol/kg i.v. inhibited bile flow and bile acid secretory rate 65 to 70% within 15 to 30 min of its administration; bile flow and bile acid secretion had returned to near control values within 3 hr. Linear regression analysis of the relationship between bile flow and bile acid secretion indicated a substantial decrease in bile acid independent flow. In contrast, neither estradiol-17 beta, estradiol-3-glucuronide nor estradiol-3-sulfate-17 beta-D-glucuronide at an equimolar dose had any inhibitory effect on these parameters. After a dose of [3H]estradiol-17 beta-D-glucuronide, 79% of the administered radioactivity was excreted in the bile in 3 hr. Estradiol-3-sulfate-17 beta-D-glucuronide was tentatively identified as the predominant biliary metabolite with estradiol-17 beta-D-glucuronide also present in substantial amounts. These data indicate that estradiol-17 beta-D-glucuronide is toxicologically active and suggest the possibility that this estrogen metabolite may induce hepatic pathology in vivo.

Animals↗

Interactive effects of prenatal cocaine and nicotine exposure on maternal toxicity, postnatal development and behavior in the rat.

Two experiments were performed to investigate the interactive effects of prenatal coadministration of cocaine hydrochloride (C) and nicotine tartrate (N). Experiment I was designed to determine doses of C and N that could be coadministered without altering maternal gestational parameters and/or fetal viability. Exposure of Sprague-Dawley rats to combined high-dose C (20 mg/kg) and high-dose N (5.0 mg/kg) on gestation days 8-21 was not more toxic to dam or fetus that that of exposure to C alone. Experiment II investigated pregnancy outcome, postnatal development, and behavior of the offspring following drug exposure to either high-dose cocaine (20 mg/kg: CS), high-dose nicotine (5.0 mg/kg: NS), or both (NC) on gestation days 8-21. N was administered by osmotic minipump and C by sc injection. Saline-injected dams, fitted with saline-fitted pumps (SS), and untreated dams, pair-fed (PF) to NC females, served as controls. Alterations in maternal variables were limited to a 10-15% decrease in food consumption in NC and CS groups. Pregnancy outcome and birth statistics were unaffected by prenatal treatment, as was offspring body weight during the first four postnatal weeks. However, the development of surface righting was delayed inC CS pups, and only CS offspring were underresponsive to the stimulatory effects of dopamine agonists on activity and stereotypy. Behavioral responses to N challenge were similar in all groups. In addition, only CS offspring showed altered behavioral responses in a spontaneous alternation task. Treatment effects on dopamine D1 and D2 binding in the caudate nucleus were not observed. The combination of N and C did not exacerbate any of the behavioral changes seen in CS offspring. These results support the hypothesis that C is a behavioral teratogen in rodents, and suggest that in the present model, nicotine can mitigate some of the consequences of in utero exposure to cocaine.

Aging↗

Pharmacokinetics of cocaine in pregnant and nonpregnant rhesus monkeys.

To determine pharmacokinetic parameters for cocaine in rhesus monkey plasma, samples were taken over several hours after i.m. administration of cocaine plus a tritiated cocaine tracer. Cocaine and its metabolites, benzoylecgonine and norcocaine, were isolated via HPLC and quantitated using liquid scintillation spectrometry. Pregnant subjects were dosed with cocaine at 0.3 (n = 3) or 1.0 (n = 3) mg/kg, whereas nonpregnant female subjects were dosed with 1.0 mg/kg (n = 3). For the pregnant subjects, pharmacokinetic studies were conducted on about gestational day 125 and areas under the concentration versus time curve (AUCs, ng/mL x h) were 64 +/- 26 (+/- SEM) and 143 +/- 12; half-lives (t1/2s, h) were 1.9 +/- 0.6 and 1.1 +/- 0.1 after 0.3 and 1.0 mg/kg i.m., respectively. For nonpregnant subjects dosed acutely with 1.0 mg/kg, the AUC was 262 +/- 63 and the t1/2 was 1.4 +/- 0.3. There appear to be few differences in the pharmacokinetic parameters of cocaine and benzoylecgonine between pregnant and nonpregnant monkeys in this study.

Animals↗

Postnatal function following prenatal reserpine exposure in rats: neurobehavioral toxicity.

Behavioral and neurochemical analyses were conducted on preweanling CD rats prenatally exposed to either 0, 0.375 or 0.750 mg/kg/day reserpine SC on gestation days 12-15. Offspring body weights were taken on test days, and pups were tested for negative geotaxis responding on postnatal day 8, developmental activity on days 12, 16 and 20, and auditory startle habituation on day 19 or 20. In addition, brains were removed from culled pups on day 1, 1 male and 1 female/litter on day 8, and animals tested for activity on day 21. Neurochemical assays were performed on whole brains from 1- and 8-day-old pups, and on caudate nucleus, frontal cortex and hippocampus of day 21 rats. Treatment resulted in dose-related decreases in maternal weight gain over gestation and mean pup weight at birth. Changes in the normal developmental activity pattern were both sex and dose dependent in treated rats. In auditory startle habituation experiments, rats exhibited a dose-related decrease in response amplitude and rate of habituation. In the day 21 females, caudate nucleus dopamine (DA) and serotonin (5-HT) concentrations and DA-receptor binding were decreased in a dose-dependent manner. Males showed less dramatic, but similar trends in caudate changes. However, hippocampal 5-HT and 5-HT receptor binding were significantly reduced only in females. Thus, sex-related behavioral alterations were accompanied by sex-related neurochemical changes, and females generally were more affected than males by prenatal reserpine treatment. The significant decrease in activity and auditory startle amplitude in the females is consistent with the suggested down regulation of the DA system in regional brain areas.

Animals↗

The disposition of 14C-trimethyltin in the pregnant rat and fetus.

Trimethyltin (TMT) is a potent neurotoxicant. For unknown reasons, age at exposure to TMT may dramatically influence the severity of TMT-induced neuropathology. We have demonstrated previously that radiolabel derived from [14C]-TMT given to pregnant dams on gestational day (GD) 17 is found in fetal brain and blood. The present study was designed to determine the distribution of radiolabel derived from [14C]-TMT to brain and other tissue in fetuses from dams dosed on either GD 12 or 17 with 7.0 mg/kg TMT chloride. Radioactivity in GD 12 and GD 17 maternal whole blood peaked 1 hour after IP treatment. Whole blood elimination half-lives were 12-15 days. Peak radiolabel concentrations in GD 12 maternal and fetal brain were only 11-30% of those from GD 17 animals, however, peak fetal brain concentrations of radiolabel were not different from their respective maternal brain concentrations. Radiolabel concentrations in liver, kidney, and adrenal of GD 17 dams were higher than those in corresponding GD 12 tissues. Combined urinary and fecal elimination of radiolabel for two weeks after dosing accounted for 31 and 22% of the GD 12 and 17 doses, respectively. It appears that gestational age influences the distribution and elimination of TMT in the rat.

Aging↗

Repeated measures designs in behavioral toxicology: application to chronic marijuana smoke exposure.

This paper discusses the application of repeated measures methods in the statistical analysis of an experiment in behavioral toxicology. The chronic marijuana smoke exposure study conducted at the National Center for Toxicological Research is used for an example of the types of problems that one encounters in analyzing these types of studies. In particular, the standard univariate analysis most frequently used for repeated measures analyses has some very restrictive assumptions on the form of the covariance matrices. These assumptions are not met in the example discussed and are rarely met in many other problems. Other possible models for analyzing repeated measures when these assumptions are not met are presented and discussed. Other problems specific to the chronic marijuana smoke exposure study that may occur in similar type studies are presented. These include pooling the experimental units into groups with comparable baselines, choosing a function of the measures to be analyzed, dealing with a large data set with many observation times and missing data, unequal group sizes and different designs for different subsets of the experimental animals. The standard univariate repeated measures analysis was chosen to analyze the data even though the violations of the covariance assumptions may lead to finding differences that do not exist (Type I or false-positive errors), since the other methods presented also had covariance assumptions that were not met or had low power. Use of Bonferroni-type multiple comparisons on the single degree of freedom contrasts of interest hopefully reduced the chances of these false-positive results.

Analysis of Variance↗

Behavioral and neurochemical effects of prenatal methylenedioxymethamphetamine (MDMA) exposure in rats.

MDMA is a hallucinogenic drug that is used by the general public as a recreational drug of abuse. The neurobehavioral consequences of prenatal MDMA exposure are unknown. Groups of pregnant rats were gavaged with 0, 2.5, or 10 mg/kg MDMA during gestation on alternate gestational days 6-18. Gestational duration, litter size, neonatal birth weights and physical appearance at birth were unaffected by MDMA treatments. Pregnancy weight gain was significantly reduced by MDMA treatment. Progeny growth, maturational parameters (eye opening and incisor eruption times), surface righting reflex, swimming performance, forelimb grip strength, milk-induced behaviors, passive avoidance behavior, figure-8 maze activity over 48 hours, the density of brain serotonin (5-HT) uptake sites, and brain 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels were unaffected by MDMA treatments. Olfactory discrimination on postnatal days (PND) 9-11 was enhanced in both male and female MDMA-treated progeny, while negative geotaxis (PND 7-10) was delayed in female pups. In contrast to progeny, MDMA caused dose-dependent decreases in 5-HT and 5-HIAA levels in discrete brain areas of the dam. It is concluded that prenatal exposure to MDMA at the levels used here produces only subtle behavioral alterations in developing rats. The dam is more at risk for MDMA-induced 5-HT depletion than is the conceptus.

3,4-Methylenedioxyamphetamine↗