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Metabolism of Acrylic Acid to Carbon Dioxide in Mouse Tissues

Metabolism of Acrylic Acid to Carbon Dioxide in Mouse Tissues. Black, K. A., Finch, L., and Frederick, C. B. (1993). Fundam. Appl. Toxicol. 21, 97-104.Acrylic acid (AA) is acutely irritating at sites of initial contact but causes little systemic toxicity probably due to its rapid metabolism to CO2 and acetyl-CoA via a secondary pathway of propionic acid catabolism. In this study, the rate of AA oxidation in 13 tissues of C3H mice was measured by incubating tissue slices with [1-14C]AA and collecting 14CO2. Oxidation of AA followed pseudo-Michaelis-Menten kinetics in the liver, kidney, and skin. Pseudo-Km values were similar among these tissues and averaged 0.67 mM. The maximal rate of AA oxidation in kidney, liver, and skin was 2890 ± 436 (mean ± SE, N = 3), 616 ± 62, and 47.9 ± 5.8 nmol/hr/g, respectively. The remaining organs oxidized AA at rates less than 40% of the rate in liver. Rates of metabolism in tissues from male and female mice were similar. 3-Hydroxypropionic acid was the only metabolite detected by high-performance liquid chromatographic analysis following incubation of tissues with [1-14C]AA. Kidney and liver also oxidized [2,3-14C]AA and [1-14C]acetate well, thus providing for the complete metabolism of AA carbons to CO2. These results demonstrate that the rate of AA metabolism varies significantly among mouse tissues and suggest that the kidneys and liver are major sites of detoxification of AA.

Genotoxic activity of 1-chloromethylpyrene in stomach epithelium in vivo: insensitivity of the stomach scintillation UDS assay.

An acknowledged weakness of current testing programmes for genotoxic hazard has been the potential insensitivity of the established mouse bone marrow micronucleus test and rat liver unscheduled DNA synthesis (UDS) assays to direct-acting or short-lived mutagens, which may be consumed at the site of initial contact. In such cases, in vivo test systems sampling tissues such as the skin or the stomach would provide valuable data. To test these principles a stomach UDS assay was evaluated using the potent locally active mutagen 1-chloromethylpyrene (1-CMP). Contrary to expectations, no UDS response was observed 16 h following 1-CMP dosage by oral gavage. To confirm the integrity of the 1-CMP used for the stomach UDS assay, a sample of the stored chemical was re-evaluated in vitro and shown to be still strongly positive in the Ames assay and to have alkylating activity at least 15 min after incubation at stomach acid pH. No UDS response was observed when test dose levels were reduced or when earlier sampling times were used. Other genotoxic endpoints were examined in stomach. 32P-Postlabelling analysis revealed high levels of adduct formation in gastric DNA. An assay utilizing electrophoresis of DNA (the comet assay) showed the occurrence of DNA damage following dosing with 1-CMP in vivo. These positive results confirmed that 1-CMP should be regarded as a potential in vivo genotoxin. The failure to detect a UDS response to 1-CMP in stomach was investigated; a strong UDS response was observed in an in vitro hepatocyte UDS assay of 1-CMP indicating that the rat was capable of repairing 1-CMP-derived DNA adducts. Pretreatment of rats with hydroxyurea depressed the level of incorporation of thymidine into DNA both in negative and positive [methyl-N-nitrosoguanidine (MNNG)] controls. The results of these studies indicated that the protease digestion method employed did not selectively or efficiently sample those cells with any UDS response to 1-CMP or MNNG, and the activity seen for the latter was most likely due to the presence of S phase cells within the digests. As a result of the finding that UDS responses were not demonstrated for the potent direct-acting mutagens 1-CMP and MNNG, the protease digestion/scintillation method for stomach UDS does not appear to have general value in a screening programme for locally active genotoxic agents.

Metabolism of Acrylic Acid to Carbon Dioxide in Mouse Tissues

Acrylic acid (AA) is acutely irritating at sites of initial contact but causes little systemic toxicity probably due to its rapid metabolism to CO2 and acetyl-CoA via a secondary pathway of propionic acid catabolism. In this study, the rate of AA oxidation in 13 tissues of C3H mice was measured by incubating tissue slices with [1-14C]AA and collecting 14CO2. Oxidation of AA followed pseudo-Michaelis-Menten kinetics in the liver, kidney, and skin. Pseudo-Km values were similar among these tissues and a veraged 0.67 mM. The maximal rate of AA oxidation in kidney, liver, and skin was 2890±436 (mean±SE, N=3), 616±62, and 47.9±5.8 nmol/hr/g, respectively. The remaining organs oxidized AA at rates less than 40% of the rate in liver. Rates of metabolism in tissues from male and female mice were similar. 3-Hydroxypropionic acid was the only metabolite detected by high-performance liquid chromatographic analysis following incubation of tissues with [1-14C]AA. Kidney and liver also oxidized [2,3-14C]AA and [1-14C]acetate well, thus providing for the complete metabolism of AA carbons to CO2. These results demonstrate that the rate of AA metabolism varies significantly among mouse tissues and suggest that the kidneys and liver are major sites of detoxification of AA.

Corrosive Acid-Induced Esophageal Intramural Pseudodiverticulosis A Study of 14 Patients

Esophageal intramural pseudodiverticulosis (EIP) is a rare disease, characterized by multiple, small flask-shaped diverticula in the esophageal wall, and best demonstrated on single-contrast barium examination. Though the condition is often associated with reflux esophagitis, Candida esophagitis, and esophageal dysmotility, corrosive-acid injury is not a commonly recognized cause. In a radiological study involving 59 patients with sequelae of corrosive-acid injury of the upper gastrointestinal (GI) tract, evaluated over a 5-year period, 14 cases (23.7%) of EIP were found. Esophageal stricture was a constant association; the diverticula tended to involve either the entire length of the stricture or its upper part. There was, however, no correlation between the length of the stricture and number of diverticula (p greater than 0.05). Endoscopic dilatation resulted in relief of dysphagia, and the diverticula regressed in number of disappeared altogether. Our experience suggests that EIP is a common sequelae of esophageal acid injuries, and that diverticula tend to form at the site of initial contact between acid and susceptible esophageal mucosa. Stricture dilatation leads to reduction or total disappearance of the diverticula.

Antigen receptors and adhesion molecules on T lymphocytes in the gut

The gut-associated lymphoid tissue represents an important site of initial contact with foreign antigens from the intestinal lumen. It is a complex immune system comprising of Peyer's patches, mesenteric lymph nodes, mucosal lymphocytes present in the lamina propria, and intraepithelial lymphocytes located on the luminal surface of the basement membrane and adjacent to the basolateral side of enterocytes. The function and immunoregulation of the gut-associated lyphoid tissue and its role in the pathogenesis of intestinal diseases are only partly understood. We summarize selected advances in understanding the cell-surface molecules involved in homing and adhesion of T cells in the gut-associated lymphoid tissue and the nature of the T-cell antigen receptor repertoire expressed by intraepithelial lymphocytes.

Genetically based animal model of depression and anxiety: Pharmacological aspect

<dm:abstracts xmlns:dm="http://www.elsevier.com/xml/dm/dtd"><ce:abstract xmlns:ce="http://www.elsevier.com/xml/common/dtd" view="all" class="author" id="aep-abstract-id1"><ce:section-title>Publisher Summary</ce:section-title><ce:abstract-sec view="all" id="aep-abstract-sec-id1"><ce:simple-para id="fsabs080" view="all">This chapter presents a summary of mammalian toxicokinetics and toxicity of chlorothalonil. Chlorothalonil is a halogenated benzonitrile fungicide with broad-spectrum activity against vegetable, ornamental, orchard, and turf diseases. Chlorothalonil is available in a wide variety of formulations including suspension concentrates, and water dispersible granules. Its mode of fungicidal action is to bind to sulfhydryl groups of amino acids, proteins, and peptides, and in doing so, it ties up free glutathione in fungal cells, thereby blocking glycolytic and respiratory enzyme pathways. Chlorothalonil has very low acute toxicity by the oral and dermal routes, although it is very toxic by inhalation. Many of the effects seen following acute exposure are consistent with irritation at the initial site of contact. However, chlorothalonil was not irritating to skin when tested in a standard skin irritation study, although dermal irritation has been observed in acute and subchronic toxicity studies in the rat and rabbit, indicating the potential for chlorothalonil to cause skin irritation following repeated or prolonged exposure.</ce:simple-para></ce:abstract-sec></ce:abstract></dm:abstracts>

Light and electron microscopic studies of the basilar papilla in the duck, Anas platyrhynchos. II. Embryonic development.

The intent of this study was to describe certain morphological aspects of cytodifferentiation of the basilar papilla in the duck, Anas platyrhynchos. The duck, with a longer incubation period than that of the chicken, has proven useful in identifying the earliest morphological changes during cyto-differentiation of the basilar papilla. Most of these changes occur first at the neural margin of the presumptive genu, at the site of initial contact by cochlear nerve fibers. A wave of differentiation of hair cells radiates abneurally, proximally, and distally, concurrent with the establishment of afferent innervation. Extracellular channels form in the papilla between cell bases just before the nerve fibers penetrate the basal lamina. Nerve fibers abut hair cell bases in the genu at the time the hair cells separate from the basal lamina on day 9. Hair cell bases contain granular vesicles and lie among the nuclei of supporting cells on day 10. Synaptic bodies are present opposite nerve endings on day 11. Efferent nerve endings appear on short hair cells in the genu on day 15 and on tall hair cells on day 17.

Methods of study of the invasion of malignant C3H-mouse fibroblasts into embryonic chick heart in vitro.

Methods of study of tumour invasiveness in vitro were investigated using the interactions between malignant virally transformed C3H mouse fibroblasts (MO4) with fragments from embryonic chick heart. Invasion of MO4 cells into the heart tissue could be demonstrated in all three-dimensional cultures. On the contrary, seeding of MO4 cells on top of a monolayer of heart cells did not mimic invasion. Precultured heart fragments were more suitable for the study of the early phase of invasion than freshly cut ones because they presented healthy well-delineated borders. Aggregates of MO4 cells proved more suitable than suspensions or monolayer fragments because they were amenable to quantitation, were not traumatized or treated with enzymes during harvest. They allowed precise control of the initial site of contact with the heart tissue. The nature of the culture medium predominantly affected the growth of the MO4 population. This factor influenced the pattern of invasion quantitatively, but did not alter the invasive capacity of the MO4 cells itself. In cultures on adhesive substrates the interaction between the MO4 cells and the heart tissue was complicated by the fact that both also interacted with the aritficial substrate. Shaker cultures appeared better than comparable static cultures because they allowed better aeration and so delayed central necrosis.