Biomedical subjects

D Neubert

Publications and source records attributed to D Neubert.

At least 37 records · Page 2Linked to original sources

PubMed1994

Embryotoxic effects of thalidomide derivatives in the non-human primate callithrix jacchus. IV. Teratogenicity of micrograms/kg doses of the EM12 enantiomers.

The dose-response of the teratogenic potency of the thalidomide (Thd) derivative EM12 was evaluated in the common marmoset (Callithrix jacchus). The smallest daily dose found to be effective was 30 micrograms EM12/kg body wt. This is the lowest dose of a Thd derivative ever reported to induce severe skeletal abnormalities. Ten micrograms EM12/kg body wt may be considered the no-observed-adverse-effect-level (NOAEL) under the experimental conditions chosen. The teratogenic potencies of the two EM12 enantiomers were tested at 100 micrograms/kg body wt, the dose which just induces an almost 100% effect in the case of the racemate. The S(-)-EM12 was found to induce typical severe limb abnormalities such as amelia, phocomelia, and radius aplasia, and none of the exposed fetuses were devoid of skeletal defects. In contrast, only few and minor skeletal defects were observed after application of the R(+) enantiomer. Although a pronounced teratogenic potency of the R(+)-EM12 can now largely be excluded, these low-dose studies are not sufficient to completely rule out any teratogenic potential of this enantiomer, since racemisation to small amounts of the S(-) form may occur in vivo. Further studies with Thd derivatives which are unable to racemise are necessary to prove the assumed complete ineffectiveness of the R(+) enantiomers.

Abnormalities, Drug-Induced↗

PubMed1994

Effects of recombinant human interleukin 6 (rhIL-6) in marmosets (Callithrix jacchus). 1. General toxicity and hematological changes.

The physiological and toxicological properties of recombinant human interleukin 6 (rhIL-6) were assessed in marmoset monkeys (Callithrix jacchus). Two experimental series were performed with daily subcutaneous administration: (a) 5 or 1000 micrograms rhIL-6/kg per day for three weeks and (b) 25, 100 or 500 micrograms rhIL-6/kg per day for 3 months. RhIL-6 was well tolerated and did not induce fever or any other non-specific signs of toxicity. The main findings were: (1) A two- to threefold increase in platelet counts at 2-4 weeks, which decreased following further continuous rhIL-6 administration; (2) increase in total white blood cells between 1 and 4 weeks of administration, including an absolute increase in granulocytes (including band forms) and basophils. A change in the number of monocytes was not detected; (3) an increase in total red blood cells, which peaked at 4 weeks, sustained elevation of red cell distribution width and a slight decrease in hemoglobin between week 1 and 4, concurrent with a distinct decrease in mean corpuscular hemoglobin at 4 weeks. This effect persisted for 9 weeks in the 100 micrograms/kg and 500 micrograms/kg groups; (4) decrease in plasma AST activity and increase in plasma protein concentration after 2 weeks of treatment; (5) no clinical or biochemical signs of renal glomerular dysfunction; (6) RhIL-6 after s.c. administration was detectable in the plasma, peak levels (mean values +/- SD) of 9.4 +/- 6.3 and 72.4 +/- 7.7 ng/ml were measured after a single dose of 100 or 1000 micrograms/kg; (7) antibodies against rhIL-6 developed within 2 weeks, increased during administration and neutralized the biological effect of rhIL-6 progressively from 4 to 9 weeks. In conclusion, aside from a mild anemia, rhIL-6 was well tolerated in marmosets and had a profound and sustained effect on thrombopoiesis. Due to the formation of neutralizing antibodies, the chronic biological effect of rhIL-6 is lost in marmosets and studies beyond 4 weeks are rendered less meaningful. The analyses of antibody formation, induction of acute phase proteins, histological changes and alterations on lymphocyte receptors will be reported in two following publications.

Analysis of Variance↗

PubMed1994

Toxicity of beta-blockers in a rat whole embryo culture: concentration-response relationships and tissue concentrations.

Beta-adrenoceptor blockers are widely used drugs for the treatment of cardiovascular diseases. Since beta-blockers cross the placenta, it is essential to consider possible adverse effects on the embryo. Six beta-adrenoceptor blockers were tested at various concentrations (10-5000 microM) in a rat whole embryo culture. Although inducing a very similar pattern of dysmorphogenetic effects (incomplete flexure, disturbed development of the neural tube, the head, the heart and the tail bud), the compounds exhibited a wide range of embryotoxic potency. Estimation of the EC50 (median-concentration producing dysmorphogenesis in 50% of the embryos) for the six compounds revealed differences of more than two orders of magnitude: propranolol 25 microM, alprenolol 30 microM, metoprolol 100 microM, pindolol 150 microM, acebutolol 500 microM, atenolol 4000 microM. Measurements of the concentrations of the various drugs in the cultured embryos at corresponding EC50 levels showed differing values: metoprolol 4.5 microM, propranolol 5.2 microM, alprenolol 8.4 microM, pindolol 9.0 microM, acebutolol 12.5 microM and atenolol 77.0 microM. With regard to the EC50 and the degree of substance transfer to the embryo it can be stated that propranolol and metoprolol show a much higher intrinsic potency to interfere with normal in vitro embryonic development than, e.g. atenolol.

Acebutolol↗

PubMed1994

Thalidomide and the immune system. 3. Simultaneous up- and down-regulation of different integrin receptors on human white blood cells.

Time-dependent changes in the surface receptor expression of various maturational and integrin receptors on peripheral blood cells were studied in two healthy human volunteers following oral applications of thalidomide (Thd). In each measurement the receptor density was quantified by prior calibration of the flow cytometer with latex beads bearing a determined number of fluorescence molecules. The effects observed in the course of the Thd-treatment were practically identical or at least very similar in both the volunteers during four different trials, and were in accord with previous results obtained in large-scale studies (68 treated animals) with non-human primates. It should be stressed that no clear-cut changes were observed in the percentage or absolute numbers of primary lymphocyte subsets such as CD3, CD4 and CD20. After the first two doses of 7 mg Thd/kg body wt the CD18 (the common beta-chain of the beta 2-integrins) marker already decreased in surface density or was no longer detectable on granulocytes, monocytes and lymphocytes. This effect persisted throughout the treatment period and slowly subsided after discontinuation of treatment. With a few days lag phase, the surface density of CD54 (ICAM-1) on granulocytes increased and many cells previously not bearing this receptor newly acquired such surface markers. On monocytes however, the CD54 receptor was lost on many cells. Within the lymphocyte fraction a loss of the CD54 marker could be noted on CD4 cells but not on CD8 cells, where an increase of the receptor expression could be observed. Other markers, such as the alpha chains of the beta 1 integrins CD49b (VLA alpha 2) and CD49d (VLA alpha 4) showed contrasting reactions to the Thd-treatment. Whereas a pronounced loss of the receptor density of CD49d was observed and only few cells with high epitope density were left in the blood at the end of the complete dosing schedule, no such effect was observable on cells bearing the CD49b epitope. A distinct reduction of the number of receptors was also noticeable on L-selectin (Leu8) bearing cells. On CD4 positive lymphocytes, the majority of the described effects on the integrin and adhesion receptors was seen on cells bearing the CD45R0 maturational epitope. This functional receptor is strongly down-regulated and the pathway of CD45RA to CD45R0 maturation is apparently altered by Thd-treatment. These multiple changes we observed may explain the large variety of therapeutic effects experienced in the treatment with Thd.

Carrier Proteins↗

PubMed1994

Contribution of CYP1A1 and CYP1A2 to the activation of heterocyclic amines in monkeys and human.

The activation of heterocyclic amines to mutagenic products by hepatic microsomal fractions from cynomolgus monkey, marmoset monkey and man was compared with the respective levels of cytochrome P450 enzymes CYP1A1 and CYP1A2. The rate of activation of 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline (MeIQx), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) to mutagens by hepatic microsomal fraction from cynomolgus monkey was very low. This was associated with a lack of constitutive expression of CYP1A1 and CYP1A2. In contrast, human hepatic microsomal fraction readily activates these heterocyclic amines and this is associated with constitutive expression of CYP1A2. Treatment of cynomolgus monkey with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes a very modest induction of CYP1A2, and a small increase in the activation of MeIQx and IQ. However, there was marked induction of CYP1A1 which was accompanied by > 10-fold increases in PhIP activation and 7-ethoxyresorufin O-deethylase (EROD), 7-methoxyresorufin O-demethylase (MROD) and aryl hydrocarbon hydroxylase activities. Following treatment of cynomolgus monkey with 3-methylcholanthrene, induction of CYP1A1, but not CYP1A2, was evident. In untreated marmoset monkey the activations of MeIQx and PhIP, as well as phenacetin O-deethylase, EROD, MROD and aryl hydrocarbon hydroxylase activities, are similar to those in man, although the activations of IQ and coumarin 7-hydroxylase activity are lower than in man. The presence of constitutive CYP1A2, and the absence of CYP1A1, in the liver of this species correspond to the situation in man. Treatment of marmoset monkey with TCDD results in increased CYP1A2 levels (4-fold), accompanied by proportional increases in the activation of MeIQx and IQ and phenacetin O-deethylase, EROD and MROD activities. The activation of PhIP is increased disproportionately, by 8-fold, most likely due to the activity of CYP1A1 which is also induced by TCDD in this species. Overall, the hepatic metabolism of heterocyclic amines by CYP1A enzymes in the untreated marmoset monkey resembles that in human more closely than that in the cynomolgus monkey. Therefore, marmoset monkey may be a more suitable model than the cynomolgus monkey for carcinogenicity studies involving MeIQx and PhIP, but not IQ.

Animals↗

PubMed1994

Evaluation of possible effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and other congeners on lymphocyte receptors in Callithrix jacchus and man.

Using fluorescence-labeled monoclonal antibodies and flow cytometry (FACScan analysis) we measured surface receptors on peripheral lymphocytes in marmosets (Callithrix jacchus) treated with TCDD in the lower nanogram per kilogram range. Additionally, some polybrominated congeners were studied as well as a 2,3,7,8-substituted dioxin containing chlorine and bromine in the same molecule. Callithrix was found to be very sensitive to the action of TCDD and the other tetrahalogenated congeners; single doses of 10-30 ng/kg body weight reproducibly induced a decrease in the percentage and absolute number of 'memory' helper T cells [CD4+CD29(bright)] and of B cells (CD20+). Subsequently, according to the hypothesis based on the marmoset data, extensive analyses on surface receptors of white blood cells were performed in workers with moderately increased body burdens of TCDD, and for further hypothesis generation > 60 triple-labeling assays were performed with each of the blood samples. No decrease in typical surface receptors (CD4+CD45R0+CD45RA-CD29(bright) or CD20+) was found in the human adult volunteers studied, but a trend toward an increase was noted. It cannot be decided whether this may be a substance-related effect, or results from a confounder (possibly age differences between the groups).

Adult↗

PubMed1994

Risk assessment for possible effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related substances on components and functions of the immune system.

Numerous reports have been published on the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on components and functions of the immune system of animal species, almost exclusively of rodents. Many of the data, obtained with very different dosing schedules, are conflicting or have not been confirmed. Since the overwhelming majority of evaluations were performed with rodents, it is not possible to perform a reliable quantitative or even qualitative risk assessment for TCDD in man based on immunological data obtained from these experiments and to extrapolate them to the situation in humans. In addition to the fact that the doses needed to induce measurable effects in the different species studied varies from 1- to 10,000-fold, there are intrinsic and general difficulties for extrapolations to human beings in the field of immunotoxicology due to the influence of different individual risk factors, e.g. smoking and drinking as well as the lack of experience and validation in this new field of toxicology. Some immunological variables were studied in populations highly exposed to dioxins. In comparison to the results obtained from nonhuman primates, no convincing evidence for substance-related effects was revealed, however, information on only a few immunological components and functions in exposed adults could be assessed so far. Except for one group of studied persons all other subjects were generally exposed to cocktails of several chemicals, vastly complicating the interpretation with respect to one isolated component of these mixtures. Results from studies on exposed children are not available yet.

Animals↗

PubMed1993

Effects of small doses of dioxins on the immune system of marmosets and rats.

There is no doubt that TCDD is capable of inducing effects on a variety of components and functions of the immune system in a variety of species. In fact, such changes seem to belong to the most sensitive variables affected by TCDD. Some of the biological effects, induced at rather high doses of TCDD exhibiting general toxicity (> 3 micrograms TCDD/kg body wt), may be considered unspecific or the result of the pronounced thymus involution. However, other effects (such as that on lymphocyte subtype patterns in marmosets or a reduced resistance of mice to influenza viruses) have been reported to occur at dose levels far from those leading to thymic involution or general toxicity. It should be remembered that the pathognomonic relevance for man of subtle modifications in the pattern of lymphocyte surface receptors is largely unknown. Until now, such deviations are considered rather as biological phenomena than indications or causes of specific diseases. Nevertheless, such changes represent clear-cut biological effects induced by TCDD. Since effects of TCDD on components and defined functions of the immune system have been revealed in several species, it would be surprising if humans were largely resistant to such effects, but reliable data in humans with high exposures to defined dioxins verified by an appropriate quantification of the exposure are scarce as of now. Data published so far have not revealed pronounced alterations of such variables. However, no studies of well-defined human populations with quantified body burdens have been performed with modern methods (such as flow cytometry) analyzing a wide variety of surface receptors. Performance of such studies is essential for a better and reliable risk assessment, and the technology is available. Some of the effects observed (such as the changes in the pattern of lymphocyte subpopulations) must certainly be considered as biological effects induced by TCDD, and the situation is similar to the induction of hepatic monooxygenases, which are also observable in this dose range. However, the relevance of such changes with respect to adverse health effects in humans is presently difficult to judge in the absence of clear-cut functional deficits demonstrated so far either in vivo or in vitro.

Animals↗

PubMed1993

Embryotoxicity induced by alkylating agents: 7. Low dose prenatal-toxic risk estimation based on NOAEL risk factor approach, dose-response relationships, and DNA adducts using methylnitrosourea as a model compound.

Prenatal-toxic risk estimation for the alkylating model compound methylnitrosourea (MNU) was performed using different procedures. Risk of low doses was estimated using linear extrapolation to zero (estimated ED0.1%: 0.1 mg/kg body wt MNU) as well as extrapolation by probit analysis based on a dose-response study (estimated ED0.1%: 1.6 mg/kg body wt). Furthermore, a "virtually safe dose" was established by means of the NOAEL risk factor approach (e.g., factor 30:0.03 mg MNU per kg body wt). In previous studies in murine embryos using MNU, we combined dose-response data and DNA adduct rate measurements and deduced that O6-methylguanine is a suitable variable for molecular dosimetry. In a tentative approach, we estimated the teratogenic risk of low doses based on the adduct rates of O6-methylguanine in the DNA of the embryos. It is concluded that in the case of steep dose-response relationships, which are typical for the majority of teratogenic effects, the NOAEL risk factor approach is more conservative than extrapolation based on probit analysis. Risk estimation using dosimetry with this model compound yields estimated incidences similar to linear extrapolation.

Abnormalities, Drug-Induced↗

PubMed1993

Time-dependent differences in the development of somites of four different mouse strains.

In studies on reproductive toxicity and especially teratogenicity, animals are often treated at defined stages of pregnancy. As a result the exposure to a certain teratogen can lead to striking differences in the formation of abnormalities in different strains of the same species. As a contribution to the discussion about the reasons for these differences, we examined the somite development of four different strains of mice during organogenesis. The embryos of pregnant females of the inbred strains DBA/2J, BALB/cJ, and C57BL/6J and of the outbred strain Han:NMRI were studied on days 9, 10, 11, or 12 of gestation. As a criterion for development the somite pairs were evaluated on the respective days. There were remarkable differences in the somite number, even within one litter. The largest variation (minimum vs. maximum) was 14 pairs of somites. The regression curves did not exhibit major differences in the speed of somite development from day 9 to day 12 between the four strains. We have to conclude from our results that the individual embryonic stages within one litter may vary by nearly 1 day, and that there may be a delay of half a day in the embryonic development between different strains of mice.

Animals↗

PubMed1993

Teratogenic potency of 2,3,4,7,8-pentachlorodibenzofuran and of three mixtures of polychlorinated dibenzo-p-dioxins and dibenzofurans in mice. Problems with risk assessment using TCDD toxic-equivalency factors.

The potency of 2,3,4,7,8-pentachlorodibenzofuran (P5CDF) and of three defined 2,3,7,8-TCDD-free mixtures of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs/PCDFs) to induce cleft palates in NMRI mice was studied. The data were compared with a dose-response curve for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The slope of the dose-response curve for P5CDF was the same as for TCDD. However, application of the International-TCDD-Toxic-Equivalency (I-TE) factor (NATO/CCMS 1988) of 0.5 overestimated the potency of the pentachlorinated congener about 2.5-fold under these experimental conditions, suggesting 0.2 as a TE factor. When assessing the cleft palate frequency on the basis of I-TEs and the weight of the substances, the potencies of the two PCDF mixtures studied were also clearly overestimated. This result was not substantially changed when using the TE factor of 0.2 for P5CDF. For the PCDD mixture studied, the cleft palate-inducing potency found largely agreed with the prediction when applying the I-TE factors. According to our data, the use of TE factors as calculated by the UBA/BGA (1985) or the NATO/CCMS (1988) are both conservative when attempting to assess the cleft palate incidence induced by PCDF mixtures in mice.

Animals↗

PubMed1993

Thalidomide derivatives and the immune system. I. Changes in the pattern of integrin receptors and other surface markers on T lymphocyte subpopulations of marmoset blood.

Treatment of marmosets (Callithrix jacchus) with thalidomide (Thd) or its derivative EM12 (which is also teratogenic, but more stable to hydrolysis) resulted in the lack of reaction of adhesion surface receptors (integrins) on T lymphocytes in venous blood. Lymphocyte subsets appeared, for example CD4+CD2-, which are not found under normal conditions. (a) There was no clear effect of the treatments on the total number of leukocytes or lymphocytes or on the total number of CD4+ or CD8+ T lymphocytes. (b) A decrease in the percentage of the cytotoxic T cells carrying the CDw29 marker (CD8+CD56+CDw29+) at a dose as low as 5 mg EM12/kg bw, and an increase in the percentage of suppressor cells carrying the CDw29 marker (CD8+CD56-CDw29+) at 10 mg EM12/kg bw were found. Similar effects were induced by Thd at somewhat higher doses, while supidimide (Sup) was less active even at the very high dose of 100 mg/kg bw. Especially at the lower doses these effects occurred with a lag phase and persisted after discontinuation of the dosing. Alterations induced in helper T cell subpopulations by Thd or EM12 were less impressive (no significant effect was observed with 5 mg EM12/kg bw). Some changes were observed at higher dose levels in the CD4+CD45RA+CDw29+ cells and the CD4+CD45RACDw29+ cells. (c) The most significant effect, reduction in the reactivity of CD2+, was detectable subsequent to daily oral doses as low as 10 mg Thd/kg or 1 mg EM12/kg bw. Peak plasma concentrations to be expected under these experimental conditions are less than 1 micrograms/ml. (d) The surface receptors found to be affected include among others: CD2 (LFA-2) and CD11a (LFA-1 alpha) and CD18 (LFA-1 beta). Clearly, CD4+ cells were found to be more susceptible to the loss of the integrin receptors than CD8+ cells. (e) The effect persisted for several weeks subsequent to the discontinuation of the dosing. (f) A rough estimate of the relative potency to reduce the CD2 receptor in the marmoset suggests EM12 to be five to ten times more potent than Thd. Sup, a Thd derivative reported to exhibit no or a low teratogenic potency, was found to be at least five times less potent than Thd. (g) The alterations of surface adhesion receptors by the substances studied in this investigation were not confined to T lymphocytes. We also observed similar effects on B lymphocytes, monocytes, and neutrophils, and many other cell types carrying such receptors might be affected.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1993

Chlorinated dibenzo-p-dioxins and dibenzofurans and the human immune system. 1. Blood cell receptors in volunteers with moderately increased body burdens.

Using monoclonal antibodies (mAbs) and flow cytometry, we studied a variety of surface receptors on lymphocyte subpopulations of workers with moderately increased body burdens of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and of other polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/PCDF), expressed here as International-Toxicity Equivalencies (I-TE). The hypothesis to be tested was whether or not humans exhibit a similar susceptibility to PCDDs/PCDFs with respect to the surface receptors found previously to respond to small doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in Callithrix jacchus. These are: helper-inducer (memory) T cells (CD4+CD45R0+CD45RA-CD29highCD11a+), CD20+ B cells, and cytotoxic T cells (CD8+CD56+/CD57+). Furthermore, 68 triple-labellings with mAbs were performed on the cells of each volunteer to possibly generate further hypotheses. It was evaluated whether any of the variables might be used as a biomarker of effects for this class of compounds. There were two main goals: (1) to evaluate whether workers with a moderately increased PCDD/PCDF-body burden [25-140 ppt TCDD or 104-522 ppt I-TE in blood fat] exhibit changes in the surface receptors of white blood cells, as observed in previous studies in non-human primates, and (2) to clarify whether persons at the upper range [10-23 ppt TCDD or 30-90 ppt I-TE in blood fat] of the body burden reference values of a not particularly exposed population show detectable deviations in these immunological variables, when compared with persons at the lower and medium range [1-3 ppt TCDD or 9-29 ppt I-TE] of these body burden reference values. Regression analysis of our data revealed slight trends for some of the biomarkers (e.g. CD45R0+). With one exception, these were all increases. None of the alterations observed are of medical relevance. The slight increase in the percentage of CD4+CD45R0+ cells remained significant even after covariant analysis taking age-related changes into account. Altogether, the data do not provide any evidence to support an assumption that moderately increased body burdens of PCDDs/PCDFs in adults induce decreases in the cellular components of the human immune system. Adult humans certainly are less susceptible to this action of PCDDs/PCDFs than adolescent Callithrix jacchus.

Adult↗

PubMed1993

Significance of embryo culture methods for studying the prenatal toxicity of virustatic agents.

Culture methods have become important tools for elucidating the prenatal toxicity of drugs and other xenobiotics. In this paper we will review how we used in vitro as well as in vivo approaches to demonstrate the teratogenic potential of aciclovir and other related virustatic agents. In addition, some new data on this topic will be given. The teratogenic potential of the virustatic agent aciclovir was not recognized in routinely performed segment-II-studies, but the first indication came from experiments with the culture of rat embryos. Subsequently, the findings were confirmed in modified in vivo tests and it became clear that out of a group of six related drugs aciclovir exhibited the highest potential for prenatal toxicity. The effects of aciclovir on limb development were not pronounced--this has been shown with in vitro and in vivo experiments as well. In vivo experiments first indicated that the prenatal development of the thymus is disturbed by aciclovir. This effect was further studied with the culture of fetal thymuses and again the effect of aciclovir could be compared with related drugs. In summary, our work with virustatics during the last years has shown that in vivo and in vitro approaches are by no means competitive and that a combination of both approaches can provide a solid basis for a toxicologic evaluation.

Abnormalities, Drug-Induced↗

PubMed1993

Modeling receptor-mediated processes with dioxin: implications for pharmacokinetics and risk assessment.

Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD), a widespread polychlorinated aromatic hydrocarbon, caused tumors in the liver and other sites when administered chronically to rats at doses as low as 0.01 microgram/kg/day. It functions in combination with a cellular protein, the Ah receptor, to alter gene regulation, and this resulting modulation of gene expression is believed to be obligatory for both dioxin toxicity and carcinogenicity. The U.S. EPA is reevaluating its dioxin risk assessment and, as part of this process, will be developing risk assessment approaches for chemicals, such as dioxin, whose toxicity is receptor-mediated. This paper describes a receptor-mediated physiologically based pharmacokinetic (PB-PK) model for the tissue distribution and enzyme-inducing properties of dioxin and discusses the potential role of these models in a biologically motivated risk assessment. In this model, ternary interactions among the Ah receptor, dioxin, and DNA binding sites lead to enhanced production of specific hepatic proteins. The model was used to examine the tissue disposition of dioxin and the induction of both a dioxin-binding protein (presumably, cytochrome P4501A2), and cytochrome P4501A1. Tumor promotion correlated more closely with predicted induction of P4501A1 than with induction of hepatic binding proteins. Although increased induction of these proteins is not expected to be causally related to tumor formation, these physiological dosimetry and gene-induction response models will be important for biologically motivated dioxin risk assessments in determining both target tissue dose of dioxin and gene products and in examining the relationship between these gene products and the cellular events more directly involved in tumor promotion.

Animals↗

PubMed1992

Effect of lithium on rat embryos in culture: growth, development, compartmental distribution and lack of a protective effect of inositol.

Lithium chloride (LiCl) was tested at various concentrations (50, 100, 150 and 200 micrograms/ml) using a rat whole-embryo culture system beginning on gestation day 9.5 (headfold stage) in order to establish a concentration-response relationship. Open neural tubes--as described in former publications (Tesh 1988)--were not induced by lithium. A significant reduction of embryonic growth and development occurred at the lowest concentration tested (50 micrograms/ml). Clear-cut dysmorphogenetic effects (absence of the eye cup, kink in the spinal anlage, "bleb" at the rostral head region) occurred at a concentration of 150 micrograms/ml LiCl. LiCl concentrations in the embryo, visceral yolk sac, exocoelomic fluid and medium were determined after the embryos had been cultured for 48 h in the presence of a moderately embryotoxic dose of LiCl (3.5 mEq/l or 150 micrograms/ml). Medium supplementation with myo-inositol in different concentrations was ineffective in antagonizing the embryotoxicity induced by LiCl.

Animals↗

PubMed1992

Abnormal thymus development and impaired function of the immune system in rats after prenatal exposure to aciclovir.

Aciclovir (synonym: acyclovir) causes abnormal thymus development in rats. After treatment on day 10 of gestation a weight reduction of the organ is obvious in 21-day-old fetuses which persists postnatally. Adult male rats exposed in utero to one or three injections of 100 mg aciclovir/kg body wt given to the dam on day 10 of pregnancy showed a reduction of the thymus weight to 333 +/- 158 mg and 276 +/- 61 mg (control: 428 +/- 92 mg; n = 10). Corresponding alterations were detectable in female offspring. Liver weight was also decreased and spleen weight (in relation to body wt) was significantly increased in the offspring after the three exposures. In a host resistance model with Trichinella spiralis the function of the immune system of rats prenatally exposed to aciclovir was examined. Six weeks postnatally 10-12 randomly selected male rat offspring of one control and two treatment groups (1 or 3 injections of 100 mg aciclovir/kg body wt on day 10 of gestation) were infected orally with 500 Trichinella spiralis muscle larvae. Before and several times after the infection blood was taken from a tail vein or obtained by decapitation for examination of the antibody titers (IgM, IgG, IgA, IgE) to antigens of T. spiralis. Six weeks after the infection the weight of relevant organs was determined and tongue preparations were used for T. spiralis muscle larvae counting. Aciclovir exposed animals showed a different immune response than control rats. IgM titers in both treatment groups were higher than in controls two weeks after the infection but not different by the end of the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)

Acyclovir↗

PubMed1992

Reproductive toxicity and toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin. 3. Effects of single doses on the testis of male rats.

The effects of a single dose of TCDD on the testis were studied in rats. The animals were treated (subcutaneously) once with TCDD doses of 0, 0.5, 1.0, 3.0, 5.0 micrograms/kg body weight. Doses of 3.0 or 5.0 micrograms TCDD/kg reduced the number of spermatids/testis significantly (60% of the controls). Electron microscopic inspection revealed that both doses led to a dissolution on the germinal epithelium. Altered germ cells at all developmental stages occurred in all testes evaluated. Doses of 0.5 or 1.0 micrograms TCDD/kg did not induce any effects in the testis; therefore, under these experimental conditions of single exposure to rats the dose of 1.0 micrograms TCDD/kg can be considered as NOAEL.

Animals↗