coids, androgens, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). A detailed description of what is currently known about the mechanisms by which retinoic acid and TCDD perturb development can be found below. Table 4-1 describes several cytosolic receptors (in this case, nuclear hormone receptors) that are involved in receptor-mediated developmental toxicity.
Membrane receptors (i.e., trans-membrane proteins) are diverse and interact with a wide variety of molecules, from small molecules, such as glutamate and acetylcholine, and small proteins, such as insulin, to large proteins, such as Wingless-Int (WNT), Sonic Hedgehog (SHH), TGFβ, and Delta signals (discussed in Chapter 6). Signaling molecules interact with a portion of the receptor on the cell’s exterior. The binding of a ligand to a membrane receptor leads to a cascade of events within the cell membrane and cell known as signal transduction, which often involves five or more steps, including second messengers (intracellular signaling compounds) (described further in Chapter 6). It is conceivable that toxicants could affect any of these steps. For example, toxicants could interfere with receptor interactions or alter the activity of intermediates of the signal-transduction cascade. The number of agents known to exert developmental toxicity via interaction with membrane receptors is smaller than that for cytosolic receptors. Several membrane receptors—the Hedgehog receptor Patched, endothelin receptors A and B, and the cation channel delayed-rectifying Ikr—are known to play a role in mediating developmental toxicity and are highlighted in Table 4-1.
Despite the few examples of toxicant interactions with membrane receptors, the mechanism might be important in understanding how certain chemicals disrupt development. Most normal developmental processes involve cell-cell signaling and are mediated by trans-membrane receptors, including inductions, cell-matrix interactions, cell proliferation, cell movement, and autocrine and paracrine effects. The potential is great, therefore, that these mechanisms are significant in developmental toxicity.
Covalent binding occurs when the exogenous molecule chemically reacts with an endogenous molecule (e.g., forming a DNA or protein adduct). Among the kinds of reactive chemicals are aldehydes, epoxides, quinonimines, free radicals, acylating agents, and alkylating agents. Exposure to these chemicals might then result in abnormal transcription or replication of DNA, or abnormal function of the adducted protein. Phosphoramide mustard, a reactive metabolite of cyclophosphamide, is an example of a developmental toxicant that forms DNA adducts (alkylation) in embryos (Cushnir et al. 1990). Many chemicals that are not initially reactive are converted by DMEs (e.g., cytochromes P450) to “potentiated” reactive derivatives. An example of a developmental toxicant that forms both DNA and protein adducts in embryos is diphenylhydantoin, whose mechanism is described below.