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Perspectives on R.E. Shenefelt's 1972 Teratology publication entitled "Morphogenesis of malformations in hamsters caused by retinoic acid: relation to dose and stage at treatment".

Dr. Ray Shenefelt’s 1972 Teratology publication (Shenefelt, 1972) describes his study of birth defects induced in golden hamsters by retinoic acid (RA). With a pathologist’s perspective, he identified a wide variety of RA-induced malformations in near-term fetuses and the critical periods for their induction. (A critical period is defined as a time in development when treatment with a specific agent will cause a specific malformation.) This was accomplished employing an acute maternal treatment paradigm that entailed administration of a single dose of all-trans RA administered at one of the quarterday intervals from day 5 3/4 to 12 3/4 of pregnancy. Each dam was treated with a dosage that was specific to the gestational stage and that had been determined to be at the fetal LD50. As illustrated in Figure 1, which is reproduced from Shenefelt (1972), the fetal LD50 ranged widely over the time course of this study, the most sensitive period (7 1/2 days of gestation) requiring a maternal dose of only 17 mg/kg to kill half of the fetuses, while at the least sensitive period (12 3/4 days of gestation) a greater than 6-fold higher dose of 110 mg/kg was needed. As a foundation for this study, examining golden hamster embryos and fetuses at 1/4or 1/2-day intervals during their gestation, Dr. Shenefelt determined a control incidence of malformations and developed a timeline of normal development for this species. For this, over 4,000 conceptuses were examined. Because embryos and fetuses of comparable chronological ages differed with respect to developmental stages, a ‘‘morphological age’’ that was based on having morphological characteristics at the center of the range observed for each time point was defined. This allowed greater precision in interpreting results of the teratology investigation, i.e., correlation of the types of RA-induced malformations with the morphologic stages of prenatal development when they are induced and speculation regarding the developmental events that were initially affected. It also allowed classification of embryos and fetuses as being morphologically advanced or retarded relative to their chronological age. Results of the RA exposure studies regarding incidences of specific malformations and their critical periods are shown in Figure 2, which is reproduced from Shenefelt’s paper (1972). Data for this study were acquired from gross examination of both external and internal structures in 623 RA-exposed near-term fetuses and of subserial histologic sections of 134 of the fetuses. For comparison, additional control fetuses were examined. Malformation rates were determined only from fetuses that were alive at the time of maternal sacrifice on day 14 1/2 of pregnancy. Malformations involving the brain and spinal cord, eyes, ears, face, teeth, heart and great vessels, lungs, gastrointestinal, urogenital, endocrine, and musculoskeletal systems were noted and classified. Among the findings of this remarkably thorough investigation was the presence of more than one critical period for some malformations. As illustrated in Figure 2, this is the case for cleft palate, both maxillary and mandibular hypoplasia, and microcephaly. While the possibility of some subtle differences in the morphology of a particular defect resulting from insult at each of its critical periods was acknowledged, none was identified. Regarding correlation of the identified critical periods with the timing of embryonic events, Dr. Shenefelt noted