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Biomedical subjects

J A Ayres

Publications and source records attributed to J A Ayres.

11 recordsLinked to original sources
PubMed2002

Fibroblast growth factor signaling regulates Dach1 expression during skeletal development.

Dach1 is a mouse homologue of the Drosophila dachshund gene, which is a key regulator of cell fate determination during eye, leg, and brain development in the fly. We have investigated the expression and growth factor regulation of Dach1 during pre- and postnatal skeletal development in the mouse limb to understand better the function of Dach1. Dach1 was expressed in the distal mesenchyme of the early embryonic mouse limb bud and subsequently became restricted to the tips of digital cartilages. Dach1 protein was localized to postmitotic, prehypertrophic, and early hypertrophic chondrocytes during the initiation of ossification centers, but Dach1 was not expressed in growth plates that exhibited extensive ossification. Dach1 colocalized with Runx2/Cbfa1 in chondrocytes but not in the forming bone collar or primary spongiosa. Dach1 also colocalized with cyclin-dependent kinase inhibitors p27 (Kip1) and p57 (Kip2) in chondrocytes of the growth plate and in the epiphysis before the formation of the secondary ossification center. Because fibroblast growth factors (FGF), bone morphogenetic proteins (BMP), and hedgehog molecules (Hh) regulate skeletal patterning of the limb bud and chondrocyte maturation in developing endochondral bones, we investigated the regulation of Dach1 by these growth and differentiation factors. Expression of Dach1 in 11 days postcoitus mouse limb buds in organ culture was up-regulated by implanting beads soaked in FGF1, 2, 8, or 9 but not FGF10. BMP4-soaked beads down-regulated Dach1 expression, whereas Shh and bovine serum albumin had no effect. Furthermore, FGF4 or 8 could substitute for the apical ectodermal ridge in maintaining Dach1 expression in the limb buds. Immunolocalization of FGFR2 and FGFR3 revealed overlap with Dach1 expression during skeletal patterning and chondrocyte maturation. We conclude that Dach1 is a target gene of FGF signaling during limb skeletal development, and Dach1 may function as an intermediary in the FGF signaling pathway regulating cell proliferation or differentiation.

Animals↗
PubMed2001

DACH: genomic characterization, evaluation as a candidate for postaxial polydactyly type A2, and developmental expression pattern of the mouse homologue.

The gene DACH is a human homologue of Drosophila melanogaster dachshund (dac), which encodes a nuclear factor essential for determining cell fates in the eye, leg, and nervous system of the fly. To investigate possible connections between DACH and inherited developmental disorders, we have characterized the human DACH genomic structure and investigated the tissue and cellular distribution of the mouse DACH1 protein during development. DACH spans 400 kb and is encoded by 12 exons. The predominant DACH transcript is 5.2 kb and encodes a 706-amino-acid protein with an observed molecular weight of 97 kDa.DACH mRNA was detected in multiple adult human tissues including kidney and heart. The mouse DACH1 protein was immunolocalized to specific cell types within the developing kidneys, eyes, cochleae, and limb buds. Data suggest genetic linkage of the limb bud patterning defect postaxial polydactyly type A (designated PAP-A2, MIM 602085) to a 28-cM interval on chromosome 13 that includes DACH. However, mutation analysis of DACH in this PAP-A2 pedigree revealed no sequence differences in the coding region, splice sites, or proximal promoter region. The data presented will allow for the analysis of DACH as a candidate for other developmental disorders affecting the limbs, kidneys, eyes, ears, and other sites of DACH expression.

Alternative Splicing↗
PubMed1992

The 5' ends of LINE1 repeats in rabbit DNA define subfamilies and reveal a short sequence conserved between rabbits and humans.

The 5' ends of five full-length LINE1 (L1) repeats from the rabbit genome (L1Oc) were mapped and their nucleotide sequences determined. Computer-generated alignments showed that these five L1Oc repeats can be divided into subfamilies, each of which has a characteristic sequence upstream of the first open reading frame (ORF1). These five L1Ocs range in size from 6.5 to 7.3 kb, with 5' ends located 76 to 1125 bp upstream of ORF1. Two of these subfamilies appear to have diverged from a common ancestor at least 66 million years ago. Comparisons of the 5' ends of L1s from rabbit, human, mouse, and rat show no common sequence 5' to ORF1, except for a 22-bp sequence that is found near the beginning of all characterized full-length L1s from rabbit and human. A statistical analysis indicates that this 22-bp aligned block is highly significant. Part of this 22-bp sequence matches the microE1 binding site in immunoglobulin gene enhancers. This strong conservation suggests that the microE1 binding site may be part of a transcriptional regulatory element at the 5' ends of rabbit and human L1 repeats.

Animals↗
PubMed1985

Chronic toxicity and oncogenicity bioassay of inhaled ethyl acrylate in Fischer 344 rats and B6C3F1 mice.

Male and female Fischer 344 rats and B6C3F1 mice were exposed to 0, 25 or 75 ppm (0, 0.10 or 0.31 mg/l) ethyl acrylate vapors, 6 hours per day, 5 days per week, for a total of 27 months. Additional rats and mice were exposed to 225 ppm (0.92 mg/l) for 6 months and then held for 21 additional months post-exposure. Histopathologic changes in olfactory portions of the nasal mucosa were present in animals in all of these three exposure groups. These microscopic exposure-related changes were concentration-dependent, primarily in terms of distribution of the lesions within the nasal cavity. Generally those areas of the nasal mucosa normally lined by olfactory epithelium were altered, while the regions lined by respiratory epithelium were relatively unaffected. There was no indication of an oncogenic response in any organ or tissue in either rats or mice. A follow-up study in which Fischer 344 rats and B6C3F1 mice were exposed to 5 ppm (0.02 mg/l) for 24-months revealed no treatment-related changes in the nasal mucosa.

Acrylates↗
PubMedDate not supplied

Metabolism of acrylate esters in rat tissue homogenates.

Methyl, ethyl and butyl acrylate were hydrolyzed to acrylic acid in rat liver, kidney and lung homogenates. The rates of hydrolysis of the various esters in these in vitro studies were comparable; hydrolysis rates were approximately 20 times higher in liver homogenates than in kidney or lung homogenates. The esters also disappeared rapidly when added to blood in vitro. However, the disappearance in blood was not associated with the appearance of acrylic acid. Ethyl acrylate was found to react spontaneously with GSH in vitro and this reaction was catalyzed greatly by enzymes in 100 000 x g liver supernatant. Acrylic acid did not react with GSH in vitro. Ethyl acrylate, but not acrylic acid, depletes non-protein sulfhydryls when added to blood in vitro. Thus, the disappearance of acrylate esters in blood in vitro could be due at least in part to binding with non-protein sulfhydryls in red blood cells rather than to hydrolysis.

Acrylates↗
PubMedDate not supplied

Inhalation toxicity of acrylic acid.

Male and female Fischer 344 rats and B6C3F1 mice were exposed to 0, 5, 25 or 75 ppm acrylic acid vapors 6 hours per day, 5 days per week, for 13 weeks. These exposure levels were selected after conducting a 2-week probe study in which 225 ppm caused pronounced growth retardation and nasal lesions in both rats and mice. The 13-week exposures had no adverse effect on the growth of male and female rats and male mice. However, mean body weight gains of female mice in the 25 and 75 ppm exposure groups were statistically significantly lower than for controls after 12 weeks of exposure. There were no pronounced treatment related effects on organ weights, hematologic parameters, clinical chemistry parameters or urinary parameters. Histopathologic examinations revealed lesions of the nasal mucosa in rats in the 75 ppm exposure group, and in some or all mice at each treatment level. The nasal lesions were primarily localized to the olfactory epithelium; the respiratory epithelium was relatively unaffected. The histopathologic observations in both rats and mice included degeneration, and inflammatory cell infiltration in the olfactory mucosa. In mice there were also instances of hyperplasia of the submucosal glands and, replacement of olfactory epithelium by respiratory epithelium. These effects were attributed to the irritant properties of acrylic acid vapors.

Acrolein↗
PubMedDate not supplied

Ethyl chloride: a two-week inhalation toxicity study and effects on liver non-protein sulfhydryl concentrations.

Male and female Fischer 344 rats (6/sex/exposure concentration) and male beagle dogs (2/exposure concentration) exposed to 0, 1600, 4000 or 10 000 ppm ethyl chloride (EtCl) for 6 hr/da, 5 da/wk for 2 weeks showed no toxicologically significant treatment-related effects on body weights; clinical chemistry, hematology, or urinalysis parameters; neurology (dogs only were examined); gross pathology or histopathology. The only treatment-related differences in organ or relative organ weights (in rats or dogs) were slight, but statistically significant increases in liver to body weight ratios of male rats exposed to 4000 or 10,000 ppm EtCl (4.9 and 7.5% respectively). Liver non-protein sulfhydryl (NPSH) concentration was measured in male Fischer rats and male B6C3F1 mice that were exposed for 6 hours to 0, 1600, 4000 or 10,000 ppm EtCl (mice were exposed to 0 or 4000 ppm EtCl only). Liver NPSH, measured 1/2 hr post exposure, was less than control values in 4000 ppm exposed rats (88% of control value), 4000 ppm exposed mice (64%), and 10,000 ppm exposed rats (89%). The slight decreases in rat liver NPSH seem consistent with the increased liver to body weight ratios. The toxicity data indicate that 2-week repeated exposures to EtCl concentrations that were up to 10 times the current A.C.G.I.H. T.L.V. (1000 ppm) caused minimal treatment-related effects in dogs and rats.

Animals↗
PubMedDate not supplied

Teratologic evaluation of inhaled epichlorohydrin and allyl chloride in rats and rabbits.

Pregnant Sprague-Dawley rats and New Zealand white rabbits were exposed to vapors of epichlorohydrin (ECH) at concentrations of 0, 2.5 or 25 ppm or to allyl chloride (AC) at concentrations of 0, 30, or 300 ppm. Exposures were for 7 hr/day on days 6 through 15 (rats) or 6 through 18 (rabbits) of gestation. Maternal effects including decreased body weight and food consumption were observed among rats inhaling 25 ppm of ECH. No evidence of an adverse effect to the embryo or fetus was observed among rats or rabbits following exposure to ECH. In the AC study maternal toxicity occurred in both rats and rabbits treated at 300 ppm. These consisted of depressed weight gain during gestation and increases in liver weight (both species) and kidney weights (rats only). Fetuses from rats exposed to 300 ppm of AC had a slight delay in skeletal development but there were no other signs of embryotoxicity. Thus, ECH and AC were not teratogenic or embryolethal in rats or rabbits following inhalation exposure to concentrations which induced effects in the maternal animals.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Ethylene glycol monomethyl ether. I. Subchronic vapor inhalation study with rats and rabbits.

Male and female Sprague-Dawley rats and New Zealand White rabbits were exposed to 0, 30, 100 or 300 ppm ethylene glycol monomethyl ether (EGME) vapors 6 hours per day, 5 days per week, for a total of 13 weeks. No rats died prior to scheduled sacrifice, but some rabbits in the 100 and 300 ppm exposure groups died or were sacrificed when moribund during the study. Body weights as well as thymus and testicular weights of rats and rabbits in the 300 ppm group were reduced as a result of the exposures. Hematologic changes occurred in rats and rabbits exposed to 300 ppm. Concentrations of total protein, albumin and globulins in serum of rats (but not rabbits) in the 300 ppm group were lower than for controls. Gross lesions in rats and rabbits exposed to 300 ppm EGME included decreased size of thymus in both sexes, decreased abdominal fat, and small flaccid testes in males. In addition there was decreased lymphoid tissue in some rabbits, as well as a slight-to-moderate decrease in size of testes in 4 of 5 rabbits in the 100 ppm group and in 2 of 5 rabbits exposed to 30 ppm. Treatment-related microscopic lesions included degenerative changes in germinal epithelium of testes in all male rats and rabbits in the 300 ppm group, as well as in 3 of 5 rabbits in the 100 ppm group and 1 of 5 male rabbits in the 30 ppm group. The only effects attributed to exposure to 30 ppm EGME in this study were slight microscopic changes in testes of 1 of 5 male rabbits.

Animals↗