Importance of early exposure to 13‐cis retinoic acid to induce teratogenicity in the cynomolgus monkey

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Abstract
The teratogenic potential of 13‐cis retinoic acid (13‐cis RA) was further assessed in cynomolgus macaques (Macaca fascicularis) following exposure to two different regimens during the preorganogenic period to determine the influence of time of treatment on the 13‐cis RA malformation syndrome established previously (Hummler et al., Teratology, 42:263–272, 1990). In experiment (Exp) 1, 13‐cis RA was orally administered once daily (2.5 mg/kg) on gestational day (GD) 16–25 and twice daily (2 × 2.5 mg/kg) on GD 26–27. In Exp 2, the same oral dose was administered once daily on GD 10–20 and twice daily on GD 21–24. Although the ear was affected at about the same incidence (6/9, 67%) in Exp 1 as previously reported, the defects were less severe. Except for hypoplastic vermis of the cerebellum (2/9, 22%), no other defects were seen. In Exp 2, the teratogenic effects of 13‐cis RA on the craniofacial skeleton (1/9, 11%), external ear (5/9, 56%), and heart (2/9, 22%) were similar to that reported by Hummler et al.; however, no thymus or cerebellar malformations were observed. Analysis of the three different treatments (GD 16–27 in Exp 1, GD 10–24 in Exp 2, and GD 10–27 in Hummler et al.) suggests that the sensitive periods in the macaque are 1) craniofacial skeleton and heart GD 10–24, 2) thymus and cerebellum >GD 24, and 3) external ear GD 16–24, although the defects are less severe following the shorter exposure. Exposure to 13‐cis RA preceding onset of morphological organogenesis appears to be a requirement for 13‐cis RA embryopathy in the cynomolgus monkey. The external ear appears to be both a uniquely sensitive biomarker for 13‐cis RA teratogenicity and an indicator of embryotoxic severity. Finally, the longer period of drug administration (2.5 mg/kg, GD 10–25, and 2 × 2.5 mg/kg, GD 26–27) used by Hummler et al. is more suited to assessment of 13‐cis RA teratogenicity in macaques due to greater concordance with the 13‐cis RA syndrome in humans.