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Scientific Frontiers in Developmental Toxicology and Risk Assessment
have been established. Some of the altered expressions include genes encoding signaling components involved in cell-cell interactions during organogenesis.
For the case of cyclopamine, a transmembrane signaling pathway is known to be disrupted by the toxicant, leading to failure of an induction needed to pattern the eye field of the diencephalon. This is an example of a transmembrane signaling pathway that is a direct target for a toxicant.
For several other toxicants (e.g., methylmercury and methotrexate), the molecular target is not known but is probably some component of a process of cellular proliferation (e.g., DNA damage, block to DNA synthesis, disrupted spindle formation, and energy depletion). In many cases, high-dose disruption of the process results in cell death by apoptosis, preceded by the cell’s attempts to restore viability by way of molecular stress and checkpoint pathways, some of which have been partially defined. Excessive cell death results in disrupted development. The developmental effects of these toxicants has been broadly defined, but most details are missing.
For a few toxicants, fetal organ function is probably compromised by processes similar to the agent’s pharmaceutical-physiological effect on the mother (e.g., ACE inhibitors). Functional defects are in the early stages of elucidation (e.g., the connection of autism to altered HOX gene expression and altered rhombomere development in the hindbrain) and the possible role of some toxicants (including thalidomide) in altering the expression of those genes). Finally, several others act by mechanisms still largely unknown, despite knowledge of the final developmental defect (e.g., diphenylhydantoin and valproic acid).
In conclusion, there are only a few examples where the molecular, cellular, and developmental information is complete enough to say the hypothesis of the mechanism of toxicity is well substantiated. In no case is the mechanism of cellular and developmental toxicity fully known both toxicokinetically and toxicodynamically. However, it should be appreciated how broad and deep the scientific understanding has to be in order to have all the facets of a hypothesized mechanism distinguished and substantiated. The variety of mechanisms by which environmental toxicants probably work should be noted: mechanisms for toxicity are cellular, developmental, or physiological. Some involve two or more of these three. Some mechanisms occur at embryonic stages, fetal stages, or both, and some affect the conceptus, the mother, or both. Recent advances in the understanding of normal development (e.g., signaling pathways and transcriptional regulatory circuits) and cell biology (e.g., the cell cycle and checkpoint pathways) have identified critical processes, which, if investigated for their alteration by developmental toxicants, can provide exciting new advances in mechanistic investigations.