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Biomedical subjects

J Buelke-Sam

Publications and source records attributed to J Buelke-Sam.

29 records · Page 2Linked to original sources
PubMedDate not supplied

The selective estrogen receptor modulator, raloxifene: reproductive assessments following preimplantation exposure in mated female rats.

Raloxifene is a nonsteroidal, selective estrogen receptor modulator being developed for postmenopausal osteoporosis. As part of an integrated reproductive toxicity assessment, two studies were conducted in which raloxifene was administered orally to CD rats during Gestation Days (GD) 0 through 5. In each study, animals received daily raloxifene doses of 0, 0.1, 1, or 10 mg/kg. In Study 1, GD 20 evaluations of maternal reproductive parameters identified dose-related increases in pre- and postimplantation loss, reductions in the numbers of corpora lutea and live conceptuses, and reduced fetal weight. The low fetal weights were consistent with an extent of morphologic development that corresponded to developmental ages up to 8 d younger than GD 20. Study 2 characterized the potential impact of this disrupted and apparently delayed implantation on gestation length, parturition, and progeny viability. Dams were allowed to deliver and rear their offspring through Postpartum Day 21. Gestation lengths were extended up to 1 week, and litter sizes were reduced in a dose-dependent manner. Nevertheless, parturition occurred normally and pup morphology, survival, and physical and behavioral development were unaffected.

Animals↗
PubMedDate not supplied

Collaborative Behavioral Teratology Study: background and overview.

Organization of the Collaborative Behavioral Teratology Study began in 1978 because of concern about potential postnatal dysfunction following developmental chemical exposure. The study design was focused primarily on the evaluation of reliability of behavioral testing methods, the sensitivity of these methods to alterations produced by prenatal chemical exposure, and the effects of litter, sex of the animals and prior testing experience on behavioral responses. The test methods and chemicals used were selected from the literature available at that time using certain specific criteria. NCTR served as the pilot testing laboratory, and five additional laboratories participated in the study, using a standardized protocol, testing equipment and procedures. The results of the study are presented in other papers in this issue, and give ample evidence for consistency of the behavioral measures used within and between studies, and within and between laboratories. The issues of sensitivity, sex, litter and prior testing experience were addressed within the framework of this study design, but further systematic evaluation of chemicals and methods is encouraged, as exemplified by the invited papers in this issue.

Behavior↗
PubMedDate not supplied

Collaborative Behavioral Teratology Study: preliminary research.

Prior to the beginning of the Collaborative Behavioral Teratology Study (CBTS), extensive preliminary experiments were conducted. Several experiments were conducted to permit the selection and verification of dosage levels of d-amphetamine sulfate and methylmercuric chloride to be used in the CBTS. These studies included evaluations of any teratogenic effects produced by selected concentrations of the chemicals, the potential pathology produced in the dams and offspring, and the postnatal behavioral consequences of the prenatal exposures. This preliminary research allowed the determination of the most appropriate experimental design for the CBTS, verified the practicality of the schedule of work, assured that all necessary procedural details were specified, and provided a database for the determination of the most appropriate statistical techniques for the analyses of the data. This paper presents the details and results of the preliminary research performed prior to beginning the CBTS.

Animals↗
PubMedDate not supplied

Collaborative Behavioral Teratology Study: protocol design and testing procedures.

This paper presents background information on the methods used in the Collaborative Behavioral Teratology Study (CBTS), the rationale behind the experimental design, and the design and specific procedures used in the CBTS. Each of the following methods is discussed: negative geotaxis, olfactory discrimination, auditory startle habituation, one-hour activity in the figure-8 maze, visual discrimination learning, 23-hour activity in the figure-8 maze, and amphetamine-stimulated activity. The CBTS was designed to determine the intra- and interlaboratory reliability of these test methods and the detection sensitivity of each method, as well as to determine the importance of several major variables (early test experience, gender, litter). The important design features which permitted these evaluations are discussed. Each laboratory conducted two independent experiments: one using d-amphetamine sulfate as the test agent and one using methylmercuric chloride. Other than the use of different agents and dosing regimens in the two studies, all other characteristics of experimental design were identical. Each study was conducted in four replicates with 4 litters/each of 4 treatment groups/replicate. The replicate design was an important feature which permitted reliability of the tests to be addressed under conditions in which several other sources of variation in responding could be identified and accounted for in the model. Other methods by which optimal testing conditions were implemented in the participating laboratories included the "blind" testing of all subjects in specific orders which were counterbalanced for treatment group, time of day, and the apparatus in which the animals were placed.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamine↗
PubMedDate not supplied

Collaborative Behavioral Teratology Study: statistical approach.

The design of the Collaborative Behavioral Teratology Study included six laboratories and two test compounds, d-amphetamine sulfate and methylmercuric chloride. For each lab-compound combination, there were four doses, four replicates (reps), four litters within each dose-rep combination, and eight pups per litter (four males and four females). Two males and two females per litter had early experience testing, the other pups in each litter were naive until day 21 of age. A repeated measures analysis of variance was used to analyze the data. The three major questions addressed were reliability, sensitivity, and effects of early testing experience. The question of litter or pup being the appropriate experimental unit also is discussed. An explanation of interactions and an example of sample size calculations are included.

Amphetamine↗
PubMedDate not supplied

Collaborative Behavioral Teratology Study: results.

Behavioral measures used in the Collaborative Behavioral Teratology Study (CBTS) were negative geotaxis (PNDs 7-10), olfactory discrimination (PNDs 9-11), auditory startle habituation (PNDs 18-19 and 57-58), 1-hr activity (PNDs 21, 60, 100 and 120), 23-hr activity (PND 100), activity following a pharmacological challenge (PND 120), and an operant, discrete trial visual discrimination task. Maternal and offspring body weights and the appearance of certain physical landmarks of development were also monitored. The design of the CBTS allowed evaluation of the reproducibility and detection sensitivity of these behavioral test methods, as well as the impact of early testing experience on later behavioral assessment, offspring sex differences in response levels and variability, and the contribution of litter-to-litter and animal-to-animal variation to behavioral measures in a standardized test protocol. The results obtained in this test system are discussed in relation to each of these factors and to the degree of overt toxicity obtained using prenatal treatment with 0, 0.5 or 2.0 mg/kg d-amphetamine sulfate, SC, on gestation days 12-15 (Study 1) or methylmercuric chloride, 0, 2.0 or 6.0 mg/kg by gavage, on gestation days 6-9 (Study 2).

Age Factors↗
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Collaborative Behavioral Teratology Study: implications, current applications and future directions.

The general conclusions from the Collaborative Behavioral Teratology Study (CBTS) and the implications for research and testing in the field of behavioral teratology are discussed. The results of the CBTS indicate that behavioral teratology data are reproducible, if appropriate attention to study design and testing procedures is maintained. The statistical detection sensitivity of most of the test procedures was excellent, requiring no more than a 5-20% change from control values to detect an effect. Litter, gender and early testing experience may contribute significant variation and should be controlled in any testing situation. The application of behavioral teratology testing and the regulatory role of data for hazard assessment and risk estimation to the human population are discussed. Future research needs were identified from the CBTS workshop discussions.

Animals↗
PubMedDate not supplied

d-Amphetamine as a behavioral teratogen: effects depend on dose, sex, age and task.

Reports on the behavioral effects of prenatal exposure to d-amphetamine in rodents are inconsistent. Activity levels have been variously reported to increase, decrease, or show no change (as in the Collaborative Study) following such exposure. As a follow-up to the Collaborative Behavioral Teratology Study, 3 experiments have been conducted at the NCTR to examine the behavioral teratogenicity of this compound following SC dosing on days 12-15 of gestation. A higher dosage (3 mg/kg) was included and evaluations involved tasks used in the Collaborative Behavioral Teratology Study (startle, figure-8 activity) and other tasks not previously undertaken at the NCTR (short-term reactivity to novel open fields, intake of sweetened solutions). Activity measures gave especially mixed results. There was no effect of prenatal exposure, even at 3 mg/kg, upon longer-term activity, before or after amphetamine challenge, in figure-8 mazes or rectangular photocell chambers, at postnatal days (PND) 47 or 120. In one experiment, changes in reactivity to brief exposure to an open field daily over 3 days were seen in higher dosage PND 135 males but not females, while higher dosage females but not males showed lowered emergence latencies at this age. In a second experiment, no exposure-related changes were seen in reactivity to an open field in offspring of either sex at PND 47 or 70. Auditory startle amplitude showed complex dose effects in these two experiments. Females exposed to 3 mg/kg had elevated startle amplitude at PNDs 47 and 120, but not at PND 19. Males in the 3 mg/kg group had elevated startle at PND 19, but not thereafter.(ABSTRACT TRUNCATED AT 250 WORDS)

Acoustic Stimulation↗
PubMedDate not supplied

Collaborative Behavioral Teratology Study: programmed data entry and automated test systems.

The automated laboratory systems described in this paper were developed for use at the National Center for Toxicological Research (NCTR) and each of five collaborating laboratories. These laboratories participated in a study designed to evaluate the intra- and interlaboratory reliability and sensitivity of several behavioral test methods used in developmental toxicity studies. This paper describes two microcomputer systems. System I was designed to control stimulus delivery to and record behavioral responses from rats during a visual discrimination learning task and to accept data from physical landmark, negative geotaxis, and olfactory discrimination evaluations. The microprocessor system was an S-100 bus, Z-80 processor with 8K PROM, 16K RAM, nine 8-bit parallel I/O ports, and one serial I/O port. For discrimination learning, the animal testing apparatus consisted of six operant chambers, equipped with two stimulus lights, two nose-poke apertures each containing a phototransmitter and receiver, an electromechanical liquid dispenser unit, and a reward bowl also containing a photodiode. Each chamber was interfaced with the microprocessor at a parallel I/O port which permitted the delivery of response- or time-contingent control signals for the lights and liquid dispenser units. System II controlled stimulus delivery and recorded behavioral responses from rats during an auditory startle habituation task, and also recorded rodent activity levels in figure 8 mazes for periods of 1, 4, or 23 hours. The microprocessor system was an S-100 bus, Z-80 processor with 8K PROM, 16K RAM, nine parallel I/O ports, an analog to digital (A/D) I/O board, and one serial I/O port.(ABSTRACT TRUNCATED AT 250 WORDS)

Acoustic Stimulation↗
PubMedDate not supplied

Sex and strain differences in the developmental activity profile of rats prenatally exposed to sodium salicylate.

Pregnant Sprague-Dawley (CD) and Long-Evans (LE) rats were treated by gavage on days 8-10 of gestation with either 0, 125 or 175 mg/kg/day sodium salicylate. Locomotor activity was monitored repeatedly for 30 min in the offspring on postnatal days 12, 16, 20, 24, 30, 60, 90 and 120 in the presence or absence of olfactory cues from home cage bedding. Prenatal exposure during organogenesis to the doses of sodium salicylate used here resulted in subtle alterations in developmental locomotor activity, the pattern of which was dependent on sex, strain and bedding condition during testing. Many more dose-related changes in activity were found in LE rats and, with one exception, these were decreased levels in treated rats. All significant dose-related differences in CD rats were increased activity levels in treated animals relative to controls. Male rats showed more dose-related changes in activity than did females, and activity testing conducted in the absence of home cage bedding cues resulted in a clearer distinction of treatment-related changes than did testing in the presence of home cage bedding. These results suggest a behavioral teratogenic effect of sodium salicylate. In addition, they point out the subtle nature of many behavioral effects in the absence of more overt toxicity and the impact factors such as strain, sex and procedural variables may have on the conclusions drawn from these studies.

Animals↗