Mycotoxin, Secalonic acid D (SAD), is capable of producing cleft palate in fetal mice following maternal exposure. A number of teratogenic agents, including hydrocortisone, are cytotoxic at high doses. Teratogens with such effects given during the development of facial processes are capable of causing cleft lip and cleft palate. Recent advances in developmental research indicate the presence of prostaglandins (PG's), serotonin (5-HT) and gamma amino brityric acid (GABA) in the developing rodent palatal processes and suggest a role for these cellular intermediates in normal development. A transient rise in palatal cyclic AMP (cAMP) levels just prior to or during the palatal elevation and fusion, a prevention or a delay of this cAMP rise by cleft-palate teratogens of diverse chemical nature (cortisone and methyl mercury), and the fact that cAMP and cGMP mediate the actions of PG's, 5-HT and GABA; all suggest that alterations in cAMP may reflect alterations in palatal levels of PG's, 5-HT, GABA or possibly other cellular intermediates. Ergot compounds, structurally related to SAD, are known to modulate the levels of PG's, 5-HT and cyclic nucleotides in the brain, suggesting the likelihood that SAD may effect one or more of the above intermediates in the palate. Experiments are designed to study; 1. the effect of SAD on cell survival and proliferation rate in the palatal process, and establish non-cytotoxic dose levels for biochemical studies; 2. the alterations in the levels of 5-HT, GABA, and cyclic nucleotides, and biosynthesis of prostaglandins associated with noncytotoxic SAD exposure in the developing palate in this strain of mice; and 3. the reversibility of the SAD induced alterations by DMSO (a solvent shown to protect mouse fetuses against SAD-induced cleft palate) and relationship of this protection to possible changes in distribution and kinetics of 14C-SAD in the fetal-maternal system. This could lead to a better understanding of the mechanism of cleft palate production by environmental teratogens and suggest approaches to the prevention of environmentally caused cleft palate.
NIH ExPorter
NIH ExPorter