determined that valproic acid selectively alters the expression of Hoxa1 in the embryo, providing an explanation for the similarity between the phenotypes of teratological cases and genetic cases of autism (Ingram and Rodier 1998). The increased understanding of ASDs is an example of how several research paths have converged to provide evidence supporting an interesting genotype-environment hypothesis.

SUMMARY

Early researchers of the causes of abnormal development used many of the same methods and animal models as developmental biologists studying normal development. Knowledge about normal developmental processes was essential to understand the developmental pathogenesis induced by chemical and physical agents, and, reciprocally, such agents at that time were used to disrupt normal development in order to understand the processes.

Our ability to understand the mechanisms by which chemicals act at the cellular and molecular levels to affect development has improved greatly during the past 2 decades. The improvement has occurred in concert with the advances in cell and developmental biology. As discussed in Chapter 6, progress in developmental biology came from the systematic analysis of developmental mutants of model animals, and progress in cell biology came from biochemical and molecular biological techniques, particularly gene cloning and sequence analysis.

Mechanism is an inclusive term for developmental toxicologists. To be complete, it should include information about (1) the toxicant’s kinetics of uptake, distribution, storage, metabolism, and excretion as it gains access to the conceptus; (2) its interaction with a molecular component of a cellular or developmental process; (3) the consequence of that interaction for the component’s function; and (4) the consequence of that altered function for the operation of cellular and developmental processes (pathogenesis), leading to a structural or functional developmental defect. Thus, a full description of a mechanism of toxicity would draw on molecular, cellular, and developmental knowledge.

The current hypotheses of the mechanisms of toxicity and the evidence supporting the hypotheses for 11 toxicants, or groups of toxicants, were reviewed. Of these, TCDD and retinoids are the exemplars at present. The hypotheses for the toxicity are quite complete and substantiated. The toxicants interact with known proteins, specific members of the bHLH and nuclear hormone receptor families, respectively, which are signal transduction components as well as genetic regulatory components. The liganded receptors activate (or perhaps repress) the expression of certain genes at abnormal times and places. The full range of genes is not yet known, but some genes are known. The products of the misexpressed genes affect developmental processes, such as cell migration, cell responses, and the expression of yet other genes. The connection of altered gene expression to defects of organogenesis is still somewhat weak, but the outlines



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