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Effects of Boric Acid on Hox Gene Expression and the Axial Skeleton in the Developing Rat
Citation:
Narotsky, M G., N. Wery, B. T. Hamby, D S. Best, N. Pacico, J. J. Picard, F. Gofflot, AND R J. Kavlock. Effects of Boric Acid on Hox Gene Expression and the Axial Skeleton in the Developing Rat . Chapter 24, The Skeleton: Biochemical Genetic and Molecular Interactions in Development and Homeostasis. Humana Press Incorporated, Totowa, NJ, 17:361-372, (2004).
Impact/Purpose:
Book chapter
Description:
Gestational exposure to boric acid (BA) causes reduced incidences of supernumerary ribs and shortening/absence of the 13th rib in the progeny of multiple laboratory species. To further explore this, Sprague-Dawley rats received 500 mg/kg b.i.d. on gestation days (GD) 6, 7, 8, 9, 10, or 11 (plug day = GD 0). GD-21 fetuses were stained for skeletal examination. BA's most noteworthy effects were apparent homeotic shifts in the axial skeleton; i.e., a given vertebra anatomically resembled an adjacent vertebra, thus leading to altered numbers of cervical, thoracic, or lumbar vertebrae. Whereas most groups generally had no such effect, about 90% of the GD-9 exposed fetuses had only six cervical vertebrae. Deficiencies in the C3-C5 region, C6, or C7 were observed in 67%, 1%, and 23% of the exposed fetuses, respectively. In contrast, GD-10 treatment caused agenesis of a thoracic/lumbar vertebra in over 60% of the fetuses. In these fetuses, the deficient region was usually T11. In view of the 90% incidence of six-cervical vertebrae in GD-9 exposed fetuses, we used this exposure regimen (500 mg/kg b.i.d. on GD 9) as an experimental model for the study of homeotic shifts. We sought to determine if these skeletal alterations could be explained by modifications of the hox code, involved in the establishment of positional information along the cranio-caudal axis of the embryo. Embryos were collected on GD 13.5 and processed for in situ hybridization. Several hox genes were selected according to the position of their cranial limit of expression in the cervical and thoracic region. A cranial shift in the cranial limit of expression of hoxc6 and hoxa6 was evident in the prevertebrae, whereas no difference was observed between control and treated embryos in the expression of hoxd4, hoxa4, hoxc5, and hoxa5. Anteriorization of the expression domain of hoxc6 and hoxa6 is consistent with the posterior transformation of cervical vertebrae, and may partially account for the phenotype observed on GD 21 in BA-exposed fetuses.