action” in the most inclusive sense, to include all events from initial molecular interactions to the developmental defect itself. Such an explanation would include the following types of mechanistic information:

  • The toxicant’s kinetics and means of absorption, distribution, metabolism, and excretion within the mother and conceptus.

  • Its interaction (or those of a metabolite derived from it) with specific molecular components of cellular or developmental processes in the conceptus or with maternal or extraembryonic components of processes supporting development.

  • The consequences of the interactions on the function of the components in a cellular or developmental process.

  • The consequences of the altered process on a developmental outcome, namely, the generation of a defect.

In Chapter 8, the committee discusses “levels of information” needed to understand inclusive mechanisms. The information is obtainable from various model systems (including in vitro and cell culture, nonmammalian animals, and mammals). Hypotheses about toxicant action in humans, based on the information from animal models, can then be strengthened or dismissed using information obtained from various levels of human data.

General Kinds of Initial Interactions of Toxicants with Cellular Molecules

Receptor-Ligand Interactions

Some chemicals interact directly with endogenous receptors for hormones, growth factors, cell-signaling molecules, and other endogenous compounds. They can activate the receptor inappropriately (agonists), inhibit the ability of the endogenous ligand to bind the receptor (antagonists), act in a way that activates the receptor but produces a less than maximal response (partial agonist), or act in a way that causes a decrease from the normal baseline in an activity under the control of the receptor (negative agonist). Receptors can be broadly classified as cytosolic/nuclear or membrane bound. Cytosolic/nuclear receptors reside within the cell and have ligands that are small and generally hydrophobic so that they can pass easily through the cell membrane. After the ligand binds to these receptors, the complex translocates to the nucleus where it interacts directly with specific sequences of DNA to activate or inactivate the expression of specific genes. Examples of cytosolic receptors are the estrogen receptors (ERa,ERb,ERR), retinoic acid receptors (RAR and RXR), and aryl hydrocarbon receptor (AHR). Agents that interact with one or more of these receptors and are known to produce abnormal development include retinoic acid and synthetic retinoids, glucocorti-

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