Research has been conducted on the toxicokinetics of some toxicants (e.g., retinoic acid, diphenylhydantoin, methotrexate, and methylmercury). For certain toxicants, routes and rates of exposure to the fetus and embryo have been identified, as have the presence of parent compounds and metabolites in the mother, fetus, and embryo. Additionally, the role of drug-metabolizing enzymes (DMEs) in the metabolism of toxicants has been studied extensively. However, knowledge about critical metabolites and their reactivity with specific target tissues is lacking for most environmental agents.

Some toxicants (e.g., retinoids, DES, and TCDD) are known to act on molecular components that function as signaling proteins and transcriptional regulators (described below). However, the committee found that little information is available on how most chemicals impact those molecular components. Where information is available, it is generally sparse and does not allow for the association of developmental defects with a toxicant’s action on specific molecular components of developmental processes.

Charge 2: Evaluate the State of the Science on Testing for Mechanisms of Developmental Effects. Major discoveries have recently been made about the components, mechanisms, and processes of normal development. Developmental processes have been identified at the molecular level in various model animals, including the fruit fly, the roundworm, the zebrafish, the frog, the chick, and the mouse. Molecular components of these processes are substantially conserved (i.e., the structure and function of the components have not changed throughout evolution) among animal phyla, including mammals; they regulate development by signaling specific cells to activate proteins called transcription regulators, which turn specific genes on and off. Seventeen signaling pathways are currently recognized, and probably only a few more remain to be discovered. These conserved pathways are used repeatedly in various combinations at different times and locations in the developing embryo and fetus. Species differences in development involve different times, locations, and combinations of these pathways. Many of the kinds of cell responses to signals also are conserved, including selective gene expression, secretion, cell proliferation, and cell migration.

The sequencing of the human genome and a variety of animal genomes is providing fundamental information about genome organization, genome evolution, and genetic polymorphisms (variations in the deoxyribonucleic acid (DNA) sequence of a particular gene within a population of organisms). Identifying polymorphisms in the human genome might provide opportunities to increase the understanding of genotype-environment interactions and human susceptibility to toxicants. For example, recent insights into the human differences in the activity of various DMEs and the genetic basis for those differences offer a promising direction for research. Components involved in developmental processes such as the signaling pathways that might be important in susceptibility are less well studied.



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