treated embryos include abnormal differentiation, migration, proliferation and apoptosis (Collins and Mao 1999). Some of these effects might not be receptor-mediated. For example, disruption of membranes, changes in phosphorylation, and increases in reactive oxygen species might play roles in retinoid teratogenicity.
The significance of the retinoids in developmental toxicology might extend further, because a range of chemicals likely mediate their developmental toxicities by interfering with endogenous retinoid signaling. Ethanol can act as a competitive inhibitor of retinol dehydrogenase activity, thus lowering retinoid synthesis, and this effect might be a component of fetal alcohol effects (Duester 1991). Similar mechanisms have been proposed for the anticonvulsants phenytoin, phenobarbital, carbamazepine, ethosuximide, and valproic acid (Nau et al. 1995; Fex et al. 1995). Inhibition of retinoid catabolism has also been implicated. Metabolism of retinoic acid via NADPH-dependent cytochrome P450 is inhibited by azole antifungal drugs (Vanden Bossche et al. 1988; Schwartz et al. 1995), which can induce retinoid-like craniofacial defects (Wang and Brown 1994). None of these examples is wholly convincing, but the overall concept is plausible, particularly because the retinoids are unusual as secreted signals in being small lipophilic molecules. Because many synthetic chemicals are also small and lipophilic, the potential for interaction might be higher than that for other peptide-based signaling pathways.
The mechanism by which TCDD induces developmental toxicity has been studied extensively (for a review, see Wilson and Safe 1998) and is one of the best understood. It is summarized here to provide an example of how a chemical interacts with an endogenous cytoplasmic receptor (in this case, a basic helix-loop-helix receptor (bHLH)) and alters the expression of several dozen genes, one or more of which might result in an adverse developmental outcome.
TCDD, an environmental pollutant, is a byproduct of the production of chlorinated products such as herbicides and wood preservatives, and is developmentally toxic in many species. Exposure in utero to TCDD causes increased mortality and growth retardation, and structural and behavioral abnormalities, including the induction of cleft palate and hydronephrosis in mice. Evidence supports the hypothesis that TCDD binds the aryl hydrocarbon receptor (AHR), allowing the receptor to bind with AH-responsive elements on DNA and leading to changes in gene expression. For example, mice with wild-type high-affinity AHR exposed to TCDD have a higher incidence of developmental abnormalities than do mice with low-affinity receptors. (The mouse Ahr gene contains a mutation that lowers the affinity of the encoded protein for DNA (Chang et al. 1993; Poland et al. 1994)). Large amounts of AHR have been localized to the palatal shelves in normal mice susceptible to the effects of TCDD (i.e., mice having high-affinity