Micronutrients and Congenital Anomalies*

Abstract: Insufficient as well as excessive amounts of essential micronutrients such as vitamins and minerals are known to be deleterious to developing embryos in mammals. However, no detailed analysis of the effects of biotin deficiency on mammalian embryos has been reported. We demonstrated that maternal biotin deficiency produced a high incidence of external and skeletal malformations in mice, although the dams showed no clinical signs of biotin deficiency during gestation. The prominent malformations were craniofacial and limb malformations such as cleft palate, micrognathia, and micromelia. A dose‐response relationship was observed in the incidences of the respective malformations. The formation of secondary palatal processes and limb buds was delayed at midgestation in these biotin‐deficient mouse embryos, probably leading later to cleft palate and limb malformations. When the teratogenicity of biotin deficiency was compared in three mammalian species, striking species and strain differences were detected.Excess retinoids are embryotoxic and teratogenic in mammals, causing especially high incidences of craniofacial and limb malformations. We examined the mechanism of action of retinoic acids (13‐cis‐, 4‐oxo‐13‐cis‐, and all‐trans‐) on the craniofacial tissues of mouse embryos using whole embryo culture and primary cell culture. In cultured embryos, retinoic acids caused overall embryonic growth retardation, particularly in the facial processes (maxillary, mandibular, and nasal). Histological examination of mouse embryos at midgestation showed that cranial neural crest cells were not migratory and demonstrated pyknotic nuclei in the mesenchyme adjacent to the epithelium in nasal processes. Biochemicalanalysis revealed that retinoic acids also inhibit DNA synthesis and the proliferation of mesenchymal cells in facial processes, a finding that is relevant to the mechanisms of retinoic acid‐induced craniofacial malformations.It is proposed that the role of micronutrients in embryonic growth and development should be evaluated at the cellular level using whole embryo culture and embryonic cell culture.