Biomedical subjects

L Dencker

Publications and source records attributed to L Dencker.

At least 37 records · Page 2Linked to original sources

PubMed1991

In vivo and in vitro toxicity of fractionated fish lipids, with particular regard to their content of chlorinated organic compounds.

Six different lipid matrices (the intact lipid (IL), four lipid fractions with different polarity, and the free fatty acids (FFAs) obtained by hydrolysis of the triacylglycerol (TAG) containing fraction) were obtained from salmon (Salmo salar) and eel (Anguilla anguilla), each collected at a contaminated and a comparatively uncontaminated catch site along the coast of Scandinavia. The lipid matrices were studied in toxicological test systems representing various biological functions of different organ systems from several species and trophic levels. The results were evaluated with particular respect to the concentrations of extractable organically bound chlorine (EOC1) in the matrices tested. In some test systems, the specimens with a higher EOC1 concentration appeared to be more toxic. For example, the TAG containing fraction (F2) from Idefjord eel, having a higher EOC1 content than F2 from Oslofjord eel, reduced the number and hatchability of eggs laid by zebrafish. Both IL and F2 of Idefjord eel increased mortality and reduced the oxygen/nitrogen-ratio in blue mussels. Non-polar compounds (F1) from Bothnian Sea salmon induced 7-ethoxyresurofin O-deethylase (EROD) activity in rainbow trout hepatocytes, whereas F1 from Senja salmon did not. F1 from Bothnian Sea salmon also reduced the number of T-cells in foetal mouse thymus analagen in vitro compared with the cell number in anlagen exposed to F1 from Senja salmon. A positive correlation between EOC1 concentration and test response was found for EROD activity in rainbow trout hepatocytes and for ATP-leakage in Erlich ascites tumour cells when testing the phospolipid containing fraction (F4). However, in most test systems the fish oils, irrespective of EOC1 content, were of low toxicity, and the observed effects need to be verified in future studies.

Animals↗

PubMed1991

Differential distribution and placental transport of 2- and 3-t-[methyl-14C]butyl-4-hydroxyanisole (BHA) in pregnant mice.

The placental transport and localization in fetal and maternal tissues of 14C-BHA isomers, 2-t-[methyl-14C]butyl-4-hydroxyanisole (2-BHA) and 3-t-[methyl-14C]butyl-4-hydroxyanisole (3-BHA), were studied in pregnant mice by whole-body autoradiography techniques. BHA isomers were given (iv 50 microCi/100 g as a tracer dose) to pregnant mice at Day 11 (organogenesis) and Day 18 (postorganogenesis) of gestation. Peak levels of radioactivity occurred in various tissues 1-4 hr after iv administration of both isomers. 3-BHA and its metabolites have a higher affinity to fatty tissues and livers of pregnant mice. The concentration of radiocarbon in maternal liver and brown fat following treatment with 14C-3-BHA was much higher than the radioactivity concentration in the corresponding tissues of mothers treated with 2-BHA. On the other hand, the fetal concentration of radioactivity was higher in animals treated with 2-BHA than in those treated with 3-BHA. The radioactivity derived from both isomers accumulated in the fetal gastrointestinal tract. In both groups the radioactivity accumulated in the maternal nasal cavity and mucosa and the gastrointestinal contents. At 24 hr after treatment, retention of radioactivity in maternal lungs, amniotic fluid, and fetal gastrointestinal tissues was observed. Results from this study indicate that there are differences in the magnitude and extent of placental transport of 3-BHA and 2-BHA. Differences also exist in maternal organ uptake and radioactivity distribution of both isomers. Findings from this study are consistent with pharmacological differences existing between the isomers.

Animals↗

PubMed1990

Histological and in vitro studies supporting decreased uteroplacental blood flow as explanation for digital defects after administration of vasodilators.

In a recent study, the vasodilating drugs nifedipine, nitrendipine, felodipine, and hydralazine induced phalangeal defects in rabbits, when given on day 16 of pregnancy. Histologically, the changes were characterized by disturbed chondrogenesis. In order to elucidate mechanisms behind the defects, the fetal concentration of felodipine was measured, and the fetal limb plates were examined histologically, at 0, 2, 4, 8, 12, and 24 hours after single oral administration of felodipine (12 mumol/kg) on day 16 in pregnant rabbits. The effects of nifedipine, nitrendipine, and felodipine were also investigated in an in vitro system, in which chick embryonic mesenchymal limb bud cells differentiated into chondrocytes. In this system, no inhibition of chondrogenesis was observed below concentrations 3 x 10(5) M. At this concentration, unspecific cytotoxicity was found. The highest fetal concentrations of felodipine were more than 500 times lower than what was required for in vitro toxicity. Histologically, the digital areas of the limb plates showed extensive edema and dilatation of marginal sinus within 2 hours. After 8 hours, rupture of the thin-walled vessels occurred with hemorrhages. Finally, small necroses and blisters were observed. Similar early changes have been reported in experiments where digital defects were induced by clamping uterine vessels. This study thus indicates that the phalangeal defects after administration of high doses of vasodilators are secondary to pharmacological action (associated with a significant reduction in the uteroplacental blood flow), and not a direct effect on fetal chondrogenesis.

Abnormalities, Drug-Induced↗

PubMed1990

Marked accumulation of valproic acid in embryonic neuroepithelium of the mouse during early organogenesis.

Valproic acid, an antiepileptic drug, causes neural tube defects in mice and man. 14C-labeled valproic acid (sodium-salt) was administered to pregnant mice on days 8 and 9 of gestation (period of high sensitivity in regard to formation of neural tube defects in this species). Two dose levels of valproic acid (1 and 400 mg/kg) were used; in each case the total radioactivity administered was the same: 400 microCi/kg or 14.7 MBq/kg. Autoradiography combined with computerized densitometry revealed that in low-dose animals most of the radioactivity was confined to maternal liver and kidney, while at high doses more activity was observed in soft tissues and fluids, including amniotic fluid. In the embryo, the neuroepithelium showed the highest concentration, irrespective of dose and survival interval (30 min, 3 h, and 6 h). Upon administration of the high dose, up to five times more radioactivity (approximately 2,000 times more valproic acid) was recovered in embryonic tissues than after the low dose. It is concluded that high doses of VPA saturate the capacities of metabolism, excretion, and protein binding in the maternal organism, resulting in a higher proportion of the dose reaching the embryo, allowing more of the drug to be accumulated by the target organ, the neuroepithelium.

Animals↗

PubMed1990

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) alters intrathymic T-cell development in mice.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was administered to 2-4-week-old mice (5, 25, and 50 micrograms/kg body wt.) and to in vitro cultures (10(-9) M) of fetal thymi. By monitoring thymocyte populations with respect to the differentiation antigens CD4 and CD8, it was found that the cell number in all thymocyte populations except for CD8+ decreased significantly compared with controls. In vivo the most marked decrease occurred among double negative (DN) and double positive (DP) cells, whereas in vitro, the DP cells were most severely affected. The cell number had already decreased to some extent by day 1 after a dose of 50 micrograms/kg body wt. of TCDD, although a severe reduction did not become apparent until day 4. There was a clear dose/response relationship between 5 and 50 micrograms/kg body wt. Autoradiography and liquid scintillation counting studies showed that incorporation of [3H]thymidine in the thymus had already decreased 24 h after TCDD treatment, with the decrease being even more pronounced at 48 h. By 96 h, the rate of cell proliferation had returned to approximately normal values. The results show that TCDD has a long-lasting effect on thymocyte abundance together with a transient effect on cell proliferation. This indicates that in addition to the initial effects of TCDD on cell proliferation, it may also more permanently disturb the normal process of elimination by means of selection.

Aging↗

PubMed1990

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treatment in vivo on thymocyte functions in mice after activation in vitro.

Thymocytes from 15-day old C57BL/6 mice, pretreated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) 4 days before sacrifice, showed an earlier response and a higher maximal cell proliferation than thymocytes from control mice upon stimulation by concanavalin A in vitro. This is partly in contrast to the conclusions from earlier published studies. IL-2 content--as measured by growth of CTLL cells--was equally high in TCDD and in control cultures at day 1. At day 2, TCDD cultures had decreased dramatically in IL-2 content, possibly due to a high rate of consumption. At this point in time, the controls still contained a high concentration of IL-2, although less than at day 1. In contrast to the increased sensitivity to mitogen stimulation, thymocytes from TCDD-treated mice induced B-cells less avidly with respect to antibody production, and could also inhibit the T-cell help of thymocytes from untreated animals, a phenomenon which could be reversed if TCDD-treated thymocytes were irradiated before culture.

Animals↗

PubMed1990

Accumulation and turnover of metabolites of toluene and xylene in nasal mucosa and olfactory bulb in the mouse.

Autoradiography of male mice following inhalation of the radioactively labelled solvents, toluene, xylene, and styrene, revealed an accumulation of non-volatile metabolites in the nasal mucosa and olfactory bulb of the brain. Since no accumulation occurred after benzene inhalation, it was assumed that the activity represented aromatic acids, which are known metabolites of these solvents. This was supported by the finding that also radioactive benzoic acid (main metabolite of toluene) and salicylic acid accumulated in the olfactory bulb. High-performance liquid chromatography revealed that after toluene inhalation (for 1 hr), nasal mucosa and olfactory bulb contained mainly benzoic acid, with a strong accumulation in relation to blood plasma, and considerably less of its glycine conjugate, hippuric acid. After xylene inhalation, on the other hand, methyl hippuric acid dominated over the non-conjugated metabolite, toluic acid. The results indicate a specific, possibly axonal flow-mediated transport of aromatic acids from the nasal mucosa to the olfactory lobe of the brain. The toxicological significance of these results remains to be studied.

Animals↗

PubMed1990

TCDD inhibits the support of B-cell development by the bursa of Fabricius.

The toxic effects produced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and its congeners include inhibition of lymphoid development. We have previously found an inhibition of B-cell development in the bursa of Fabricius of chick embryos treated with TCDD congeners in ovo. In the present study, the bursae of ten-day-old chick embryos were removed and cultured on filter paper for 24 hr in media with or without TCDD or 3,3',4,4'-tetrachlorazoxybenzene (TCAOB). Following culture, the bursae were transplanted onto the chorioallantoic membrane (CAM) of ten-day-old eggs of the same strain or of a strain expressing a different B-cell surface alloantigen. After 5 days on the CAM the number of B-cells was determined or the grafts were sectioned for subsequent immunohistochemistry. Results were as follows: 1) A lower number of lymphoid cells (dose dependent) was observed in the TCDD-treated transplants amounting to 40-50% of that in the controls at 10(-9) M TCDD. Higher concentrations of TCDD compromised survival of the grafts. A single concentration of TCAOB (10(-8) M) was tested, resulting in a lymphoid cell number of 60% of that of the controls. 2) The bursal epithelium showed relatively normal development even in cases where B-cell development was affected. 3) Lymphoid cells in the grafted bursae originated from the embryo of the host egg. These findings suggest that the TCDD congeners had a direct effect on the bursa of Fabricius, leading to an inhibition of lymphoid development. It is likely that the microenvironment is affected by these compounds, thus resulting in a decrease in the attraction of stem cells and/or in the capacity to induce proliferation of the colonizing cells.

Animals↗

PubMed1990

Foetal and maternal distribution of inhaled mercury vapour in pregnant mice: influence of selenite and dithiocarbamates.

The distribution of mercury after inhalation of metallic mercury vapour (6-8 mumols 203Hg0/kg b.wt.) was studied in pregnant mice (day 17 of gestation) after pretreatment with selenite (10 mumols Se/kg b.wt. intraperitoneally 1 hr before inhalation), thiram, disulfiram or diethyldithiocarbamate (1 mmol/kg orally 2 hr before inhalation of Hg0). For comparison, the effects of thiram, disulfiram and diethyldithiocarbamate on the distribution of mercury after administration of ionic mercury (7 mumols 203HgCl2/kg b.wt. intravenously) were also studied. Selenite pretreatment caused a longer retention of mercury in maternal tissues but decreased the foetal concentrations after 203Hg0 inhalation, similarly to what has been shown previously after administration of ionic mercury (Hg2+). Pretreatment with the three dithiocarbamates markedly increased the uptake in maternal brain and fat and decreased the foetal concentrations after intravenous injection of 203HgCl2. In contrast, no change in foetal uptake and only slight changes in maternal tissue concentration of mercury were observed after treatment with the dithiocarbamates followed by inhalation of 203Hg0, compared with 203Hg0 inhalation alone. The results are in favour of a firmer binding of mercury after Hg0 inhalation, when oxidation of Hg0 to Hg2+ occurs intracellularly, than after Hg2+ injection. Further studies, using repeatedly low dose administration of selenium, are needed to draw any conclusions concerning the protective effects of selenium after exposure to metallic mercury vapour.

Administration, Inhalation↗

PubMed1990

Localization of specific retinoid-binding sites and expression of cellular retinoic-acid-binding protein (CRABP) in the early mouse embryo.

Retinoids (vitamin A derivatives) are important for normal embryogenesis and retinoic acid, an acidic derivative of vitamin A, was recently proposed to be an endogenous morphogen. Several retinoids are also potent teratogens. Using an autoradiographic technique, we have identified tissues and cells in early mouse embryos that are able to specifically accumulate a radiolabelled synthetic derivative of retinoic acid. Strong accumulation of radioactivity was seen in several neural crest derivatives and in specific areas of the CNS. Gel filtration analyses of cytosols from embryos that received the radiolabelled retinoid in utero suggested that cellular retinoic acid-binding protein (CRABP) was involved in the accumulation mechanism. Immunohistochemical localization confirmed that cells accumulating retinoids also expressed CRABP. Strong CRABP immunoreactivity was found in neural crest-derived mesenchyme of the craniofacial area, in visceral arches, in dorsal root ganglia and in cells along the gut and the major vessels of the trunk region. In CNS, CRABP expression and retinoid binding was largely restricted to the hindbrain, to a single layer of cells in the roof of the midbrain and to cells in the mantle layer of the neural tube. Our data suggest that cells in the embryo expressing CRABP are target cells for exogenous retinoids as well as endogenous retinoic acid. Retinoic acid may thus play an essential role in normal development of the CNS and of tissues derived from the neural crest. We propose that the teratogenic effects of exogenous retinoids are due to an interference with mechanisms by which endogenous retinoic acid regulates differentiation and pattern formation in these tissues.

Animals↗

PubMed1989

Effects of immunosuppressive chemicals on lymphoid development in foetal thymus organ cultures.

A murine foetal thymus organ culture system was employed to screen a number of immunotoxic chemicals for direct thymus toxicity. The toxic effects caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and its congeners on the system used had previously been shown to be similar to those caused in vivo on lymphoid development. The most potent compound tested was the corticosteroid fluocinolone acetonide, which caused a 50% inhibition of lymphoid development (EC50) at a concentration of 5 x 10(-11) M. The EC50 of TCDD was around 5 x 10(-10) M while that of 4 beta-phorbol 12-myristate 13-acetate (TPA) was ca 10(-7) M. TCDD and its congeners are believed to act via binding to the Ah receptor. Other known or presumed ligands of this receptor, which are potent inducers of P1-450 (P-448) -dependent polysubstrate monooxygenase activities, were considerably less toxic with EC50 levels varying between 10(-5) M (7,12-dimethylbenz(alpha-) antracene, alpha-naphthoflavone, benzo(alpha)pyrene) and 10(-4) M (beta-naphthoflavone and 3-methylcholantrene). Dinaphtho/2,3-b,5,6-b/dioxin and indolo/2,3-b/carbazole showed toxicity at 5 x 10(-6)-10(-5) M and 5 x 10(-5) M respectively. TCDD, TPA, and fluocinolone showed additive effects when added two by two in different combinations. Thus fluocinolone, known to counteract the toxicity and epidermal growth factor (EGF) cell-surface receptor-decreasing activity caused by TPA in other cell types, failed to decrease TPA toxicity in the thymus culture system.

Animals↗

PubMed1988

Effects of the TCDD congeners 3,3',4,4'-tetrachlorobiphenyl and 3,3',4,4'-tetrachloroazoxybenzene on lymphoid development in the bursa of Fabricius of the chick embryo.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and its congeners, such as 3,3',4,4'-tetrachlorobiphenyl (TCB) and 3,3',4,4'-tetrachloroazoxybenzene (TCAOB), act on targets in the immune system, probably by interacting with the Ah-receptor, causing a characteristic pattern of effects typified by inhibition of lymphoid development in the thymus. There are, however, also reports of effects on B cells. Birds have a well-defined site of B-lymphocyte development, the bursa of Fabricius, analogous to the thymus for T cells. Thus, we wanted to determine whether this organ is suitable for studying effects on B-cell development. TCB and TCAOB were administered by injection into the air sacs of White Leghorn eggs on Day 13 of incubation. Effects observed on Day 19 were as follows: (1) There was a reduction in bursal dry weight but not in body weight in the treated groups. (2) The number of lymphoid cells in the bursae decreased in a dose-dependent manner, and bursae from high-dose groups (300 and 30 micrograms/kg egg of TCB and TCAOB, respectively) were almost completely devoid of lymphoid cells. For the reduction of lymphoid cell number, the ED50 for TCB and TCAOB was approximately 45 and 1.4 micrograms/kg egg, respectively. (3) Histological sections showed that embryos from treated egges contained fewer bursal follicles and that follicles contained fewer lymphoid cells compared with controls. (4) Aryl hydrocarbon hydroxylase activity was 30 and 50 times that of the control at high doses of TCB and TCAOB (estimated ED50: 200-300 and 4 micrograms/kg egg, respectively). These findings suggest that lymphoid development in the bursa of Fabricius of the chick embryo is inhibited by TCDD congeners.

Animals↗

PubMed1988

Selective incorporation of thiouracil into murine metastatic melanomas.

The uptake and retention of 14C-thiouracil and 125I-thiouracil in small lung metastases of B16 murine melanoma was studied in beige mice injected intravenously with melanoma cells. By impulse counting of excised tumor and organ pieces, a high concentration of radioactivity was found in the lung metastases, as compared to normal tissues. The highest tumor/organ concentration ratios appeared 24 h after injection of the radiolabeled thiouracil. A separate autoradiographic study on the disposition of 14C-thiouracil in mice with melanoma metastases confirmed the impulse counting results and also showed the absence of any other site of retention of radioactivity except for hair follicles and to some extent the thyroid. The selective uptake of 14C- and 125I-thiouracil in melanomas depends on their acceptance as false melanin precursors, making them specific markers for growing melanin. The results indicate that radiolabeled thiouracil may be useful for clinical diagnosis and, possibly, therapy of malignant melanotic melanomas.

Animals↗

PubMed1988

Effects of TCDD and its congeners 3,3',4,4'-tetrachloroazoxybenzene and 3,3',4,4'-tetrachlorobiphenyl on lymphoid development in the thymus of avian embryos.

Thymus anlagen from 11-day-old chick and 14-day-old turkey and duck embryos were cultured in media containing 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) for 5 days. The maximal TCDD-induced decrease in lymphoid cell number of chick embryo thymus (to about 60% of the control number) occurred at concentrations of 10(-10) M and above. To produce the same effect on lymphoid cell number in the cultures of thymus anlagen from turkey and duck embryos, about a 100-fold higher concentration of TCDD was needed. The toxicity of the TCDD congeners 3,3'4,4'-tetrachloroazoxybenzene (TCAOB) and 3,3',4,4'-tetrachlorobiphenyl (TCB) to embryonic chicken thymus was tested in vitro and in ovo. In chick embryo thymus cultures, TCAOB and TCB were about two orders of magnitude less toxic than TCDD. Injection of TCAOB and TCB into chicken eggs preincubated for 11 days resulted in a dose-dependent decrease in thymic lymphoid cell number 5 days later, declining to about 14% of the controls at 10 micrograms TCAOB/kg egg. The ED50 value was estimated to be 3.6 and 60 micrograms/kg egg for TCAOB and TCB, respectively.

Animals↗

PubMed1988

Extrahepatic sites of metabolism of halothane in the rat.

Rats were given 14C-halothane intravenously and whole-body autoradiography with freeze-dried sections, or with sections extracted in trichloroacetic acid, water, and organic solvents, was carried out to trace tissues accumulating halothane metabolites. In vitro incubations of tissue homogenates were performed to examine the capacity by the various organs to form tissue-bound 14C from the 14C-halothane. Autoradiography of isolated organs after incubation with 14C-halothane was performed to study the tissue localization of halothane metabolites formed under in vitro conditions. A localization of halothane metabolites was observed in several extrahepatic tissues in vivo, and the in vitro experiments showed a capacity by the same tissues to transform 14C-halothane to metabolites that bind strongly to tissue components. In addition to the liver, the other tissues shown to have a marked halothane-metabolizing capacity were the nasal mucosa, lateral nasal gland, mucosa of the tongue, cheek, soft palate (but not the hard palate), pharynx, larynx, oesophagus, and the tracheo-bronchial mucosa. The in vivo data obtained indicated a diffusion of the halothane over the walls of the large intestine and the caecum, followed by the formation of apparently reductive metabolites by intestinal microbes and a binding of the metabolites to the intestinal contents. The localization of halothane metabolites in the upper alimentary and respiratory pathways is correlated to the presence of cytochrome P-450 at these sites.

Animals↗

PubMed1987

3,3'4,4'-Tetrachlorobiphenyl in pregnant mice: embryotoxicity, teratogenicity, and toxic effects on the cultured embryonic thymus.

3,3',4,4'-Tetrachlorobiphenyl (TCB) is a known ligand of the Ah-receptor. When TCB was given to Ah-responsive C57BL/6 mice at gestation day 11, 12 or 13, a pattern of embryotoxic effects similar to those of TCDD was produced. This pattern included death and resorptions of the conceptus (peak sensitivity at day 11), as well as characteristic malformations such as cleft palate, dilated kidney pelvis (peak sensitivity day 12), and thymus hypoplasia (peak sensitivity day 13). The ED50 for cleft palate induction was found to be about 100 mg/kg, as compared to 30 micrograms/kg for TCDD (earlier results). The binding affinity of TCB for the Ah-receptor has been reported to be two orders of magnitude lower than that of TCDD. When TCB was introduced into a thymus organ culture (thymi taken from day-14 embryos), the lymphoid cell development was inhibited with an approximate EC50 of 5 X 10(-8) M. This is approximately 100 times higher than that of TCDD and in good agreement with the receptor binding affinities of both compounds. The difference in in vivo toxicity between TCB and TCDD can be explained by a more rapid metabolism and excretion of TCB.

Administration, Oral↗

PubMed1987

Preferential localization of 3H-pentosanpolysulphate to the urinary tract in rats.

Endogenous glycosaminoglycans probably have a protective effect in the urinary tract, e.g. against stone formation. The synthetic sulphated polysaccharide pentosanpolysulphate (PPS) has been suggested to exert a similar protective effect e.g. by inhibition of crystallization and bacterial anti-adhesion. We have studied the distribution in rats of tritium-labelled PPS. Chromatography showed this material to contain two distinct peaks with approximate molecular weight around 2.700 (60-70%) and 1.000 (30-40%) daltons. PPS was administered orally and intravenously (5 mg/kg b.wt.) to Sprague-Dawley rats, which were killed 1 and 4 hours later, respectively, and subjected to whole-body autoradiography. Autoradiograms of sections from intravenously injected rats showed an extensive distribution of radioactivity in the whole animal, with a notable labelling of connective tissues, while bone and cartilage had low activity. There was upper intestine activity, suggesting some hepatic excretion. The most conspicuous finding, however, was the high concentration in urine and a preferential localization of activity corresponding to the lining of the urinary tract (pelvis, ureter, and bladder). The distribution was similar, but the activity lower after oral administration. In one experiment, PPS was applied intravesically under anaesthesia, with and without epithelial destruction caused by instillation of 0.4 M HCl. After vigorous rinsing, with saline, the radioactivity was still retained in the bladder wall. In other intravenous experiments, the bladder was extirpated, everted and rinsed in saline or urea of increased osmolality. High amount of radioactivity could be rinsed off by 0.5 M saline. Chromatography of the rinsing solution showed presence of both fractions of PPS previously found in the injection solution.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1987

Saturable accumulation of retinoic acid in neural and neural crest derived cells in early embryonic development.

Retinoic acid (RA) binds to a cytosolic protein distinguishable from the cellular retinol (R) binding protein. Recent studies, showing an influence by R and RA on genomic expression, suggest an interaction with the cell nucleus mediated by the specific binding proteins in a manner resembling that of steroid hormones. RA can irreversibly stimulate in vitro differentiation of teratocarcinoma cells and support early embryonic development in vitamin A depleted animals. This study demonstrates a saturable, highly specific and regional accumulation of RA in the neuroepithelium and developing CNS that occurs in early but not in late fetal development in the mouse. The results suggest that a binding protein, or some other cellular mechanism for accumulation of RA is expressed in the neural cells only during restricted periods of development. High levels are recorded also in regions where cranial neural crest cells are known to migrate, and later in the visceral arches and maxillary areas, the mesenchyme of which is known to be partly derived from migrating cranial neural crest cells. The specific accumulation of RA in embryonic neural and cranial neural crest cells is in line with animal experiments and human clinical data, showing that retinoids specifically impair CNS, eye, ear, and facial development.

Animals↗