A Practical Approach, Second Edition=Ronald D. Ho.pdf

EXPERIMENTAL APPROACHES TO EVALUATE MECHANISMS OF DEVELOPMENTAL TOXICITY 27experiments with thalidomide is that although the cell-signaling processes controlling the developmentaldynamic processes may be conserved, dissimilar conservation of drug metabolism genes inthese various species may result in toxicokinetic differences. Hence, the use of “active metabolites”and correction for dose-to-target concentrations of thalidomide and its metabolites may be veryimportant for such mechanistic determinations. Such investigations would help to weave togethersignificant mechanistic clues for thalidomide effects on limb development.2. Cell-Cell CommunicationThe interaction between cells and their environment during fetal development plays a significantrole in both cell differentiation and morphogenesis. This interaction leads to information transferand can occur through direct cell-cell contact, through the activation of membrane-bound cellularreceptors, or through the associations created between a cell and the surrounding extracellularmatrix. Cell fate determination by specific cell interactions of the cell and its surrounding environmentis conditional specification and is dependent upon extracellular factors. 30 If the extracellularsignal causes a specific manifestation of one differentiation fate over others, the process is referredto as instructive induction. In contrast, the other form of conditional specification, permissiveinduction, results from a cell that already is committed to a specific differentiation path but onlyexpresses this differentiation phenotype after exposure to a signal. A good example of this is seenin limb development (see Figure 2.3) where a complex three-dimensional morphogenic signalinggradient is established across the limb bud. 1,30Appositional induction results from tissue interactions where signaling and responding tissuescome together and a common response is induced in the contact region. The fundamental importanceto normal development of this system was recognized by Wilson 5 in a discussion on the role ofaltered cell membrane function as a contributor to teratogenesis. Under the most severe chemicalexposure conditions, altered membrane integrity will likely result in cytolysis and cell death. Thisoccurs primarily as a result of the inability of a cell to maintain a normal physiologic ionic balanceand osmolarity due to an altered membrane permeability. Thus, at this extreme, monitoring cytotoxicityis an indirect and nonsubtle measure of altered membrane integrity. Less extreme examplescan result in functional changes, such as the excess cell proliferation seen at the fusion points inTCDD-exposed palatal shelves. 31–33Although much mechanistic information is lacking, there is some understanding of the role ofaltered membrane function and the importance of intracellular communication, cell adhesion, cellmigration, cell shape, and cellular receptors in developmental toxicology. Of particular interest arerecent investigations into the role of adhesion molecules on normal membrane function in cellmigration.A key cellular process occurring during differentiation is the migration of cells to new locations.Examples of this include: neural crest cells, which develop into a variety of cell types; precardiacmesodermal cells, which form the heart; and neurons, which migrate to various regions of thecerebrum from the ventricular zones following cell division. 34 In general, cell migration reliesheavily on cell-cell interaction, particularly cell adhesion. For example, the migrating neuron isbelieved to receive guidance cues from the extracellular environment and the extracellular matrix,as well as through contact between the neuron and supporting glial and neuronal cells. 35–46 Whenthese cues are altered by changing the chemical composition of the extracellular matrix, dramaticchanges in differentiation patterns occur; this is one technique that can be used to define the essentialnature of this matrix for developmental processes.Intracellular cytoskeletal components, such as microtubules and actin, provide a structural basisfor migration, 47,48 while extracellular cell adhesion molecules provide support and guidance for themigrating cell by offering a preferred substrata. 35,49 Extracellular adhesion molecules are also likelyto be involved in signal transduction, which results in directional guidance cues and cell motility. 48The proper functioning of the intracellular cytoskeleton and extracellular adhesion molecules is© 2006 by Taylor & Francis Group, LLC