Timing and pattern of expression of alkaline phosphatase was examined during early differentiation of the 1st arch skeleton in inbred C57BL\6 mice. Embryos were recovered between 10 and 18 d of gestation and staged using a detailed staging table of craniofacial development prior to histochemical examination. Expression of alkaline phosphatase is initiated at stage 20n2 in the plasma membrane of mesenchymal cells in the distal region of the first arch. Expression is strongest in osteoid (unmineralised bone matrix) and presumptive periosteum at stage 21n32. Mineralisation begins at stage E23. Expression is present in the mineralised bone matrix. Secondary cartilages form in the condylar and angular processes by stage M24. The cartilaginous cells and surrounding cells in the processes are all alkaline phosphatase-positive and surrounded by the common periosteum, suggesting that progenitor cells of the processes, dentary ramus and secondary cartilages all originate from a common pool. Nonhypertrophied chondrocytes of Meckel's cartilage express alkaline phosphatase at stage M23. Expression in these chondrocytes is preceded by the expression in their adjacent perichondrium. This is true of chondrocytes in all other cranial cartilages examined. 3-D reconstruction of expression in Meckel's cartilage also revealed that the chondrocytes of Meckel's cartilage which express alkaline phosphatase and the matrix of which undergoes mineralisation are those surrounded by the alkaline phosphatase-positive dentary ramus. By stage 25, coincident with mineralisation in the distal section of Meckel's cartilage, most chondrocytes are strongly positive. The perichondria of malleus and incus cartilages express alkaline phosphatase at stage M24. Nonhypertrophied chondrocytes along these perichondria also express alkaline phosphatase. Superficial and deep cells in the dental laminae of incisor and 1st molar teeth become alkaline phosphatase-positive at the bud stage, stages 21n16 and 21n32, respectively. Dental papillae are negative until stage M24 when alkaline phosphatase expression begins in the dental papillae and follicles of the incisor teeth and the dental follicles of the 1st molar teeth. The dental papillae of the 1st molar teeth express alkaline phosphatase at stage 25. Expression in the dental papillae and follicles appears to coincide with cellular differentiation of follicle from papilla. The presumptive squamosal, ectotympanic and gonial membrane bones, lingual oral epithelial cells connected to the dental laminae of the incisor teeth, hair follicle papillae and sheath and surrounding dermis all express alkaline phosphatase in a stage-specific manner.
ABSTRAm. Neurotransmitter systems in the developing brain are generally protected from growth retardation associated with nutritional deprivation. To investigate if such protective mechanisms extend to similar tissues in the peripheral sympathetic system, maturation of the chromaffin cells of the adrenal medulla and development of their centrally derived splanchnic innervation were evaluated in rats whose nutritional status had been altered during the neonatal period by increasing (16-17 pups/ litter) or decreasing (five to six pups/litter) the litter size from the standard (11-12 pups/litter). Ontogeny of adrenal catecholamine stores and activities of catecholamine-biosynthetic enzymes tyrosine hydroxylase and phenylethanolamine N-methyltransferase were monitored, along with activity of choline acetyltransferase, a marker enzyme for the preganglionic neurons innervating the chromaffin cells. Neonatal nutritional deprivation slowed body weight gain and retarded development of the chromaffin cells, as evidenced by subnormal catecholamine stores, tyrosine hydroxylase and phenylethanolamine N-methyltransferase activities. The effects persisted despite the complete recovery of body wr ights postweaning. The developmental alterations were not caused by overcrowding stress, as plasma corticosterone levels were not elevated in the large litter group. Neonatal nutritional enrichment promoted body weight gain but failed to enhance development of adrer.al catecholamines; tyrosine hydroxylase and phenylethanolamine N-methyltransferase activities were elevated only in the preweaning period. In contrast to effects on the chromaffin cells, altered neonatal nutritional status had only minor, transient effects on the development of the centrally derived cholinergic innervation of the adrenal and produced only small changes (~1 0 % ) in brain tyrosine hydroxylase activity. These results suggest that, unlike central transmitter systems, maturation of chromaffin cells is adversely affected by neonatal nutritional deprivation; ontogenetic gains may already be close to optimum at normal nutritional status. (Pediatr Res 24: 583-587, 1988) Abbreviation ANOVA, analysis of variance Growth and development of the newborn are influenced profoundly by nutritional status (1-3). Thus, in rats, manipulation of litter size produces marked differences in growth rates that are associated with changes in cell replication and differentiation, in structure and size of individual tissues, and in maturation of organ function. In contrast, development of the CNS is spared during neonatal nutritional deprivation and shows little or no enhancement of maturation during overnourishment (4). Recent studies confirm that selective intracellular and multicellular mechanisms participate in this process: maturational patterns of the ornithine decarboxylase/polyamine system, which regulates macromolecule synthesis during development, are maintained in brain regions at the expense of disruption of the same pathway in other organs (4). In fact, neural signals de...
Biologically based dose-response (BBDR) models represent an emerging approach to improving the current practice of human health-risk assessment. The concept of BBDR modeling is to incorporate mechanistic information about a chemical that is relevant to the expression of its toxicity into descriptive mathematical terms, thereby providing a quantitative model that will enhance the ability for low-dose and cross-species extrapolation. Construction of a BBDR model for developmental toxicity is particularly complicated by the multitude of possible mechanisms. Thus, a few model assumptions were made. The current study illustrates the processes involved in selecting the relevant information for BBDR modeling, using an established developmental toxicant, 5-fluorouracil (5-FU), as a prototypic example. The primary BBDR model for 5-FU is based on inhibition of thymidylate synthetase (TS) and resultant changes in nucleotide pools, DNA synthesis, cell-cycle progression, and somatic growth. A single subcutaneous injection of 5-FU at doses ranging from 1 to 40 mg/kg was given to pregnant Sprague-Dawley rats at gestational day 14; controls received saline. 5-FU was absorbed rapidly into the maternal circulation, and AUC estimates were linear with administered doses. We found metabolites of 5-FU directly incorporated into embryonic nucleic acids, although the levels of incorporation were low and lacked correlation with administered doses. On the other hand, 5-FU produced dose-dependent inhibition of thymidylate synthetase in the whole embryo, and recovery from enzyme inhibition was also related to the administered dose. As a consequence of TS inhibition, embryonic dTTP and dGTP were markedly reduced, while dCTP was profoundly elevated, perhaps due to feedback regulation of intracellular nucleotide pools. The total contents of embryonic macromolecules (DNA and protein) were also reduced, most notably at the high doses. Correspondingly, dose-related reductions of fetal weight were seen as early as GD 15, and these deficits persisted for the remainder of gestation. These detailed dose-response parameters involved in the expression of 5-FU developmental toxicity were incorporated into mathematical terms for BBDR modeling. Such quantitative models should be instrumental to the improvement of high-to-low dose and cross-species extrapolation in health-risk assessment.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.