developmental toxicants are now known, upstream events that initiate and regulate this pathway in mammalian postimplantation embryos are unknown but oxidative stress clearly plays a role (Nebert et al. 2000). In particular, it is not known how cells in the embryo perceive exposure to a developmental toxicant and then respond to the insult. The ability of cells to perceive a stimulus or perturbation and then transduce these events into appropriate intracellular responses is commonly referred to as signal transduction. Although little is known about the interaction between developmental toxicants and signaling pathways in mammalian embryos, a recent report showed that heat shock can rapidly activate the stress-activated protein kinase pathways mediated by c-Jun terminal kinase (JNK) and p38 (Wilson et al. 1999), as well as the unfolded protein stress pathway involving a variety of chaperon proteins (Welch 1991; Sidrauski et al. 1998).
Recent discoveries regarding mutations responsible for the genetic susceptibility to autism spectrum disorders (ASDs) are an example of how studies of developmental toxicity can lead to breakthroughs in understanding the etiology of human birth defects, even when the defects are ones with strong genetic components (for a review, see Rodier 2000).
ASDs are among the most common congenital anomalies, occurring at a rate of 2-5 per 1,000 births (Bryson et al. 1988; Bryson and Smith 1998). Until recently, little was known about the causes and even less about the nature of the CNS injury underlying the symptoms. Family studies had indicated that unknown genetic factors account for about 90% of the variance (Bailey et al. 1995), but linkage studies provided few regions, and no genes, unambiguously linked to autism (Myers et al. 1998; Philippe et al. 1999). The family studies suggested that environmental factors are also involved (Le Couteur et al. 1996) but could not identify any of those factors. In 1994, it was discovered that exposure of the closing neural tube of the human embryo to thalidomide, a well-known teratogen, could produce autism at a high rate (Strömland et al. 1994). Valproic acid (Christianson et al. 1994) and ethanol (Nanson 1992) have also been implicated as teratogens that increase the risk of autism. The critical period for induction of autism by thalidomide was determined from the somatic defects of the patients with autism, each of whom also had malformed ears and hearing deficits. This stage of development—days 20-24 of gestation, which is the period of neural tube closure—is much earlier than the periods usually considered in studies of neuroteratology, because only a few neurons of the brain stem form so early. Most of these are motor neurons for cranial-nerve nuclei (Bayer et al. 1993), and cranial-nerve dysfunctions are indeed present in the thalidomide cases. Figure 4-1 shows a comparison of brain-stem neuroanatomy of a control and a patient with autism.
Using the information about the critical period, Rodier and colleagues were