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Comparative Evaluation of the Combined Osteolathyritic Effects of Two Nitrile Combinations on Xenopus Embryos

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Comparative Evaluation of the Combined Osteolathyritic Effects of Two Nitrile Combinations on Xenopus Embryos Toxicology 147 (2000) 193–207 www.elsevier.com/locate/toxicol Comparative evaluation of the combined osteolathyritic effects of two nitrile combinations on Xenopus embryos Douglas A. Dawson a,*, Melissa A. Cotter a, Deidre L. Policz a, Deborah A. Stoffer a, Jason P. Nichols a, Gerald Po¨ch b a Department of Biology/Toxicology, Ashland Uni6ersity, 401 College A6enue, Ashland, OH 44805, USA b Institute of Pharmacology and Toxicology, Uni6ersity of Graz, Graz, Austria Received 30 November 1999; accepted 17 March 2000 Abstract Two nitrile combinations, b-aminopropionitrile (bAPN) with aminoacetonitrile (AAN) and bAPN with bAPN (as a sham combination), were evaluated using the frog embryo mixture toxicity assay to determine their combined osteolathyritic effects and to compare the results with theoretical effects for two combined effects models. In separate tests each nitrile was tested with copper sulfate to determine the importance of copper in osteolathyrogen-induced disruption of connective tissue cross-linking. Frog embryos (Xenopus lae6is) were exposed for 96 h, with daily solution removal and replacement. Preserved tadpoles were evaluated for osteolathyritic lesions. For the nitrile:nitrile combinations, the x2 goodness-of-fit test was used to compare the resulting mixture-response curves to theoretical curves for dose-addition and independence. For bAPN with AAN, the combined osteolathyritic effect for five of the seven mixture curves generated was greater than expected for each of the combined effects models. For bAPN with bAPN, the combined effect for all seven mixture curves was consistent with dose-addition, the combined effect expected for chemicals inducing toxicity by the same mechanism. For the nitrile:copper combinations, the EC50 for bAPN-induced osteolathyrism was increased two- to threefold (i.e. made less toxic) by co-administration with copper sulfate, while the EC50 for AAN-induced osteolathyrism was unchanged. The results are consistent with the idea that bAPN and AAN induce osteolathyrism, at least in part, by different mechanisms. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: b-Aminopropionitrile; Aminoacetonitrile; Copper sulfate; Dose-addition; Independence; Chemical mixture toxicity 1. Introduction This research was conducted in compliance with the Ani- Osteolathyrism is defined as the failure of devel- mal Welfare Act and other federal statutes and regulations oping connective tissue fibers to cross-link prop- relating to animals and experiments involving animals and erly (Selye, 1957). Developing collagen and elastin adhered to principles stated in the Guide for Care and Use of Laboratory Animals, NIH Publication 86-23 (1985 ed.). fibers are cross-linked using lysyl oxidase to oxi- * Corresponding author. dize the amino side group of peptidyl lysine 0300-483X/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0300-483X(00)00196-7 194 D.A. Dawson et al. / Toxicology 147 (2000) 193–207 residues within collagen and elastin into peptidyl affects proper connective tissue cross-linking. a-aminoadipic-d-semialdehyde (Pinnell and Mar- With the complexity of the cross-linking pro- tin, 1968). These aldehydes can then form the cess, there are several opportunities for chemical covalent cross-linkages found in collagen and insult to be disruptive. As a result, osteolathyrism elastin fibers by condensing with amino groups or might occur through more than one mechanism. other peptidyl aldehydes (Kagan, 1986). Lysyl Some of the mechanisms that have been proposed oxidase (LO) is a copper-requiring enzyme that for osteolathyrism include: direct binding of the uses lysyltyrosine quinone as a cofactor (Wang et agent to LO (Tang et al., 1983), copper chelation al., 1996). Inhibition of LO activity adversely (Dasler and Stoner, 1959), aldehyde blockage Fig. 1. Frog embryo mixture toxicity assay design with 36 treatments. The design gives seven mixture-response curves: two with the concentration of chemical ‘A’ held at a fixed value with increasing concentrations of chemical ‘B’ (shaded columns), two vice versa (shaded rows) and three fixed-ratio curves in which the concentrations of both chemicals increase (diagonal lines). The -fold EC50 values are based on a 1.2 factor, with 1.0 representing the EC50 for osteolathyrism for each chemical when tested alone. D.A. Dawson et al. / Toxicology 147 (2000) 193–207 195 Table 1 Concentration-osteolathyrism data for frog embryos exposed to chemical ‘A’ alone and chemical ‘B’ alone for tests of bAPN:AAN and bAPN:bAPN Treatment no. bAPN:AAN bAPN:bAPN Conc.a No. affectedb %c Conc.a No. affectedb %c Chemical ‘A’ alone 20.028 7 14 0.024 3 6d 3150.041 30 0.035 6 13e 4 0.05820 40 0.050 15 30 50.070 32 64 0.060 27 55d 6 0.08434 72f 0.072 35 70 7 0.12149 98 0.104 49 98 Chemical ‘B’ alone 8 0.24 6 12 0.024 1 2d 9 0.3512 25d 0.035 7 14d 10 0.50 19 38 0.050 25 51d 11 0.6030 60 0.060 33 67d 120.72 38 76 0.072 36 72 13 1.0447 94 0.104 48 96 a mg/l-formula weight corrected. b Osteolathyritic. c For 50 survivors unless noted. d 49 survivors. e 48 survivors. f 47 survivors. (Levene, 1971), oxidative stress (Ghate, 1985), attributed to bAPN (Levene and Carrington, and disruption of the cofactor (Bird and Levene, 1986). In addition, quantitative structure-activity 1982; Kagan and Trackman, 1991). relationship (QSAR) studies did not develop a Osteolathyrism can be induced by a variety of single high-quality QSAR equation for oste- chemicals, including: nitriles, ureides, hydrazides, olathyrism induced by various acid hydrazides, hydrazines (Levene, 1961), alkyl carbazates (Daw- thiosemicarbazides, benzoic acid hydrazides, and son et al., 1991) and dithiocarbamates (Bancroft alkyl carbazates (Schultz and Ranney, 1988; Daw- and Prahlad, 1973). Among the nitriles capable of son et al., 1990, 1991), suggesting that more than inducing osteolathyrism are b-aminopropionitrile one mechanism of osteolathyrism exists among (bAPN), aminoacetonitrile (AAN) and methylene the various chemical classes. aminoacetonitrile (Levene, 1961). The mechanism Frog embryos, including Xenopus lae6is (Ban- for bAPN-induced osteolathyrism is reported to croft and Prahlad, 1973) and Microhyla ornata be direct binding of the agent to the enzyme, as (Ghate and Mulherkar, 1980), are susceptible to the compound has been shown to covalently bind chemically-induced osteolathyrism. Primary oste- LO, with the amount of inactivation proportional olathyritic effects include, at lower concentra- to the amount of bAPN bound (Tang et al., tions, small dorso-ventral bands of 1983). Whether this is the general mechanism of disorganization within the notochord or an osteolathyrism for some of the other osteolathyro- outpocketing of the ventral margin of the noto- gens, however, is not clear. For example, work chord. These initial lesions are clearly observed with the chick indicated that semicarbazide (a within the notochord of the transparent tadpoles ureide) may have a mechanism of osteolathyritic using a dissecting microscope. At higher oste- action that is different from the one that has been olathyrogen concentrations extensive disorganiza- 196 D.A. Dawson et al. / Toxicology 147 (2000) 193–207 tion, enlargement and/or folding of the notochord the chemicals induce toxicity by different mecha- and disruption of the notochordal sheath are ob- nisms (Po¨ch et al., 1996). Initial evaluations of the served, leading, at the gross level, to a ‘wavy-tail’ approach (Dawson and Po¨ch, 1997; Mentzer et appearance (Schultz et al., 1985; Dawson et al., al., 1999) have examined osteolathyrogen combi- 1990). Notochord effects have been further char- nations because of the potential for different acterized using electron microscopy to include mechanisms of action among the different chemi- disorganization of collagen fibers and, in some cal classes. With this possibility it was hypothe- instances, absence of the elastic externa (Schultz sized that osteolathyrism would provide a et al., 1985; Riggin and Schultz, 1986). rigorous test of the toxicity and statistical The frog embryo mixture toxicity assay (Daw- methodologies developed and determine if the son and Po¨ch, 1997), a derivation of FETAX approach is sensitive enough to detect variations (Dumont et al., 1983), was developed to deter- in the resulting combined effects that may be mine the toxicity of binary chemical mixtures and indicative of chemicals acting by different specific to attempt to relate that toxicity to common or mechanisms (i.e. direct enzyme binding, copper different mechanisms of chemical action. This is chelation, cofactor disruption, etc.). Identification done by statistically comparing the experimental of such variations would provide direction for results with theoretical effects for each of two examining potential mechanistic differences at the combined effects models: dose-addition and inde- biochemical level. As a part of this project, which pendence. A dose-addition combined effect is ex- will examine many osteolathyrogen combinations pected when two chemicals induce toxicity by the across several chemical classes, two nitrile:nitrile same mechanism of action, while a combined combinations: bAPN with AAN and bAPN with effect consistent with independence indicates that bAPN were tested. To determine the importance Table 2 Concentration-osteolathyrism data for frog embryos exposed to the fixed AAN concentrations with increasing bAPN concentra- tions, expected numbers for dose-addition and independence models of combined effects, and data fit to the models Treatment no. [bAPN]a No. osteolathyritic No.b expected if dose-addition No.b expected if independence [AAN]a =0.35 mg/l per treatment 140.014 25 22 13 19c 0.028 38 30 15 23c 0.041 47 36 20 29c 0.058 48 41 29 330.08450 46 40 340.12150 48 47 x2 =8.2 x2 =101.1 d.f.=5 d.f.=5 P\0.10 PB0.0005 [AAN]a =0.5 mg/l per treatment 150.01442 26 18 170.020 45 30 18 24 0.041 50 39 24 30c 0.058 49 42 31 36 0.175 50 49 49 x2 =22.1 x2 =112.9 d.f.=4 d.f.=4 PB0.0005 PB0.0005 a mg/l-formula weight corrected.
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