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FETAX interlaboratory validation study: phase III--Part 1 testing.

The Frog Embryo Teratogenesis Assay-Xenopus (FETAX) is a 96-h whole embryo developmental toxicity screening assay that can be used in ecotoxicology and in detecting mammalian developmental toxicants when an in vitro metabolic activation system is employed. A standardized American Society for Testing and Materials (ASTM) guide for the conduct of FETAX has been published, along with a companion atlas that aids in embryo staging and identifying malformations. As part of the ASTM process, a three-phase interlaboratory validation study was undertaken to evaluate the repeatability and reliability of FETAX. Seven different participants collaborated in the study. In Phase I, FETAX proved to be more repeatable and reliable than many bioassays. However, some excessive variation was observed in a few laboratories. An initial lack of assay experience by some technicians caused variation. Phase II showed far less intra- and interlaboratory variability than Phase I. Non-teratogens showed the most consistent results, while more variability was observed for the two teratogens tested. Interlaboratory coefficient of variation values for all endpoints ranged from 7.3 to 54.7. Phase III--Part 1, using coded samples and test concentration ranges selected by each laboratory, showed results similar to Phase I. Analysis of the causes of variation suggested that some technicians judged some embryos to be malformed while others consistently judged similar embryos as normal. Concentration ranges tested by some of the laboratories varied greatly and a new protocol for selecting concentrations for initial testing was written to reduce variation from this source. Testing to date suggests that FETAX is as repeatable and reliable as other standard bioassays.

Aminopropionitrile↗
PubMed1983

Classical syndromes in occupational medicine: dimethylaminopropionitrile.

Dimethylaminopropionitrile, used as a catalyst in the manufacture of polyurethane, was responsible for two epidemics of urinary retention, sexual dysfunction, and peripheral neuropathy in 1978. Most affected workers recovered promptly, but some have had persisting neuropathy, sexual and bladder dysfunction, and CNS symptoms. The mechanism of neurotoxicity appears to be interference with axoplasmic transport. The catalyst that caused the problem was withdrawn from the market after swift governmental action.

Aminopropionitrile↗
PubMed1978

Ultrastructural identification of collagen and glycosaminoglycans in notochordal extracellular matrix in vivo and in vitro.

Notochordal extracellular matrix consists of a continuous basal lamina, amorphous materials and microfibrils embedded in the ground substance of low electron density. Together they comprise the notochord sheath and are of considerable interest because of their suspected role in early embryonic tissue interactions. The notochord is particularly well-suited to morphological investigation of extracellular matrix because it is one of the few embryonic epithelia which produces ultrastructurally recognizable stroma in vitro without the advantage of a collagenous substratum. Furthermore, these matrix components produced in vitro are morphologically identical to those observed in vivo. The present study used ruthenium red staining to demonstrate that notochordal microfibrils exhibit collagen-like cross-banding patterns both in vivo and in vitro. Collagenase and testicular hyaluronidase digestion studies designed to localize collagen and glycosaminoglycans show a reduction of microfibrillar diameters by 30-35%. Furthermore, these enzyme treatments frequently result in enhanced striations of microfibrils. When cis-hydroxyproline (a proline analog) or beta-aminoproprionitrile (BAPN, a lathyrogenic compound) is added to the culture medium, a similar reduction in microfibrillar diameters is seen. Moreover, increased ruthenium red-positive surface coats and large collagen fibrils are frequently present in BAPN-treated cultures, implying a stimulatory metabolic effect. We conclude that most, if not all, notochordal extracellular matrix components are composed of both collagen and glycosaminoglycans and suggest that the entire extracellular matrix should be considered a macromolecular composite which acts in concert to induce or stabilize developmental interactions.

Aminopropionitrile↗
PubMed1984

The effect of beta-aminoproprionitrile on the periodontal ligament: II. Radioautographic study of collagen secretion from fibroblasts.

Fibroblasts are distributed evenly throughout the periodontal ligament (PDL) of normal mice. In mice fed beta-aminoproprionitrile (beta-APN) the fibroblasts undergo aggregation to form palisades of closely juxtaposed cells abutting pools of acellular collagenous matrix. Individual fibroblasts within these aggregates retain their polarized cytoplasmic organization and continue to synthesize and secrete collagen. However, unlike normal PDL fibroblasts, the beta-APN-treated cells appear immobilized by well-developed cell-to-cell adherens-type junctions along their lateral surfaces. We studied collagen secretion from beta-APN-treated fibroblasts by light and electron microscopic radioautography after injection of 3H-proline. Newly synthesized collagen was secreted from the distal ends of the beta-APN-aggregated fibroblasts as a distinct band of labeled material, resembling the pattern of matrix deposition seen in osteogenesis and dentinogenesis. The radioactive band of collagenous matrix was displaced further away from the fibroblasts at 2 and 4 days after 3H-proline injection as more collagen was secreted. This pattern of radiolabeled collagen secretion confirmed previous observations that PDL fibroblasts are highly polarized and that collagen secretory granules are extruded from the distal or secretory pole of the cell. In normal PDL the even distribution of fibroblasts and the complex interrelationship of their distal cell processes leads to a diffuse pattern of silver grain deposition, masking the oriented flow of new collagen from the distal ends of individual fibroblasts. Analysis of electron microscopic radioautographs revealed that newly synthesized collagen was packaged and secreted from beta-APN-treated fibroblasts via the normal cytoplasmic pathways but at a slower rate.

Aminopropionitrile↗
PubMed1977

Stress-generated potentials in bone: effects of collagen modifications.

The effect of collagen modification on the magnitude of stress-generated potentials has been studied. A whole bone model has been developed for determining the effects of collagen crosslinking on the electrical signals. Increased crosslinking results in larger electrical signals, and such increases result whether in vivo or in vitro changes in the collagen are made.

Aging↗
PubMed1991

Role of the extracellular matrix in tissue-specific gene expression in the sea urchin embryo.

The role of extracellular matrix (ECM) in the differentiation of tissue types was examined in embryos of Strongylocentrotus purpuratus. We have examined the expression of various tissue-specific molecular markers after disrupting the ECM by culturing embryos in the presence of beta-aminoproprionitrile fumarate (BAPN), which disrupts collagen deposition, and beta-D-xyloside, which disrupts proteoglycan metabolism. The markers examined included accumulation of primary mesenchyme-specific mRNA (SM 50); an aboral ectoderm-specific mRNA (Spec 1); and a gut-specific enzyme, alkaline phosphatase. Treatment with BAPN or beta-D-xyloside results in developmental arrest at the mesenchyme blastula stage. Although spicule formation is inhibited, the accumulation of SM 50 transcripts and the synthesis of most of the prominent spicule matrix proteins is similar to that of control embryos. Spec 1 mRNA, in contrast, while accumulating to a significant extent when collagen and proteoglycan metabolism is disrupted, does accumulate to a level somewhat lower than that seen in control embryos. Additionally, the postgastrula rise in gut-specific alkaline phosphatase is reversibly inhibited by BAPN and xyloside treatment. These results demonstrate a differential effect of the ECM on expression of tissue-specific molecular markers.

Alkaline Phosphatase↗
PubMed1988

Acetylcholine receptor clustering and triton solubility: neural effect.

Previous studies by Prives et al. (1980, 1982a and b) have shown that acetylcholine receptors (AchRs) are extracted from muscle cells in vitro by Triton X-100 at different rates, and that clustered receptors extract most slowly. The present study was aimed at comparing the relative extractability of receptors in clusters with those in intercluster regions and the role of neural factors in regulating this extractability. Using primary rat muscle cells in vitro we confirmed that receptor extraction with Triton X-100 does not fit a single exponential but has more than one rate, and that in control cells clustered receptors extract more slowly than do receptors in intercluster regions. The major new observation in this study was that neural extract lowered the overall Triton extraction rate of intercluster receptors to that of clustered receptors. Additional new observations include the findings that (1) both clustered and intercluster receptors show multiphasic extraction rates; (2) stabilization of AchRs against Triton extraction increases with time in the surface membrane; (3) the effect of neural extract on Triton extractability of AChR is dependent on factors that control RNA synthesis, cytoskeletal elements, and collagen; (4) fixation and/or buffer washes accelerate receptor extraction only in cells that are treated with Triton, but not in control cells; (5) in control cells (not exposed to neural factors) Triton X-100 causes new clusters to form. From experiments using Con A we suggest that the Triton-induced new clusters may not be formed by a redistribution of receptors but are, most likely, due to the presence of groups of intercluster receptors with extraction rates lower than those of surrounding receptors.

Aminopropionitrile↗
PubMed1980

An ultrastructural study of fibroblasts derived from bovine ligamentum nuchae and their capacity for elastogenesis in culture.

Fibroblast cultures were readily propagated from fetal bovine ligamentum nuchae. The ligament cells were easily cultured by standard techniques and were maintained in culture flasks for up to 57 days. During this time they accumulated an extensive extracellular matrix which contained the main structural elements of the parent tissue, namely collagen and elastic fibres. Elastogenesis was seen to proceed in two phases: the formation of parallel bundles of 10--12 nm wide microfibrils followed by the deposition within these bundles of amorphous elastin-like material. Elastic fibres were not produced in cultures that were supplemented with ascorbic acid either in the absence or presence of the lathyrogen BAPN.

Aminopropionitrile↗
PubMed1975

The use of in vitro procedures in teratology.

The capabilities of investigators in the fields of teratology and toxicology are greatly enhanced by the use of tissue culture procedures in unraveling the mechanisms of drug action. Techniques currently available for the culture of postimplantation mammalian embryos permit evaluation of their metabolic responses to potential teratogens even when the length of time embryos survive and develop in culture is too short to allow a conventional teratologic survey of malformations. A simple procedure for culturing mouse embryos during early organogenetic stages is described in this report that will be of value to teratologists; it avoids the requirements of special glassware and equipment by using ordinary capped test tubes which are rotated tomaintain and efficient nutritional and gaseous evnironment. Some studies concucted with this procedure to monitor the metabolism of embryo during the first 24 h of culture are summarized. Another aspect of tissue culture, organ culture, provides further manipulative capability by which embryonic organs can be maintained for long periods of time during which they develop and differentiate to an extent that their morphological and biochemical responses to a teratogen can usually be made. Comparative effects of several teratogenic agents and the relative concentration of each that produces a similar degree of response are summarized. It is concluded that organs are more sensitive to teratogens in culture than they are in vivo, and that different teratogens possess enough specificity to isolate their simple growth-retarding effect from the role they play in distrubing other specific developmental events.

Abnormalities, Drug-Induced↗
PubMed1981

Teratogenic effects of proline analogue L-azetidine-2-carboxylic acid in hamster fetuses.

The teratogenic effects of L-azetidine-2-carboxylic acid (LACA) were evaluated in hamsters. Single or multiple intraperitoneal injections of LACA were given on gestational days 7-12. Fetal weights were significantly reduced in several LACA-treated groups as compared to controls. The frequency of external anomalies was significantly higher than controls in only two LACA-treated groups: 7.2% in 600 mg/kg on day 12 and 9.6% in 200 mg/kg/day on days 10-12. Subcutaneous hemorrhage and cleft palate were the most frequently occurring externally visible defects. Skeletal anomalies such as retarded ossification, synchronous vertebral ossification and shortening of bones were found in a high percentage of LACA-treated fetuses. The major teratological effect of LACA appeared to be the retardation of skeletal development.

Abnormalities, Drug-Induced↗
PubMed1981

Correlation between alterations in Meckel's cartilage and induction of cleft palate with beta-aminoproprionitrile in the rat.

The lathyrogen beta-aminoproprionitrile (BAPN) induces cleft palate in rats when administered at a critical time in secondary palate formation. BAPN is known to inhibit the crosslinking of newly synthesized collagen, but its primary site of action in producing cleft palate is unknown. In this study time-mated Sprague-Dawley rats were given a single oral dose of 600 mg/kg BAPN at five known gestational ages in the 48 hours before palatal shelf elevation, and the fetuses were studied on days 16, 17 and 18. Evaluation of craniofacial relations and palate development in BAPN-treated heads revealed that delayed palatal shelf elevation and resulting cleft palate were related to retrognathia of the mandible. However, shortening of the mandible was due primarily to vertical and lateral bending of Meckel's cartilage. High and retruded tongue positions that were present with the deformities in Meckel's cartilage interfered with palatal shelf movement to the horizontal plane. The group treated with BAPN at 15 days 7 hours, approximately 24 hours before normal palatal shelf elevation, had the most severe defects in Meckel's cartilage, the longest delay in palatal shelf elevation and the highest incidence of cleft palate. Inhibition of crosslinking of collagen in Meckel's cartilage appeared to weaken the cartilage during the critical period in facial development when extention of the tongue and mandible beneath the primary palate is required to facilitate palatal shelf elevation.

Aminopropionitrile↗
PubMed1993

Effects of heparin and other glycosaminoglycans on elastin production by cultured neonatal rat lung fibroblasts.

Proteoglycans are important structural elements of the extracellular matrix, and may contribute to the dynamic architecture of the lung and also influence pulmonary gas and solute exchange. The potential for proteoglycans and glycosaminoglycans to modulate the synthesis and deposition of elastin, another important extracellular matrix component of the lung, has not been established. Therefore the effects of glycosaminoglycans on the steady-state level of elastin mRNA, the incorporation of [3H]valine into tropoelastin, the distribution of soluble elastin in the medium and cell layer, and insoluble elastin deposition have been examined using cultured neonatal rat lung fibroblasts. Heparin decreases the soluble elastin content of the culture medium while increasing the soluble elastin content of the cell layer. This altered partitioning of soluble elastin is associated with an increase in steady-state elastin mRNA and an increase in the deposition of insoluble elastin in the extracellular matrix. Some of these effects may result from the binding of heparin to soluble elastin at physiological concentrations of NaCl. The galactosamine-containing glycosaminoglycans, chondroitin sulfate and dermatan sulfate, differ from heparin in that they increase the quantity of soluble elastin in the culture medium and decrease the deposition of insoluble elastin in the extracellular matrix. Proteoglycans, which are present in most elastic tissues, may participate in the regulation of elastin synthesis and deposition during periods of new elastin formation.

Aminopropionitrile↗
PubMed1993

Extracellular matrix (mesoglea) of Hydra vulgaris III. Formation and function during morphogenesis of hydra cell aggregates.

Hydra, as a member of the phylum Cnidaria, is characterized by a body lining organized as an epithelial bilayer with an intervening extracellular matrix (ECM) termed the mesoglea. Previous studies have established that the mesoglea has components indicative of mammalian ECM such as type IV collagen, laminin, fibronectin, and heparan sulfate proteoglycan, and these components appear to play a critical role in hydra head regeneration. A remarkable feature of hydra is its ability to reorganize into its adult structure within 96 hr to 7 days from pellets formed from dissociated hydra cells. This regenerative model has been termed the hydra cell aggregate system. The present study has been designed to characterize the biogenesis of mesoglea in hydra cell aggregates and to determine its role in morphogenesis of aggregates. We find that hydra cell aggregates first form an epithelial bilayer by 12 hr of development and then subsequently develop a mesoglea. Morphogenesis of hydra structure then follows formation of the mesoglea. Immunofluorescence studies indicate that mesoglea components are first deposited between the epithelial bilayer by about 12-17 hr of pellet formation, and pulse-labeling studies indicate that the translation rate of matrix components peaks by 48-72 hr of development. Ultrastructural studies indicate that a mature mesoglea is formed by 48-96 hr of pellet formation. Drugs such as beta-aminoproprionitrile and 2,2'-dipydridyl, which interfere with the cross-linking of collagens, and p-nitrophenyl-beta-D-xylopyranoside, which interferes with the addition of GAG moieties to proteoglycan core molecules, were found to reversibly block development of hydra cell aggregates. Transmission electron microscopy studies indicate that these drugs affect the ultrastructure of the mesoglea. In addition, both polyclonal and monoclonal antibodies raised to isolated mesoglea were found to block development of hydra cell aggregates. These studies indicate that (1) mesoglea formation is rapid and precedes morphogenetic processes during aggregate development, and (2) formation of mesoglea is essential for normal morphogenesis of hydra cell aggregates.

2,2'-Dipyridyl↗
PubMed1994

Prevention of collagen crosslinking increases form-deprivation myopia in tree shrew.

To examine whether collagen crosslinking is important for the regulation of refractive development, tree shrews were treated with agents that block collagen crosslinking [beta-aminoproprionitrile (beta-APN), or D-penicillamine (DPA)] and underwent monocular deprivation (MD) of form vision by eyelid closure to induce myopia. MD began on the first day of visual exposure and continued for 75 days. After 15-20 days of visual exposure, daily intraperitoneal injections of beta-APN (beta-APN MD animals, n = 5) or DPA (DPA MD animals, n = 5) were administered for 17-21 days. beta-APN open animals (n = 5) received the same injection schedule, but both eyes remained open. Saline MD animals (n = 5) received i.p. saline and MD. At 75 days of visual exposure, the MD eyes of beta-APN treated tree shrews were highly myopic (-23.6 +/- 3.3 D) in comparison to their open control eyes. This was markedly greater than the difference in saline MD animals (-11.0 +/- 0.8 D). DPA MD animals showed a relative myopia of -14.3 +/- 2.2 D. The structural correlate of the myopia, elongation of the vitreous chamber in the deprived eyes relative to the control eyes, was significantly greater in the beta-APN MD animals 0.53 +/- 0.03 mm, which was not significantly different from the saline MD group. Thinning of the posterior sclera, but not the cornea, was observed in the deprived eyes of beta-APN treated tree shrews, along with a tessellated appearance to the fundus. The eyes of the beta-APN open animals showed no significant differences from normal. Beta-APN MD and DPA MD treated chickens did not develop greater myopia or vitreous chamber elongation than standard MD chickens. The selective effect of the lathyritic agents on the deprived eyes in tree shrew suggests that collagen crosslinking interacts, in the mammalian sclera, with a retinally-derived signal to regulate the elongation of the eye in myopia.

Aminopropionitrile↗