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D Neubert

Publications and source records attributed to D Neubert.

At least 55 records · Page 3Linked to original sources
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↗
PubMed1992

Effects of a single haloperidol application to neonatal and early postnatal rats on the neurotransmitter content in the corpus striatum.

We investigated the influence of the dopamine antagonist haloperidol on the neurotransmitter content in the developing rat brain. Dopamine (DA), serotonin (5-HT) and the corresponding metabolites dopac, HVA and HIAA were determined in the corpus striatum of the rat between day 1 and day 21 pn by HPLC with electro-chemical detection. A consistent increase in the content of dopamine was found during postnatal development. The concentrations (ng/g wet tissue; mean +/- standard deviation) increased from 793 +/- 237 on day 1 pn to 4584 +/- 581 on day 21 pn, but remained still lower than in adult animals (9763 +/- 494). Similar results were found for the metabolites dopac and HVA. The content of dopac increased from 59 +/- 22 (day 1 pn) to 551 +/- 59 (day 21 pn) and the content of HVA from 53 +/- 18 (day 1 pn) to 419 +/- 41 (day 21 pn). Both metabolites were also about two times lower than in adult animals (dopac 1090 +/- 282, HVA 744 +/- 206). In contrast to dopamine and its metabolites we found no age-dependent changes in the content of 5-HT from day 1 pn (99 +/- 11) to day 14 pn (121 +/- 21). A remarkable increase in the content of 5-HT was seen from day 14 pn to day 21 pn (438 +/- 56), reaching almost adult levels (570 +/- 92). The metabolite HIAA was nearly three times higher on day 21 pn (610 +/- 123) than on day 14 pn (223 +/- 28) and two times higher than in adults (321 +/- 58).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Polyhalogenated dibenzo-p-dioxins and dibenzofurans and the immune system. 4. Effects of multiple-dose treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on peripheral lymphocyte subpopulations of a non-human primate (Callithrix jacchus).

Non-human primates (Callithrix jacchus) were treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) over a period of 30 weeks, and lymphocyte subpopulations of venous blood were monitored using monoclonal antibodies and flow cytometry (FACScan). There was no clear-cut change in the total lymphocyte population during this study. In the first part of the study the new-world monkeys (marmosets) were treated for 24 weeks with a weekly dose of 0.3 ng TCDD/kg body wt. At the end of this treatment period a level corresponding to an actual cumulative dose of about 2.5-2.7 ng TCDD/kg body wt was expected. The percentage and the absolute number of the CD4+CDw29+ cells ("helper inducer" or "memory" cells) surmounted the physiologically occurring increase. Concomitantly the percentage of the CD4+CD45RA+ cells ("suppressor-inducer" or "naive" cells) decreased. There was, at the same period, no change in the total T cell population (CD2+ cells) or in the cells carrying the CD8 or the CD4 epitope. When increasing the weekly dose to 1.5 ng TCDD/kg body wt, a transient increase in the percentage and the absolute number of the CD8+CD56+ cell population ("cytotoxic T cells") was observed 3 weeks after the increase in dosing. At this time the expected decrease in the percentage or the absolute number of CD4+CDw29+ cells was just detectable and this decline was at its maximum 6 weeks after switching to the higher weekly doses. The reduction in the percentage and the absolute number of CD4+CDw29+ cells persisted 5 weeks after discontinuation of the dosing, but this cell population was again within normal limits 7 weeks later. Because the two subpopulations are changed in opposite directions, the ratio CD4+CDw29+/CD4+CD45RA+ is a very sensitive measure of the effect induced by TCDD. There was a pronounced decrease in the percentage of the CD20+ cells (B1 cells), but their percentage and number rapidly normalized, in contrast to the CD4+CDw29+ cells, when the dosing was discontinued. At the end of the treatment period the apparent body burden was calculated to correspond to an actual dose of about 9-10 ng TCDD/kg body wt. Such an actual dose level might be assumed to be reached under steady-state conditions in chronic experiments with daily doses of about 135 pg TCDD/kg body wt (assuming a half-life for TCDD in the marmoset of 6-8 weeks). Extrapolations of the results obtained at higher doses to very low exposures is not justified with respect to the effects induced by TCDD on the immune system of marmosets. At lower doses the effect is clearly reversed.

Animals↗
PubMed1992

Thalidomide and the immune system. 2. Changes in receptors on blood cells of a healthy volunteer.

Thalidomide (Thd) was given in two trials (total daily dose: 5 or 8 mg Thd/kg body weight, respectively) for five and three days to a healthy male volunteer, and various receptors were analyzed on white blood cells before, during and after (up to 30 days) the treatment period. There were neither marked deviations in the absolute number of total leukocytes nor in the percentage of total lymphocytes or monocytes throughout the study period. The most pronounced changes were observed in the surface receptors on CD4 ("helper cells") cells and leukocytes bearing the CD11b (Mac 1) and other integrin and adhesion receptors. Other changes included shifts in the ratio cytotoxic cells/suppressor cells as well as a reduction of the receptor density (passage from bright to dim) in T helper cells bearing CD45RO "memory" markers. Simultaneously, the number of B cells was found to be increased as was the percentage of some adhesion receptors on CD8+ cells. Unlike in previous experiments in which Thd was administered to marmoset monkeys, no effect could be seen in cells bearing the CD2 (LFA-2) epitope.

Antibodies, Monoclonal↗
PubMed1991

High-performance metal chelate affinity chromatography of cytochromes P-450 using Chelating Superose.

High-performance metal chelate affinity chromatography [immobilized metal ion affinity chromatography (IMAC)] using Chelating Superose (iminodiacetic acid adsorbent) was investigated for its suitability in purifying phenobarbital-induced rat liver microsomal cytochrome P-450 isozymes (P450) and optimized for preparative purposes. Starting with an 8-aminooctyl-Sepharose fraction of partially purified P450, it was found that only Ni(2+)- and Cu(2+)-charged columns could bind P450. No binding was ever observed when Zn2+, Co2+, Mn2+, Cd2+, Fe3+, Fe2+ or Tl3+ ions were employed. Of eight commonly used elution buffers, imidazole and tryptamine were found to cause some denaturation of P450. For desorption of proteins bound to Ni(2+)-charged columns, the following order of decreasing elution buffer strength was determined: cysteine approximately histidine greater than glycine greater than histamine greater than tryptophan greater than ammonium chloride. During protein desorption with some of these buffers, metal ions were found to bleed from the gel, resulting in P450 denaturation. This could be eliminated by prebleeding the charged columns prior to sample application and had an effect on product recovery and homogeneity. Ni2+ and glycine were chosen as a standard for further optimization involving sample adsorption conditions as influenced by equilibration buffer, detergent, load capacity and flow, gradient and temperature conditions. In this way, potassium phosphate (pH 7.75) and 0.4% Emulgen 911 were used to equilibrate a 1.6-ml column and purify 20-50 nmol of P450 (5-15 mg of protein) within 15 min. One gradient fraction consisted of a single sodium dodecyl sulphate-polyacrylamide gel electrophoresis band as judged by silver staining and represented about 25% of the total P450 applied to the column; total recoveries were usually more than 80%. Comparison with the molecular weights and spectral, catalytic and immunological properties of P450 forms isolated according to established procedures indicated that the form isolated here using Chelating Superose comprises mainly P450 2B1 (PB-B). A method is described for fully automated, programmable column regeneration and sample runs.

Animals↗
PubMed1991

Isolation of cytochrome P-450 components from marmoset liver microsomes by high-performance liquid chromatography.

A fast protein liquid chromatographic (FPLC) system with pre-packed and laboratory-packed columns was used for the analytical and preparative isolation of marmoset monkey cytochrome P-450 (P450) and NADPH-P450-reductase. Chromatographic separations also allowed the recovery of cytochrome b5, NADH-b5-reductase and epoxide hydratase. Cholate-solubilized liver microsomes from phenobarbital-induced marmosets were crudely purified on 8-aminooctyl-Sepharose or 6-aminohexyl-Sepharose and then fractionated into several isoenzyme groups using hydroxyapatite. Further purification on Mono S or CM-Sepharose and finally on phenyl-Superose, phenyl-Sepharose or octyl-Sepharose yielded a P450 fraction which was apparently homogeneous as judged by sodium dodecyl sulphate-polyacrylamide gel electrophoresis in the automated Phast system using silver staining. Removal of excess of non-ionic detergent was effected by hydroxyapatite columns, and this was compared with other methods. For the isolation of P450 isoenzymes from untreated marmosets, Mono Q columns were employed and yielded at least two highly purified forms. NADPH-P450-reductase was recovered from the 8-aminooctyl-Sepharose column or crudely fractionated on DEAE-Sepharose Fast Flow. Subsequent purification via 2',5'-ADP-Sepharose and Superose 12 chromatography resulted in a homogeneous preparation.

Animals↗
PubMed1991

In vitro and in vivo studies on the prenatal toxicity of five virustatic nucleoside analogues in comparison to aciclovir.

Several virustatic agents are known to be teratogenic in laboratory animals. Since routinely performed in vivo studies do not always offer the best conditions to detect the teratogenic potential of a drug, we used a combined in vivo/in vitro approach for comparative studies on the prenatal toxicity of five nucleoside analogues. Rat embryos were exposed for 48 h to various concentrations of vidarabine-phosphate (VAP), ganciclovir (GCV), 2',3'-dideoxyadenosine (ddA), 2',3'-dideoxycytidine (ddC) and zidovudine (= azidothymidine, AZT) in a whole-embryo culture system. The steepness of the concentration-response curves as well as the induced abnormality pattern (head, neural tube, shape) were similar for these compounds. However, a wide range in embryotoxic potency was observed: VAP was the most potent compound (100% abnormal embryos at 25 microM) in this in vitro system, while AZT showed the lowest potency to interfere with normal embryonic development (40% abnormal embryos at 3000 microM). In addition to these experiments we treated rats on day 10 of gestation with three s.c. injections (8 a.m.; 12 a.m.; 4 p.m.) of 200 mg of each drug/kg body wt. The embryos were evaluated on day 11.5 of gestation, i.e. at a time of development corresponding to the developmental stage at the end of the whole-embryo culture. The same criteria were used as during the in vitro studies for the evaluation of these in vivo exposed embryos. With VAP and GCV we obtained similar results with both exposure routes (in vitro and in vivo), while no abnormalities were detectable with the other compounds after exposure in utero.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗
PubMed1991

Reproductive toxicity and toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin. 2. Problem of paternally-mediated abnormalities in the progeny of rat.

Possible effects on the next generation after long-term exposure (subcutaneous administration) of male rats to very high doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were studied. Two dose regimes were applied: TCDD-25 (initial dose: 25 micrograms/kg body wt; maintenance dose: 5 micrograms/kg body wt, once weekly) and TCDD-75 (initial dose: 75 micrograms/kg body wt; maintenance dose: 15 micrograms/kg body wt). Male rats were treated for 10 weeks before mating and then throughout the entire 12 week mating period. They were mated to unexposed virgin females. One group of pregnant females was used for teratological evaluations, and another group was allowed to deliver. No significant differences were observed in the number of implantations or fetuses per litter, and resorption rate, and fetal weight between the controls and TCDD-treated groups. No gross-structural anomalies occurred in any of the fetuses sired by TCDD-treated males. In the TCDD-25 group an increased frequency of two types of variations was observed which also occur in controls: incompletely ossified fingers (TCDD-25 = 5.1%, controls = 2.6%), and incompletely ossified ossa zygomatica (TCDD-25 = 1.8%, controls = 0.5%). In the TCDD-25 group a slight but statistically significant increase was observed in the rate of stillbirths (TCDD-25 = 1.3%, controls = 0.1%), apparently due to an unusually low frequency occurring in the controls (overall historical controls = 0.6%). There was no difference in postnatal mortality (TCDD-25 = 1.3%, controls = 1.3%). Taken together, despite the very high doses of TCDD used, the data do not provide evidence for biologically significant paternally-mediated developmental toxicity in the fetuses and newborn.

Abnormalities, Drug-Induced↗
PubMed1991

Polyhalogenated dibenzo-p-dioxins and dibenzofurans and the immune system. 3. No immunosuppressive effect of 2,3,7,8-TCDD in the popliteal lymph node assay (PLNA) in rats.

We used a modified version of the popliteal lymph node assay in rats to investigate the immunosuppressive potential of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In 10 months we conducted 3 experimental series. Animals were treated with single s.c. injections of TCDD and 7 days later human red blood cells (HRBC) were injected s.c. into the right hind footpad of the rat. Another 7 days later, both popliteal lymph nodes were prepared, weighed, the cell number was counted and the quotients ("index") of these variables from the treated and the untreated side were determined. The doses applied in three experimental series were 600', 60, 6, 0.6, and 0.06 ng TCDD/kg body wt. In the first experimental series only the three highest doses were tested, in a second experimental series doses of 60, 6, 0.6, 0.006 ng TCDD/kg body wt were applied. Combining the results of these two experimental series, a statistically significant difference was found in the cell number index between the controls and the two highest doses tested (60 and 600 ng/kg body wt; p less than 0.01). This result was recently published as an abstract (Korte et al. 1990). However, with slight methodological changes in the third series of experiments (doses applied: 600, 60, 6, 0.6, and 0.06 ng TCDD/kg body wt) and using a greater number of animals we could not confirm these preliminary results. No difference was seen in the immune response to the antigen challenge in controls and in any of the treatment groups. We conclude that TCDD does not clearly influence the immune response as observed in the popliteal lymph node assay under our experimental conditions.

Animals↗