Secalonic acid D-induced changes in palatal cyclic AMP and cyclic GMP in developing mice

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Abstract
Secalonic acid D (SAD) induces cleft palate in the developing mouse by an unknown mechanism. To investigate possible roles of cyclic nucleotides (cAMP and cGMP) in the teratogenesis of SAD, cAMP and cGMP levels were measured in the extracts of fetal palates of gestational age 130 through 1612 (dayshours). Fetuses were obtained from pregnant CD-1 mice treated on day 110 of gestation, with either 5% (wt./vol.) sodium bicarbonate (NaHCO3, control) or 30 mg/kg of SAD in 5% NaHCO3, intraperitoneally (i.p.). Radioimmunoassay was used to quantitate cyclic nucleotide levels. Cyclic AMP levels peaked on day 1412 of gestation in controls. In the SAD group there was a significant decrease in cAMP levels on days 1312 and 140 of gestation and a decrease of 30% in total cAMP on days 130 through 140 of gestation, with little or no change at the peak on day 1412. On day 1512, however, the SAD group had a 68% increase in palatal cAMP level over the control. Control levels of cGMP appeared to follow a diurnal pattern reaching maximal levels at the end of the dark cycle. In contrast, SAD decreased the cGMP level by 31% on day 1312 (P < 0.05) and increased it 100% above that of the control level on day 150 (P < 0.01). Total cGMP during days 150 through 1612 of gestation was 33% higher than control (P < 0.01). The number of clefts in the SAD group was significantly higher at all points following palate closure in the control fetuses (140 through 1612) with values ranging from 20% to 34% versus 0% in the control (P < 0.01–0.005). Morphological changes on days 130 through 150 indicated a failure of shelf elevation in middle and posterior palatal regions of SAD-treated fetuses. These results suggest that the induction of cleft palate by SAD is associated with dynamic changes (initial decrease followed by later increase), in vivo, in established cyclic nucleotide patterns and support a mechanistic role for cyclic nucleotide-mediated cellular processes in normal as well as abnormal palate development.