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G L Kimmel

Publications and source records attributed to G L Kimmel.

At least 19 recordsLinked to original sources
PubMed1991

Activity profiles of developmental toxicity: design considerations and pilot implementation.

The available literature was searched for quantitative test results from both in vitro and in vivo assays for developmental toxicity for five model compounds: cyclophosphamide, methotrexate, hydroxyurea, caffeine, and ethylenethiourea. These compounds were chosen on the basis of their extensive utilization in a variety of assay systems for developmental toxicity as evidenced by their representation in the ETIC database (each generally has 100-500 citations encompassing multiple test systems). Nine cellular-based assays, six assays using whole embryos in culture, as well as Segment II and abbreviated exposure tests for mammalian test species are included in the database. For each assay, the critical endpoints were identified, each of which was then provided a three-letter code, and the criteria for extraction of quantitative information were established. The extracted information was placed into a computerized reference file and subsequently plotted such that the qualitative (positive/negative) and quantitative (e.g., IC50, highest ineffective dose (HID), lowest effective dose (LED] results across all test systems could be displayed. The information contained in these profiles can be used to compare qualitative and quantitative results across multiple assay systems, to identify data gaps in the literature, to evaluate the concordance of the assays, to calculate relative potencies, and to examine structure-activity relationships.

Animals↗
PubMed1991

Relationship between fetal weight and malformation in developmental toxicity studies.

Exposure to developmental toxicants may cause fetal malformations, increase prenatal death rates and reduce fetal weight at term. However, there has been little formal study of the relationship among these effects. Certainly, no statistical methods are currently available to jointly analyze these effects of exposure. As a preliminary step in developing such methods, simple exploratory analyses were conducted using a series of ten studies conducted for the National Toxicology Program. Because fetal weight and malformation status were both reported for all live fetuses, the data permitted an exploration of the correlation between these two outcomes. The data show a clear pattern wherein malformed fetuses tended to be lighter at term than nonmalformed fetuses. While these patterns cannot be used to draw inferences regarding the biological relationship between fetal weight and malformation, they do suggest the potential value in developing statistical models for the joint effect of exposure on fetal weight and malformations.

Animals↗
PubMed1989

Influence of symmetrical polychlorinated biphenyl isomers on embryo and fetal development in mice. II. Comparison of 4,4'-dichlorobiphenyl, 3,3',4,4'-tetrachlorobiphenyl, 3,3',5,5'-tetrachlorobiphenyl, and 3,3',4,4'-tetramethylbiphenyl.

Outbred albino (CD-1) mice were given the following biphenyl isomers by gavage in cottonseed oil on Days 6-15 of gestation: 4,4'-dichlorobiphenyl (DCB) at 16, 32, and 64 mg/kg/day; 3,3',4,4'-tetrachlorobiphenyl (3,4-TCB) at 1,2,4,8,16,32, and 64 mg/kg/day; 3,3',5,5'-tetrachlorobiphenyl (3,5-TCB) at 64 mg/kg/day; and 3,3',4,4'-tetramethylbiphenyl (TMB) at 64 mg/kg/day. The mice were killed on Day 18 of gestation, necropsies were performed on the dams, and the fetuses were examined for external, visceral, and skeletal malformations. Although DCB was toxic to the dams at 64 mg/kg/day, developmental toxicity was not detected. 3,4-TCB administration was followed by a significant (p less than 0.01) increase in the average percentage of malformed fetuses per litter at 4 (7.2%), 8 (9.8%), 16 (25.4%), 32 (50.0%), and 64 (75.0%) mg/kg/day versus the vehicle control group (1.1%). None of the dosages tested was lethal to any of the dams. Significant decreases in maternal weight gain were observed at 16 mg/kg/day and above; however, the differences from the control value most likely were due to significant decreases in the mean number of live fetuses per dam, as the result of reductions in the number of implants per dam, and significant increases in the incidence of resorptions. Vaginal bleeding and other evidence of abortifacient effects also were present in several dams in groups receiving 3,4-TCB at 16 mg/kg/day and above. Cleft palate and hydronephrosis (significantly increased at dosages of 4 mg/kg/day and above) were the predominant malformations detected. Thus, 3,4-TCB was found to be toxic to the conceptus at dosages of 4 mg/kg/day and above. Neither 3,5-TCB nor TMB showed indications of maternal or developmental toxicity at 64 mg/kg/day.

Animals↗
PubMed1989

Prenatal reserpine exposure alters cardiovascular parameters in rat offspring.

Electrocardiograms (ECGs) and blood pressures (BPs) were recorded and evaluated in postnatal rats that had been exposed in utero to 0.375 or 0.75 mg reserpine/kg/day sc on Gestational Days (GD) 12-15. These doses caused reduced maternal weight gain during pregnancy and decreased pup body weight at birth, as well as reduced heart weight during the preweaning period. There were no changes in other maternal parameters or in litter size. During the postweaning period, pup body weight was reduced only at the highest dose at Postnatal Days (PND) 30 and 60. By PND 342, the weight reduction was no longer significant when compared to controls. Lead II ECGs were recorded in conscious animals on PND 30, 60, and 342; BPs were recorded in anesthetized animals on PND 346. Several ECG parameters were attenuated by prenatal reserpine exposure: R wave and S wave amplitudes and the QRS interval in males, and the PR interval in females. The BP recordings showed that low-dose males had significantly higher pulse pressures than did high-dose males, but neither group was significantly different from controls. Following an intraarterial norepinephrine challenge, resultant peak pulse pressure was greater in high-dose females than in controls. These results indicate that subtle, long-term, sex-specific alterations in cardiovascular parameters were produced by prenatal reserpine treatment at doses that altered body weight in young animals at PNDs 30 and 60, but this change was no longer apparent at PND 342.

Animals↗
PubMed1987

Short-term developmental toxicity testing: considerations in the validation process.

The development and validation of short-term tests that assess developmental toxicity have received increased attention due to the large number of agents that need to be tested and the desirability to reduce the overall use of animals in research and safety evaluation. The Short-Term In Vivo Reproductive Toxicity Test was developed to help meet this need and to provide a method for prioritizing agents for further testing. This report provides a brief overview of the risk assessment process and a focus on the aspects of test validation that should be considered when evaluating short-term tests. It is intended to give the reader an appreciation for many of the considerations that must go into developing and validating a short-term test, and to indicate areas within the risk assessment process where inclusion of such a test may be appropriate.

Animals↗
PubMed1987

Effect of prenatal reserpine exposure on development of the postnatal rat heart.

Previous studies have suggested that reserpine treatment may result in altered heart development. In order to more fully investigate this possibility, reserpine was administered s.c. at 0, 0.375, or 0.75 mg/kg/day to pregnant rats on gestation days 12-15. Maternal weight gain, as well as pup weight on postnatal day (PND) 1, was significantly reduced in a dose-dependent manner. Litter size was unaffected, but reserpine-treated dams had more dead pups than did control dams. On PND 1, litters were randomly standardized at ten pups each for analysis on PNDs 5, 8, 15, and 22. Pup body weight and heart weight were reduced in a dose-related manner at all ages measured. The decreased heart weights were probably due to decreases in cell number. Beta-adrenergic receptor concentration was significantly reduced only on PND 5, at the low reserpine dose, and was not considered to be a treatment effect. Prenatal reserpine exposure had no effect on levels of basal cardiac ornithine decarboxylase (ODC), an enzyme associated with growth and development. Cardiac ODC stimulation by insulin and isoproterenol also showed no effects of maternal reserpine treatment. The results suggest that maternal reserpine treatment may lead to adverse effects in the developing offspring.

Aging↗
PubMed1986

Effect of prenatal propranolol exposure on development of the postnatal rat heart.

Maternal propranolol (PRO) treatment has previously been associated with adverse effects on the fetus and neonate. In the present study, pregnant rats were treated with PRO (25 or 50 mg/kg/day s.c.) on gestation days 8-20 to assess its possible effects on the developing heart. Maternal weight gain and pup weight on postnatal day (PND) 1 were reduced in a dose-dependent manner; litter size was unaffected. Pup body weight and heart weight both showed a dose-related decrease at all ages tested (PNDs 5/6, 8/9, 15/16, and 22/23). Since heart protein, but not DNA, was similarly reduced, the decrease seen in heart weight most likely reflects a decrease in cell size instead of cell number. Basal ornithine decarboxylase (ODC), an enzyme associated with growth and development, was unaffected by maternal PRO treatment. Insulin and isoproterenol stimulation of ODC, suggested markers for testing the function of the sympathetic pathway to the heart and of the heart's ODC response system, respectively, also showed no PRO-related response. In conclusion, prenatal PRO exposure resulted in reduced body weight, heart weight, and heart protein, but had little effect on heart DNA or ODC activity. Since PRO treatment also reduced maternal weight gain, the adverse effects seen in the pups may be due to generalized PRO toxicity. The results suggest that when high PRO doses were used clinically, the careful monitoring of maternal weight gain during pregnancy might be useful in predicting adverse fetal effects.

Age Factors↗
PubMed1986

Effect of prenatal imipramine exposure on development of the postnatal rat heart and brain.

Imipramine (IMI) was administered s.c. at 0, 5, or 10 mg/kg/day to pregnant rats on gestation days 8-20 to assess possible alterations in postnatal heart and brain development. Maternal weight gain was significantly reduced in a dose-response manner, but litter size and pup weight on postnatal day (PND) 1 were unaffected. On PND 1, litters were culled to 10 pups for analysis on PNDs 4/5, 7/8, 14/15, and 21/22. Pup body weight was not affected at any age measured, but heart weight was significantly reduced at 10 mg/kg IMI on PNDs 4/5 and 7/8. Brain weight was increased in a dose-related pattern on PNDs 4/5 and 7/8 and was significantly higher at 5 mg/kg IMI on PND 14/15. No significant effect was observed in heart or brain protein and DNA content or in cardiac beta-adrenergic receptor concentration. Prenatal IMI exposure had no effect on basal cardiac ornithine decarboxylase (ODC), an enzyme associated with growth and development, but basal brain ODC was lower at 5 mg/kg IMI at all ages measured. Cardiac ODC stimulation by insulin was unaffected by prenatal exposure to IMI, but isoproterenol-stimulated ODC was increased on PND 21/22 at 5 mg/kg IMI. In conclusion, the IMI-related changes in several parameters suggest that when maternal IMI treatment is used, alterations in postnatal heart and brain development must be considered as possible outcomes.

Aging↗
PubMed1986

Insulin stimulation of ornithine decarboxylase activity in developing rat heart.

Ornithine decarboxylase (ODC; EC 4.1.1.17) is an important enzyme in the synthesis of polyamines and is associated with growth and differentiation. Insulin stimulation of cardiac ODC has been proposed as a marker of the functional completion of the sympathetic pathway to the rat heart. However, earlier studies, using subsaturating substrate concentrations and a single time point measurement after insulin treatment, have been inconsistent concerning the postnatal age at which significant insulin stimulation of ODC occurs. The present study, using a validated near-saturating substrate assay, examines more thoroughly early neonatal insulin induction of cardiac ODC with respect to both the magnitude and the time course of response. Insulin (20 IU/kg s.c.) significantly increased ODC activity at several time points at each postnatal age measured (days 2, 5, 8, 15 and 22), with maximum ODC activity occurring by 2.5 to 3 hr after insulin injection at all ages. Insulin-stimulated ODC activity was increased over control levels by 86, 84, 87, 150 and 127% on days 2, 5, 8, 15 and 22, respectively. These results demonstrate that age is not a variable in the time of peak insulin stimulation of ODC activity and, in contrast to earlier reports, show that significant insulin induction of cardiac ODC activity occurs reliably across ages in the early postnatal period. The inconsistency of earlier studies may be due to a number of factors, including the use of subsaturating enzyme assays only, known to be subject to several types of error.

Age Factors↗
PubMed1985

Identification of the cellular retinoic acid binding protein (cRABP) within the embryonic mouse (CD-1) limb bud.

Retinoic acid, a physiologically active metabolite of vitamin A, is known animal teratogen. Among other malformations, limb abnormalities are produced and are attributed to a selective inhibition of differentiating prechondrogenic mesenchyme resulting in reduced or absent cartilage elements. Evidence is available that the cellular retinoic acid binding protein (cRABP) may be important in mediating the biological effects of retinoic acid. In this study, the cRABP has been identified by sucrose gradient sedimentation analysis in the gestation day 10 (Theiler stages 16-17) mouse forelimb bud, which contains retinoic-acid-sensitive prechondrogenic mesenchyme. Saturation analysis demonstrated values for the apparent dissociation constant (Kd) of 2.0 and 2.2 X 10(-9)M and for the total specific binding capacity for [3H]-trans-retinoic acid of 24.5 and 25.6 pmoles per mg cytosolic protein. The binding specificity of the forelimb bud cRABP for all-trans-retinoic acid was demonstrated in competition assays using all-trans-retinol, all-trans-retinal, and 13-cis-retinoic acid. In addition, 13-cis-retinoic acid was demonstrated to have a lower affinity for the cRABP than all-trans-retinoic acid, a result which may be related to the lower teratogenic potency of the 13-cis-retinoic acid. Thus, the cRABP was demonstrated in the mouse forelimb bud at a time of susceptibility for the production of limb malformations by retinoic acid. The role of the cRABP in the mechanism of retinoic acid teratogenicity remains to be delineated.

Animals↗
PubMed1985

In vitro tests in screening teratogens: considerations to aid the validation process.

The need for improving the process of assessing teratogenic hazards has led to an increased interest in the potential for using in vitro systems as screens of developmental toxicity. The Consensus Workshop on In Vitro Teratogenesis Testing addressed many of the basic questions relative to the development and validation of these systems, and stressed the need to establish a well-controlled approach to that validation process [Kimmel et al, 1982]. It is obvious that this process has just begun and that considerable work remains. This paper indicates some of the areas that should be addressed in any in vitro study relative to experimental design and data reporting that may be helpful to that process.

Abnormalities, Drug-Induced↗
PubMed1984

Ontogeny of cardiac ornithine decarboxylase and its beta adrenergic responsiveness in the rat.

Ornithine decarboxylase (ODC) is a marker of tissue growth and development and, because sympathetic stimulation of beta adrenergic receptors acutely increases ODC in the adult rat heart, measurement of this enzyme can be used to indicate the functional intactness of the beta adrenergic receptor system in the heart. Changes in the postnatal ontogenetic pattern of this enzymatic activity may also indicate abnormal development and ODC appears to be particularly useful in evaluating the effects of prenatal insult on cardiac development. The present study examines the pattern of basal ODC activity and its developing sensitivity to beta adrenergic stimulation during the perinatal period in order to establish a data base for studies on the effect of various environmental agents on the developing cardiovascular system. ODC activity was measured in rat hearts on gestation day (GD) 20 through postnatal day (PND) 28 under saturating conditions of L-ornithine and pyridoxal 5-phosphate. Basal ODC activity fell from 3 nmol of CO2/hr/mg of protein at GD 20 to less than 0.5 nmol of CO2/hr/mg of protein at PND 18, rising again to nearly 1 nmol of CO2/hr/mg of protein at PND 22. The beta adrenergic agonist isoproterenol (10 mg/kg s.c.) resulted in peak ODC stimulation at 4 hr postinjection on PNDs 6, 14 and 21; however, no response was seen at PND 1 at this dose or at GD 20 (300 micrograms/kg s.c.). In dose-response studies, isoproterenol produced a maximal response at 10 mg/kg s.c., resulting in increases from control of 67, 230 and 1700% at PNDs 6, 14 and 21, respectively, indicating that the sensitivity of the heart to beta adrenergic stimulation increases with age, during the perinatal period.

Animals↗
PubMed1983

Characterization of estrogen binding in uterine cytosol from the fetal rhesus monkey.

Cytosol receptor binding of 17 beta-estradiol was demonstrated in the uterus of the late-gestation, fetal rhesus monkey. Sucrose density gradient analysis performed in low-ionic strength buffer indicated a binding component with a sedimentation coefficient of 6-7 S. Under high-ionic strength conditions, the component shifted to a sedimentation coefficient of approximately 4 S. The specificity of the receptor for estrogens was indicated by inhibition of [3H]estradiol binding by both natural and synthetic estrogen competitors, but not by progesterone. Saturation analysis indicated a high degree of nonspecific binding with saturation of specific binding occurring at 2-3 nM. Computer-assisted Scatchard analysis of the data resolved a one-receptor model having a limited number of binding sites and an apparent dissociation constant of 10(-10) M. The interaction of estrogens with the fetal uterus and the cellular mechanisms which permit this interaction are discussed in relation to the development of models for extrapolation to the human.

Animals↗
PubMed1983

A selection of candidate compounds for in vitro teratogenesis test validation.

The Consensus Workshop on In Vitro Teratogenesis Testing recommended that test validation be facilitated by a listing of agents with defined teratogenicity; subsequently, a panel was convened to review and select such agents. This communication established a list of 47 compounds or conditions which demonstrate a wide range of teratogenicity in vivo. The agents were chosen primarily on the strength of the literature base denoting their in vivo effects. The tables note a number of general biological and toxicological characteristics for each agent, and the details of representative in vivo teratology studies are summarized and referenced. This list is intended to serve as a base for in vitro teratogenesis test validation and should prove useful in developing and identifying those systems which will contribute to a more effective testing program.

Abnormalities, Drug-Induced↗