General Kinds of Pathogenesis

Once the toxicant has interacted with an endogenous molecule, the function of the endogenous molecule will be altered to an extent depending on the dose and duration. In the developing embryo, the function of the endogenous molecule can be seen as having a cellular and a developmental role, simply because the embryo is composed of cells whose activities are directed to a developmental outcome. From the current knowledge of cell biology, various general classes of function can be cited as susceptible to alteration. Any of these might be affected as part of a toxicant-induced pathogenic process. The classes of function include altered

  • gene expression,

  • patterns of apoptosis (programmed cell death),

  • replication, cell cycle, cell proliferation,

  • secretion, endocytosis, uptake, migration, adhesion, and

  • signal transduction.

Certain chemicals might affect more than one of these processes. There is mechanistic value in knowing which of these cell biological processes is affected.

All cells of all stages of development engage in the cell activities listed above. For an understanding of developmental consequences, however, more specific information is needed about which particular molecular components of which particular processes of development are affected. Some cell biological effects, such as failed cell proliferation or failed cell migration, might be several steps removed from the initial effect of the toxicant and several steps from the final effect of the altered cell behavior on development (e.g., a craniofacial defect). The challenge in recent years has been to identify particular molecular components of cellular and developmental processes, discern their activities, and understand the toxicant-caused alteration of activity. The recent information from cell and developmental biology has been essential for the progress in the understanding of mechanisms of toxicity.

Known Mechanistic Information on Selected Chemicals

The remainder of this chapter reviews the current hypotheses of mechanisms by which chemicals are thought to cause developmental toxicity. Eleven chemicals, listed alphabetically, are used to illustrate different mechanisms. For some chemicals, a great deal of evidence has been gathered supporting certain aspects of the mechanisms. For others, data are sparse and the understanding of the mechanism is incomplete. Experimental approaches used to study mechanisms of developmental toxicity are highlighted. In the near future, these approaches can be used in conjunction with new approaches from developmental biology and



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