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L Dencker

Publications and source records attributed to L Dencker.

At least 19 recordsLinked to original sources
PubMed2001

Immunohistochemical localization of retinoid binding proteins at the materno-fetal interface of the porcine epitheliochorial placenta.

Retinol and retinoic acid that are potent modulators of gene expression are vital for development and growth of the conceptus. Apart from being transported across the placenta, retinol and retinoic acid may also be active in the placenta per se. Three proteins involved in 1) serum transport of retinol (retinol binding protein [RBP]), 2) cellular transport and metabolism of retinol (cellular RBP [CRBP] I), and 3) retinoic acid (cellular retinoic acid binding protein [CRABP] I), respectively, have been located by immunohistochemistry during gestation in the porcine placenta. This is a diffuse epitheliochorial placenta composed of areolar-gland subunits, where transport of larger molecules takes place, and interareolar regions, where gas-exchange and trophoblast absorption of hemotroph occur. Immunoreactive-RBP (ir-RBP) as well as CRBP I (ir-CRBP) was detected in uterine glands and in areolar trophoblasts, suggesting that RBP-retinol is secreted by the glands and absorbed by the trophoblasts. Both proteins were present also at the interareolar regions, with ir-CRBP in both the uterine epithelium and the apposing trophoblasts, but ir-RBP only in the former. The localization of ir-CRABP was, in contrast, strictly limited to interareolar trophoblasts. Together these findings suggest that 1) the areolar gland subunits are important for transport of retinol and retinol-RBP, and 2) retinoid binding proteins are involved in the development and growth of the porcine placenta.

Animals↗
PubMed2000

Gene structure, expression analysis, and membrane topology of RDH4.

The murine retinol dehydrogenase RDH4 oxidizes several cis-isomers of retinol into their corresponding aldehydes. We have determined the structure of the murine gene, investigated the temporal and spatial expression of the enzyme, and analyzed the membrane topology of the enzyme. The gene has four translated exons, and several alternatively spliced exons in the 5'-untranslated region were identified. Immunohistochemical analysis showed expression of RDH4 in developing and adult mouse eye, particularly in the retinal pigment epithelium. In nonocular adult tissues, including liver, kidney, lung, and skin, RDH4 expression was widespread. The results suggest that RDH4 may have a dual and tissue-specific role in oxidation of 9-cis- and 11-cis-isomers of retinol into 9-cis-retinal and 11-cis-retinal, respectively. Furthermore, the lumenal orientation of the enzyme domain in the ER suggests that oxidation of both cis-isomers of retinol occurs in the ER.

Alcohol Oxidoreductases↗
PubMed2000

Measurement of DNA damage by the comet assay in rat embryos grown in media containing high concentrations of vitamin K(1).

It has been suggested that vitamin K(1) (phylloquinone) can cause genetic damage in rapidly dividing cells and that this should be considered in the risk/benefit analysis of the prophylactic use of vitamin K(1) in the newborn. Usual intramuscular administration of 1mg of vitamin K(1) to the newborn gives peak plasma levels of 1-2 microg/ml (approximately 2-4 microM). To investigate the possible harmful effects of high concentrations of vitamin K(1), rat embryos undergoing rapid cell division in the organogenic period were cultured for 46 hours in rat sera containing either 1, 10 or 100 microg of added vitamin K(1) per ml (2, 22 or 222 microM). At the end of the culture period the embryos were dissociated and the cells examined for evidence of DNA damage using the alkaline version of the comet assay. Control embryos were cultured in sera without added vitamin K(1) and positive controls were control embryos exposed to hydrogen peroxide at the end of the culture period. The results did not show any evidence of DNA damage in the vitamin K(1) exposed embryos. The positive controls showed a significant increase in tail length, moment and inertia. In conclusion, under the experimental conditions used, high concentrations of vitamin K(1) did not induce primary DNA damage in cells from rat embryos grown in vitro.

Animals↗
PubMed1999

CRBP I and CRABP I localisation during olfactory nerve development.

Retinoic acid appears to play a role during the formation of the olfactory system. Immunohistochemistry was used to localise the cellular retinoid binding-proteins for retinol (CRBP I) and retinoic acid (CRABP I) in the embryonic and adult olfactory system. Our results indicate that RA produced by the CRBP I-expressing 'glia-like' cells may act as a neurotrophic factor for the CRABP I-expressing immature olfactory axons.

Animals↗
PubMed1998

The identification of a 9-cis retinol dehydrogenase in the mouse embryo reveals a pathway for synthesis of 9-cis retinoic acid.

The ligand-controlled retinoic acid (RA) receptors and retinoid X receptors are important for several physiological processes, including normal embryonic development, but little is known about how their ligands, all-trans and 9-cis RA, are generated. Here we report the identification of a stereo-specific 9-cis retinol dehydrogenase, which is abundantly expressed in embryonic tissues known to be targets in the retinoid signaling pathway. The membrane-bound enzyme is a member of the short-chain alcohol dehydrogenase/reductase superfamily, able to oxidize 9-cis retinol into 9-cis retinaldehyde, an intermediate in 9-cis RA biosynthesis. Analysis by nonradioactive in situ hybridization in mouse embryos shows that expression of the enzyme is temporally and spatially well controlled during embryogenesis with prominent expression in parts of the developing central nervous system, sensory organs, somites and myotomes, and several tissues of endodermal origin. The identification of this enzyme reveals a pathway in RA biosynthesis, where 9-cis retinol is generated for subsequent oxidation to 9-cis RA.

Alcohol Oxidoreductases↗
PubMed1998

Susceptibility in utero and upon neonatal exposure.

Important determinants or principles in developmental toxicology are: (1) genotype; (2) developmental stage when an insult is hitting; (3) mechanisms of action; (4) pharmacokinetics of the drug in the mother, conceptus and the neonate; (5) the manifestations of embryo/foeto- and neonatal toxicity such as death, malformations, growth inhibition and functional disturbances; and (6) dose-effect and dose-response relationships. The present paper will give a broad review of some important developmental events and sensitivity periods, such as the preimplantation period, the period of gastrulation, organogenesis and placental formation, the foetal and neonatal period during which xenobiotics can cause perturbation in the normal development. Mostly pharmaceuticals are used as examples due to their often well documented effects and sometimes known sensitivity periods. For the postnatal period, some neurotoxic pesticides and environmental pollutants, known to affect adult behaviour in experimental animals after perinatal exposure, are given as examples.

Abnormalities, Drug-Induced↗
PubMed1997

Retinoid binding proteins in mouse yolk sac and chorio-allantoic placentas.

In the adult, as well as in the embryo, a number of specific extra- and intracellular binding proteins such as the plasma retinol binding protein (RBP), the cellular retinol binding protein type I (CRBP I), and also the cellular receptors for RBP are thought to regulate transport and metabolism of retinol (vitamin A). Since the regulation of materno-fetal transport of vitamin A is not well understood, we examined the localization of these proteins during the development of the mouse chorio-allantoic and yolk sac placentas. The labyrinthine region of the chorio-allantoic placenta, where exchange of substances can occur between the maternal and fetal circulations, did not contain RBP (mRNA or protein) or antigen(s) similar to the bovine RBP-receptor p63, whereas the visceral endoderm of the yolk sac placenta, the second site for materno-fetal transport, did. Furthermore, only the endodermal cells of the visceral yolk sac appeared to strongly accumulate radiolabelled retinoids. The cellular retinol binding protein (CRBP I) was detected both in the trophoblast layer of the placental labyrinth closest to the fetal endothelium (layer III), and in the visceral endoderm of the yolk sac. Together, these findings suggest that the yolk sac placenta mediates retinol transfer to the embryo/fetus throughout the entire gestation. The chorio-allantoic placenta, on the other hand, does not appear to have this capacity, while the presence of CRBP I does suggest a retinol-metabolizing capability.

Animals↗
PubMed1996

Stereoselective distribution of the teratogenic thalidomide analogue EM12 in the early embryo of marmoset monkey, Wistar rat and NMRI mouse.

Thalidomide administration during early gestation results in specific and dramatic limb defects in primates, but not in laboratory rodents such as the rat and mouse. The thalidomide analogue EM12 [2-(2,6-dioxopiperidine-3-yl)-phthalimidine] was used in the present study because this compound is metabolically more stable and teratogenically more potent than thalidomide in the monkey. We have administered the pure enantiomers, since we have previously shown that S-EM12 proved to be much more teratogenic in the monkey than R-EM12. In maternal plasma, placenta and embryo of the pregnant marmoset monkey (Callithrix jacchus) and Wistar rat, the concentrations were investigated of the enantiomers and their metabolites after administration of R- and S-EM12. With whole body autoradiography the distribution in the embryo, including the target tissue, the embryonic limb bud was examined in the NMRI mouse and marmoset monkey. Our investigations showed that both the R- and the S-enantiomers were transferred to the embryo during organogenesis [monkey, gestation day (GD) 61; rat, GD 12; mouse, GD 10]. The gestation period chosen was toward the end of the thalidomide-sensitive stage, but yielded sufficient gestational material for analysis. Considerable amounts of the enantiomers were produced via racemization of the administered pure enantiomers and were present in maternal plasma as well as in placenta and embryo. In the monkey, the racemization were stereoselective: the S-enantiomer was eliminated more slowly in the monkey than the R-enantiomer, possibly because of stereospecific binding and metabolism. In the plasma and embryo of both rat and monkey, the metabolites were detected in considerably lower concentrations than EM12, emphasizing the importance of the parent drug in regard to the teratogenic effect. The whole-body autoradiography in marmoset and mouse showed high radioactivity in the embryonic CNS, the branchial apparatus and in the limb buds. The S-enantiomer of EM12 was more strongly concentrated than the R-enantiomer in these areas. In the limb buds, the highest concentrations of radioactivity were observed in the periphery, sometimes at the very tip of the buds. Accumulation of radioactivity in limb buds and neural epithelium relative to other areas of the embryo was much more pronounced in the monkey than in the mouse. Future studies must demonstrate if this accumulation has implications for the mechanism of thalidomide teratogenesis in primate species.

Animals↗
PubMed1996

Nuclear import of cellular retinoic acid-binding protein type I in mouse embryonic cells.

Using confocal microscopy we show that cellular retinoic acid-binding protein type I (CRABP I), expressed in several embryonic cell types, displays a compartmentalized subcellular distribution. The protein was excluded from the nucleus in some cells, while in others it accumulated in the nucleus. In the rat cerebellar cell line ST15A, which expresses CRABP I, the protein was found in the cytoplasm with a prominent nuclear exclusion. Addition of retinoic acid to embryos in vivo and to ST15 A cells in vitro did not affect the localization of the protein. Localization of CRABP I and CRABP I fused to a nuclear localization signal expressed in transfected cells, suggested that cell-specific factors may regulate nuclear import of CRABP I. The potential role of a CRABP I-controlled nuclear import of retinoic acid is discussed.

Animals↗
PubMed1995

The effect of mercury vapour on cholinergic neurons in the fetal brain: studies on the expression of nerve growth factor and its low- and high-affinity receptors.

The effects of mercury vapour on the production of nerve growth factor during development have been examined. Pregnant rats were exposed to two different concentrations of mercury vapour during either embryonic days E6-E11 (early) or E13-E18 (late) in pregnancy, increasing the postnatal concentration of mercury in the brain from 1 ng/g tissue to 4 ng/g tissue (low-dose group) or 11 ng/g (high-dose group). The effect of this exposure in offspring was determined by looking at the NGF concentration at postnatal days 21 and 60 and comparing these levels to age-matched controls from sham-treated mothers. Changes in the expression of mRNA encoding NGF, the low- and high-affinity receptors for NGF (p75 and p140 trk, respectively) and choline acetyltransferase (ChAT) were also determined. When rats were exposed to high levels of mercury vapour during early embryonic development there was a significant (62%) increase in hippocampal NGF levels at P21 accompanied by a 50% decrease of NGF in the basal forebrain. The expression of NGF mRNA was found to be unaltered in the dentate gyrus. The expression of p75 mRNA was significantly decreased to 39% of control levels in the diagonal band of Broca (DB) and to approximately 50% in the medial septal nucleus (MS) whereas no alterations in the level of trk mRNA expression were detectable in the basal forebrain. ChAT mRNA was slightly decreased in the DB and MS, significantly in the striatum. These findings suggest that low levels of prenatal mercury vapour exposure can alter the levels of the NGF and its receptors, indicating neuronal damage and disturbed trophic regulations during development.

Animals↗
PubMed1995

Oil-induced arthritis in DA rats: tissue distribution of arthritogenic 14C-labelled hexadecane.

As part of the study of the pathogenesis of oil-induced arthritis in DA rats, the tissue dissemination of arthritogenic oil labelled with 14C has been determined. Rats received labelled hexadecane in arthritogenic doses by the intradermal route and were killed at 1 and 6 h, 2, 10, 14, 18 and 27 days after injection. Whole-body autoradiography was performed and localization of radioactivity in different organs was investigated. With the exception of the injection site, the lymph nodes showed the highest content of radioactivity throughout the study. Radioactivity could be seen in the popliteal, inguinal and axillary lymph nodes. Detailed examination of lymph nodes revealed at 1 h radioactivity in the subcapsular sinus of the lymph node. By 10 days the activity had spread to the cortex and paracortex, apart from the subcapsular sinus. The activity in other lymphoid organs, such as the bone marrow and spleen, was more transient, with a peak at 2 days. Oil disseminating to joints was not prominent: very little radioactivity was observed in the knee joints of both non-arthritic and arthritic animals. From these data it is suggested that the adjuvant oil exerts its major proarthritogenic activity in the lymph nodes rather than directly in the joints.

Alkanes↗
PubMed1995

The cellular retinoic acid binding proteins.

The two cellular retinoic acid binding proteins, CRABP I and CRABP II, belong to a family of small cytosolic lipid binding proteins and are highly conserved during evolution. Both proteins are expressed during embryogenesis, particularly in the developing nervous system, craniofacial region and limb bud. CRABP I is also expressed in several adult tissues, however, in contrast, CRABP II expression appears to be limited to the skin. It is likely that these proteins serve as regulators in the transport and metabolism of retinoic acid in the developing embryo and throughout adult life. It has been proposed that CRABP I sequesters retinoic acid in the cytoplasm and prevents nuclear uptake of retinoic acid. A role in catabolism of retinoic acid has also been proposed. Recent gene targeting experiments have shown that neither of the two CRABPs are essential for normal embryonic development or adult life. Examination of CRABP I expression at subcellular resolution reveals a differential cytoplasmic and/or nuclear localization of the protein. A regulated nuclear uptake of CRABP I implies a role for this protein in the intracellular transport of retinoic acid. A protein mediated mechanism which controls the nuclear uptake of retinoic acid may play an important role in the transactivation of the nuclear retinoic acid receptors.

Amino Acid Sequence↗
PubMed1993

Non-overlapping expression of CRBP I and CRABP I during pattern formation of limbs and craniofacial structures in the early mouse embryo.

Retinoic acid (RA), a physiological metabolite of retinol (vitamin A), is thought to be of importance for pattern formation in the developing embryo. However, the mechanism by which RA is generated, as well as the site of its formation in the developing embryo, is still unknown. In this paper, we show that radiolabelled retinol, administered to pregnant mice, is accumulated in specific locations in the embryos. As revealed by immunohistochemistry using antibodies to cellular retinol-binding protein I (CRBP I), retinol accumulates in regions of the embryo expressing CRBP I. In limbs and craniofacial structures, CRBP I expression and retinol accumulation was seen in endoderm and surface ectoderm. Most mesenchymal cells of the limbs and craniofacial structures did not express detectable levels of CRBP I but instead expressed cellular retinoic acid-binding protein I (CRABP I). Previous results have demonstrated that CRABP I is involved in accumulation of RA in the embryo. Thus, the spatially closely related but non-overlapping domains of expression of CRBP I and CRABP I suggests a role of a retinol/RA pathway in epithelial-mesenchymal interactions during pattern formation of limbs and of craniofacial structures.

Animals↗
PubMed1992

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) inhibits the activation of antigen-specific T-cells in mice.

There are conflicting data in the literature regarding target cells in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced immunotoxicity. In the present study, adult male C57BL/6 mice were exposed to TCDD (50 micrograms/kg) 4 days prior to immunization with ovalbumin (OVA). The effect of TCDD on the specific immune response in vivo was determined by T-cell proliferation and IL-2 production in response to either OVA or anti-mouse-CD3 antibodies plus PMA in vitro. The antigen-specific T-cell proliferation and IL-2 production in response to OVA were significantly suppressed by TCDD, while the polyclonal response to anti-CD3 antibodies plus PMA was not affected. This indicates that even at a high dose of TCDD the intra T-cell signalling pathways in resting cells are not disturbed, but TCDD selectively impairs the antigen-specific activation of T-cells. Since activated T-cells are required in antibody responses to T-dependent antigens, the low number of such cells observed in the present study, may well explain the suppressive effects of TCDD on humoral immunity reported previously.

Animals↗
PubMed1992

Behavioural effects of neonatal metallic mercury exposure in rats.

The effect of neonatal exposure of rats to mercury vapour (Hg0), at the concentration 0.05 mg/m3, 1 h (low dose) or 4 h (high dose), on the behaviour in adulthood were studied. Exposure occurred on days 11-17 (the period of rapid brain growth). Tests for spontaneous motor activity were performed at the ages of 2 and 4 months. Rats exposed to the high dose Hg0 showed a marked increase in variables locomotion and total activity but a decrease for rearing when tested at 2 months of age. At 4 months of age these rats showed a marked hypoactivity with respect to all three variables. Rats exposed to the low dose showed no significant differences at 2 months compared to controls. However, at the age of 4 months the same pattern (increase in variables locomotion and total activity but a decrease for rearing) already noticed in the high dose group at 2 months was observed. In the spatial learning tasks applied, the radial arm maze and circular swim maze, neonatally exposed pups showed a retarded acquisition to the former, while there was no difference compared to controls in the latter. These data indicate that neonatal exposure to mercury vapour results in similar behaviour changes as reported from offspring prenatally exposed to mercury vapour or methylmercury. Furthermore, exposure for 1 week to concentrations around Swedish threshold values (TLV) for 1 or 4 h resulted in dose and age-related behavioural changes.

Age Factors↗
PubMed1991

Effects of polychlorinated biphenyls with Ah receptor affinity on lymphoid development in the thymus and the bursa of Fabricius of chick embryos in ovo and in mouse thymus anlagen in vitro.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and its congeners bind to the Ah receptor and are known to cause thymic atrophy in most experimental animal species and also to inhibit lymphoid development in the embryonic thymus (T-cells) and in the bursa of Fabricius of chick embryos (B-cells). The coplanar polychlorinated biphenyls (PCBs) 3,3',4,4'-tetrachlorobiphenyl (TCB), 3,3',4,4',5-pentachlorobiphenyl (PeCB), and 3,3',4,4',5,5'-hexachlorobiphenyl (HCB) (relatively strong Ah receptor ligands) and the mono-ortho-chlorinated analogues of TCB and PeCB (relatively weak Ah receptor ligands) were administered to chick embryos by air chamber injection on Day 13 of incubation. The numbers of lymphoid cells (on Day 19) in the thymus and the bursa of Fabricius were lower, in a dose-dependent manner, in embryos treated with the coplanar PCBs compared with controls. Approximate ED50 values for inhibition of bursal cell development were 4 micrograms for PeCB, 50 micrograms for TCB, and 300 micrograms/kg egg for HCB. The most immunotoxic of the mono-ortho-chlorinated analogues of TCB and PeCB were about 1000 times less potent than PeCB. The in vitro effects of the PCBs were studied in organ cultures of thymi from 15-day-old mouse fetuses. The three coplanar chlorobiphenyls inhibited lymphoid development in this culture system in a dose-dependent manner. PeCB was only about 10 times less potent (EC50 approximately 2 x 10(-9) M) than than TCDD (EC50 approximately 2 x 10(-10) M), whereas HCB and TCB were about 100 times less toxic than PeCB. No inhibition of lymphoid development by the mono-ortho-chlorinated PCBs was observed using concentrations as high as 10(-6) M.

Animals↗
PubMed1991

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induced suppression of the local immune response.

TCDD suppressed the normal immune response in popliteal and inguinal lymph nodes, when administered i.p. (50 micrograms/kg) to C57BL/6 mice, 4 days before immunization with the T-dependent antigen ovalbumin (10 micrograms/pad) in the hind foot pads. A hampered increase in lymph node cell number and a reduced frequency of antigen-specific B-cells were observed, despite the fact that cell proliferation in vivo was normal. While the restimulation of lymph node cells in vitro with ConA or LPS was normal, suggesting that the APC function was largely unaffected, the OVA-induced proliferation was greatly reduced. The anti-OVA antibody (ab) concentration both in serum and in supernatants of cultured lymph node cells was lower than in controls. In contrast, the production of anti-BSA ab upon LPS stimulation was normal. This indicates that the ability of the B-cells to produce ab and to proliferate was not disturbed. The DTH assay clearly showed an impaired T-cell function in TCDD-treated animals. Since APC or B-cells have appeared normal in their functions tested in this study, we propose that TCDD disturbed T-cell functions, leading to an impaired activation of B-cells.

Animals↗