tories (Cooper et al. 1998; Incardona et al. 1998). Although many of the mechanistic details are lacking, both groups showed that cyclopamine inhibits SHH signaling.

Diethylstilbesterol (DES)

DES was prescribed from the 1940s to the 1970s to prevent pregnancy loss. DES was found to be a transplacental carcinogen and teratogen (affecting the hypothalamo-hypophysial axis and reproductive organs) in humans approximately 25 years after its introduction into women’s health care (Herbst et al. 1971; Herbst 1981; Kaufman et al. 1980; Goldberg and Falcone 1999). Even more time passed before it was demonstrated to be a transplacental carcinogen in the mouse (McLachlan et al. 1980; C. Miller et al. 1998; Walker and Haven 1997), rat (Baggs et al. 1991; Henry and Miller 1986), and hamster (Khan et al. 1998).

Mechanistically, DES has produced a rich field for investigating mechanisms of teratogenic and carcinogenic action. Such animal and human observations place DES among the agents that can modify not only the estrogen receptor activity but also expression of uterine lactoferrin through signal transduction mechanisms (Newbold et al. 1997). More recent evidence has implicated chromosomes 3 and 6 as sites for gene control resulting in not only carcinogenesis but also teratogenesis (Hanselaar et al. 1997).

Recent investigations have coupled the effects of DES in the developing mouse female reproductive tract with downregulation of WNT7A, resulting in abnormal smooth-muscle proliferation (C. Miller et al. 1998). WNT7A is normally expressed in the luminal epithelium of the uterus. Following DES exposure in utero, low levels of WNT7A transcripts were detected at birth. Such alterations in the reproductive tract following DES exposure are consistent with knockout mice lacking Wnt7a having malformed female reproductive tracts (Miller and Sassoon 1998).

All of these investigations implicate the role of gene control and modification by estrogenic agents that might be more effective not only because of their estrogenic properties but also because of their pharmacokinetics and metabolism (Miller et al. 1982; Henry et al. 1984; Henry and Miller 1986). Thus, in the human, further questions are being raised about the gene-environment interactions based on the collection of experience with the use of DES during pregnancy (Hanselaar et al. 1997).


Diphenylhydantoin (DPH; common name, phenytoin) is an anticonvulsant used to treat epilepsy. It produces abnormal development in fetuses whose mothers take the drug during pregnancy. Abnormalities include facial dysmorphism

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