Altered axial skeletal development.
ABSTRACT The axial skeleton is routinely examined in standard developmental toxicity bioassays and has proven to be sensitive to a wide variety of chemical agents. Dysmorphogenesis in the skull, vertebral column and ribs has been described in both human populations and in laboratory animals used to assess potential adverse developmental effects. This article emphasizes vertebrae and rib anomalies both spontaneous and agent induced. Topics discussed include the morphology of the more common effects; incidences in both human and experimental animal populations; the types of anomalies induced in the axial skeleton by methanol, boric acid, valproic acid and others; the postnatal persistence of common skeletal anomalies; and the genetic control of the development of the axial skeleton. Tables of the spontaneous incidence of axial anomalies in both humans and animals are provided.
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ABSTRACT: Differences in the physiology and biological susceptibilities of adults and infants have led to growing interest in safety evaluation methods for exposures from infant formula packaging. In addition to potential physiological differences, infants aged 0 - 6 months may consume a sole source of food, infant formula or breast milk, and consume higher amounts of food relative to body weight compared to adults. While the duration of the exposure is short compared to the expected lifespan of the individual, it occurs during a period of important developmental processes. The purpose of this document is to (1) review key biological and exposure elements that may impact the evaluation of safety for food contact products intended for use by infants, (2) summarize the current reproductive and developmental toxicity testing protocols available, and (3) identify potential data gaps concerning this period of development.Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 05/2014; · 2.99 Impact Factor
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ABSTRACT: Valproic acid (VPA), widely used to treat epilepsy, bipolar disorders, and migraine prophylaxis, is known to cause neural tube and skeletal defects in humans and animals. Aminobenzensulfonamide derivatives of VPA with branched aliphatic carboxylic acids, namely 2-methyl-N-(4-sulfamoyl-phenyl)-pentanamide (MSP), 2-ethyl-N-(4-sulfamoyl-phenyl)-butyramide (ESB), 2-ethyl-4-methyl-N-(4-sulfamoyl-phenyl)-pentanamide (EMSP), and 2-ethyl-N-(4-sulfamoyl-benzyl)-butyramide (ESBB), have shown more potent anticonvulsant activity than VPA in preclinical testing. Here, we investigated the teratogenic effects of these analogous compounds of VPA in NMRI mice. Pregnant NMRI mice were given a single subcutaneous injection of either VPA at 1.8 or 3.6 mmol/kg, or MSP, ESB, EMSP, or ESBB at 1.8, 3.6, or 4.8 mmol/kg on gestation day (GD) 8. Cesarean section was performed on GD 18, and the live fetuses were examined for external and skeletal malformations. Compared with VPA, which induced neural tube defects (NTDs) in fetuses at 1.8 and 3.6 mmol/kg, the analog derivatives induced no NTDs at dose levels up to 4.8 mmol/kg (except for a single case of exencephaly at 4.8 mmol/kg MSP). Skeletal examination showed several abnormalities mainly at the axial skeletal level with VPA at 1.8 mmol/kg. Fused vertebrae and/or fused ribs were also observed with MSP, ESB, EMSP, and ESBB, they were less severe and seen at a lower incidence that those induced by VPA at the same dose level. In addition to exerting more potent preclinical antiepileptic activity, teratology comparison indicates that aminobenzensulfonamide analogs are generally more weakly teratogenic than VPA.Birth Defects Research Part B Developmental and Reproductive Toxicology 08/2013; · 1.97 Impact Factor
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ABSTRACT: Osterix (Osx) is an important transcriptional factor for bone formation; however, its role in spine development has not been determined. The goal of the present study is to observe the role of Osx in spine development. Deletion and overexpression of Osx were achieved in Osx knockout and transgenic mice, respectively, to determine the effect of Osx on spine development. With 2.3-kb type I collagen as a promoter, Osx were deleted in mice, and overexpression of Osx was obtained in Osx transgenic mice. Video, X-ray radiology, histology, tartrate-resistant acid phosphatase staining, Safranin O staining, and immunohistochemistry were used to assess the effect of Osx deletion and overexpression on spine development. This study was supported by National Science Foundation of China (81271935) and Foundation of State Key Laboratory of Trauma, Burns and combined injury (SKLZZ SKLZZ201124). No potential conflict of interest to disclose. Overexpression of Osx did not have an obvious effect on spine development, whereas deletion of Osx led to severe spine deformities that included wedged vertebrae, spinal stenosis, and congenital scoliosis. Also, Osx deactivation resulted in shortened vertebrae and excessive bone volume in the vertebrae. TRAP staining showed that activity of osteoclasts decreased in Osx-null mice, and examination with TdT-mediated dUTP nick end labeling revealed that the apoptosis rate at the growth plate decreased significantly in Osx-null mice. Excessive formation of bone was positive for Safranin O staining. Osx plays an important role in spine development, and its deactivation leads to severe spine deformities.The spine journal: official journal of the North American Spine Society 11/2013; · 2.90 Impact Factor