title: Inhibition of adenylate cyclase in perfusion mouse palate by secalonic acid D.
abstract: Glucocorticoids (GC) induce cleft palate (CP) in the offspring of exposed pregnant mice. Glucocorticoids induce prostaglandin (PG) synthesis inhibition via reduced arachidonic acid (AA) release from membranes, and this results from inhibition of phospholipase A2. This metabolic event is associated with reduced palatal cAMP levels in the prefusion stages (d 13 of gestation). The mycotoxin secalonic acid D (SAD) induces CP in the offspring born to treated mothers, elevates maternal plasma corticosterone levels, and reduces prefusion palatal cAMP levels. In addition, an increase in cAMP was noted in the postfusion period (d 15 of gestation). Since exogenous AA given simultaneously to GC-exposed mothers may protect against GC-induced CP in the offspring, such a possibility was tested for SAD. Pregnant CD1 mice given a teratogenic dose of SAD (30 mg/kg, ip, on gestational d 11) were simultaneously treated with maximal tolerated doses of AA (200 mg/kg, sc, on gestational d 11, 12, and 13). At term, no significant reduction in SAD-induced CP was seen as a result of AA treatment. To evaluate if SAD-induced alterations in palatal cAMP are due to reduced palatal membrane-associated adenylate cyclase (AC) activity during pre- and postfusion periods, SAD-treated mothers were sacrificed at 12-h intervals between gestational d 13.5 and 15.5, palate shelves were collected from the fetuses, and AC activity (cAMP formed/mg protein/min) was assayed in the presence or absence of the enzyme stimulator, sodium fluoride (NaF). Although SAD did not alter unstimulated AC activity, it significantly reduced the NaF-induced stimulation of enzyme activity in the prefusion period. This inhibition could not be reversed by excess GTP in the incubation mixture. Since NaF stimulation of AC indicates post-receptor-site function involving GTP-binding and catalytic units, and since addition of GTP failed to correct SAD-induced alteration of NaF stimulation of the enzyme, it is suggested that SAD may inhibit the AC sensitivity to stimuli by its effect on the catalytic unit in a manner that does not affect enzymic basal activity.
authors.affiliation: Department of Veterinary Biomedical Sciences, University of Missouri-Columbia 65211.
authors.forename: R V
authors.initials: RV
authors.lastname: Reddy
authors.forename: M M
authors.initials: MM
authors.lastname: Eldeib
authors.forename: C S
authors.initials: CS
authors.lastname: Reddy
mesh_terms: D000262:Adenylyl Cyclases / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D016718:Arachidonic Acid / Q000008:administration & dosage*; D002972:Cleft Palate / Q000139:chemically induced / Q000517:prevention & control*; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D051379:Mice; D010159:Palate / Q000187:drug effects / Q000196:embryology / Q000201:enzymology*; D011247:Pregnancy; D012969:Sodium Fluoride / Q000494:pharmacology; D014966:Xanthenes / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D044004:Xanthones
chemical_list: D014966:Xanthenes; D044004:Xanthones; D016718:Arachidonic Acid; C009218:secalonic acid; D012969:Sodium Fluoride; D000242:Cyclic AMP; D000262:Adenylyl Cyclases