A comparative investigation of fetal skeletal anomalies in rats induced by acetylsalicylic acid with single- and double-staining techniques

Dodo, Tetsushi; Fukuta, Tetsuya; Uchida, Keiji; Mineshima, Hiroshi; Okuda, Yasuyuki; Okada, Fumihiro; Katsutani, Naruo; Hirano, Kazuyuki; Aoki, Toyohiko

doi:10.1016/j.yrtph.2009.05.014

Cited by 6 publications

(7 citation statements)

References 16 publications

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“…Little is known about the repairability of discontinued rib cartilage at present. Dodo et al (2009) reported results (the persistence of acetylsalicylic acid-induced discontinued rib cartilage until PND 21) that are opposite to the presently observed findings. A possible explanation for the discrepancy between the results of Dodo et al (2009) and the present study is that this phenomenon might involve a chemical-specific mode of action, suggesting that VPA-induced discontinued rib cartilage, but not acetylsalicylic acid-induced discontinued rib cartilage, might be reversible after birth.…”

Section: Resultscontrasting

confidence: 97%

Repairability of skeletal alterations induced by sodium valproate in rats

Kirihata

Ban

Nakamori

et al. 2018

Congenital Anomalies

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The present study aimed at examining postnatal repairability of sodium valproate-induced skeletal alterations in rats. Sodium valproate (400 mg/kg) or the vehicle (distilled water) was orally administrated to pregnant Sprague-Dawley rats from gestation days 9 to 11. Fetuses and pups were obtained on gestation day 21 and postnatal day 11, respectively, and their skeletons were stained with Alizarin red S and Alcian blue and examined. Sodium valproate-induced costal and vertebral alterations in the fetuses included discontinued rib cartilage, fused rib, full or short supernumerary rib, bipart ossification of thoracic centrum, supernumerary lumbar vertebrae, and lumbarization. In pups, however, discontinued rib cartilage was not observed, and the incidence of a short supernumerary rib was significantly lower than that in the fetuses, suggesting that these alterations are postnatally repairable.

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Section: Resultscontrasting

confidence: 97%

Repairability of skeletal alterations induced by sodium valproate in rats

Kirihata

Ban

Nakamori

et al. 2018

Congenital Anomalies

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“…As for FCB in rodents, the toxicological significances in terms of a drug-induced change are also unclear, although there are some reports related to the mechanisms of FCB. 4,7,27 In humans, congenital abnormalities in the carpal bones are possibly associated with hand malformations, 28,29 and FCB is known as one of the clinical phenotypes of Muenke syndrome (craniosynostosis). Mechanistically, the mutation of fibroblast growth factor receptor 3 (FGFR3), which is a regulatory factor for bone and cartilage development, is considered to be responsible for inducing craniosynostosis.…”

Section: Discussionmentioning

confidence: 99%

“…The double-staining technique with Alizarin Red S for ossified bones and Alcian Blue for cartilages (modified Inouye's bone-cartilage double-staining) [16][17][18] was performed for skeletal examination according to the procedures described previously. 7…”

Section: Maternal and Fetal Evaluationmentioning

confidence: 99%

“…Although cartilaginous changes are induced by several drugs such as cyclophosphamide and sodium valproate, in some cases Alizarin Red S staining alone could not detect the changes; and the importance of cartilaginous changes was not considered due to the unclear biological significance. [4][5][6][7] Among cartilaginous changes, discontinuous rib cartilage (DRC) and fused carpal bone (FCB) are easily identified in rat fetuses using Alcian Blue staining. In a previous study to evaluate the utility of Alcian Blue staining, we demonstrated that acetylsalicylic acid given at 125-500 mg/kg to pregnant rats on gestation day (GD) 10 induced irreversible cartilaginous changes consisting of DRC and FCB in the fetus.…”

Section: Introductionmentioning

confidence: 99%

“…In a previous study to evaluate the utility of Alcian Blue staining, we demonstrated that acetylsalicylic acid given at 125-500 mg/kg to pregnant rats on gestation day (GD) 10 induced irreversible cartilaginous changes consisting of DRC and FCB in the fetus. 7 Since these changes were observed at lower doses than those which produced malformations in the ribs and hands in rats (750-1000 mg/kg), 8,9 DRC and FCB were considered a more sensitive endpoint for identifying fetal cartilaginous and ossified skeletal changes.…”

Section: Introductionmentioning

confidence: 99%

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Increases in discontinuous rib cartilage and fused carpal bone in rat fetuses exposed to the teratogens, busulfan, acetazolamide, vitamin A, and ketoconazole

et al. 2010

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Skeletal changes induced by treatment of pregnant rats with four potent teratogens, busulfan, acetazolamide, vitamin A palmitate, and ketoconazole, were evaluated using Alizarin Red S and Alcian Blue double-staining to investigate the relationship between drug-induced skeletal malformations and cartilaginous changes in the fetuses. Pregnant rats (N = 8/group) were treated once or twice between gestation days (GDs) 10 to 13 with busulfan at doses of 3, 10, or 30 mg/kg; acetazolamide at 200, 400, or 800 mg/kg; vitamin A palmitate at 100,000, 300,000, or 1,000,000 IU/kg; or ketoconazole at doses of 10, 30, or 100 mg/kg. Uterine evaluations and fetal external and skeletal examinations were conducted on GD 20. Marked skeletal abnormalities in ribs and hand/forelimb bones such as absent/ short/bent ribs, fused rib cartilage, absent/fused forepaw phalanx, and misshapen carpal bones were induced at the mid- and high-doses of busulfan and acetazolamide and at the high-dose of vitamin A palmitate and ketoconazole. Increased incidences of discontinuous rib cartilage (DRC) and fused carpal bone (FCB) were observed from the low- or mid-dose in the busulfan and acetazolamide groups, and incidences of FCB were increased from the mid-dose in the vitamin A palmitate and ketoconazole groups. Therefore, DRC and FCB were detected at lower doses than those at which ribs and hand/forelimb malformations were observed in the four potent teratogens.

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