Structure-activity relationships for osteolathyrism: I. Effects of altering the semicarbazide structure.

摘要: The toxic and osteolathyrogenic effects of 15 chemicals reflecting modifications semicarbazide [H2N-N(H)-C(=O)-NH2] were evaluated using the Frog Embryo Teratogenesis Assay: Xenopus (FETAX). Osteolathyrism, failure connective tissue fibers to cross-link correctly, is expressed as gross alterations in long axis embryo a sinusoidal configuration notochord. Alteration (addition or subtraction) at hydrazino (H2NNH-) end molecule sharply reduces activity. amino (H2N-) results graded response. replacement oxygen with sulfur causes no loss Among myriad events constituting vertebrate organogenesis formation intercellular elements such collagen elastin. Failure this developing elastin polymerize properly termed osteolathyrism (Selye, 1957). An agent, therefore, any chemical that produces increased fragility extractability (Levene, 1973). This thought result because inhibition copper-requiring enzyme lysyl oxidase (Harris et al., 1974) necessary for extracellular cross-linking both (Bailey, 1968) (Barrow maturation. Studies experimentally-induced have utilized number 1These studies supported by National Institute Environmental Health Sciences Grant R01 ES04209 T.W.S. 2 Supported U.S. Protection Agency under Cooperative Agreement CR813158 3 part CR-813158 University Tennessee, College Veterinary Medicine, Agriculture, Center Excellence Livestock Diseases Human Health. TRANS. AM. MICROSC. SOC., 107(2): 113-126. 1988. ? Copyright, 1988, American Microscopical Society, Inc. content downloaded from 207.46.13.110 on Fri, 09 Dec 2016 05:44:01 UTC All use subject http://about.jstor.org/terms SOC. natural synthetic 1961). One compound semicarbazide. Neuman al. (1956), an effort produce liver damage chick embryos similar observed following administration aminoguanidine, injected into incubating eggs. Although had effect liver, it did induce skeletal abnormalities those described Chang (1954) exposure beta-aminopropionitrile. initial documentation potential was followed Dasler (1958) Sprague-Dawley rats Levy (1959) salamander toad embryos. These latter investigations axial malformations treated individuals suggested strong direct-acting teratogen. Recent work our laboratory has documented in-depth embryotoxic teratogenic (Schultz 1985) benzoyl hydrazine (Riggin & Schultz, 1986) frog assay vitro bioassay early laevis referred FETAX (Frog Xenopus) developed screening system (Dumont 1983). several advantages system, including cost time effectiveness. In addition, classic experimental embryological developmentally relevant mammals undergoing (i.e., cleavage, gastrulation, organogenesis) comparable other vertebrates. investigation, we used explore structure-activity relationships examining relative toxicity osteolathyrogenicity series are structural MATERIALS AND METHODS Embryos obtained adult pairs human chorionic gonadotropin ovulation amplexus. Healthyappearing mid-blastula selected individually dissecting microscope. Groups 25 each placed 60 x 15mm Pyrex dishes 10-ml solutions graduated concentrations test solution (625 mg NaCl, 96 NaHCO3, 30 KCl, CaC12, CaSO4 2H20, 75 MgSO4 per liter distilled water) (Dawson Bantle, 1987). Control 100% solution. tested (Table I). Each purchased commercial source (Aldrich Chemical Company, Milwaukee, Wisconsin, U.S.A.) not repurified prior use. Stock concentration equal highest made fresh diluent. stock adjusted pH 7.2 final appropriate dilutions solutions. For concentration-effect experiments, h 23?C 0.5 incubator 12L/12D photoperiod. A minimum three replicates series. h, surviving fixed 10% neutral buffered formalin. mortality, types mal114 VOL. 107, NO. 2, APRIL 1988