Rv. Reddy et al., INHIBITION OF ADENYLATE-CYCLASE IN PREFUSION MOUSE PALATE BY SECALONIC ACID-D, Journal of toxicology and environmental health, 41(2), 1994, pp. 175-185
Glucocorticoids (GC) induce cleft palate (CP) in the offspring of expo
sed pregnant mice. Glucocorticoids induce prostaglandin (PG) synthesis
inhibition via reduced arachidonic acid (AA) release from membranes,
and this results from inhibition of phospholipase A(2). This metabolic
event is associated with reduced palatal cAMP levels in the prefusion
stages (d 13 of gestation). The mycotoxin secalonic acid D (SAD) indu
ces CP in the offspring born to treated mothers, elevates maternal pla
sma 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-expos
ed mothers may protect against CC-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 tr
eated with maximal tolerated doses of AA (200 mg/kg, sc, on gestationa
l 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 al
terations in palatal cAMP are due to reduced palatal membrane-associat
ed adenylate cyclase(AC) activity during pre- and postfusion periods,
SAD-treated mothers were sacrificed at 12-h intervals between gestatio
nal d 13.5 and 15.5, palate shelves were collected from the fetuses, a
nd AC activity (cAMP formed/mg protein/min) was assayed in the presenc
e 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 CTP in the incubatio
n mixture. Since NaF stimulation of AC indicates post-receptor-site fu
nction involving CTP-binding and catalytic units, and since addition o
f CTP failed to correct SAD-induced alteration of NaF stimulation of t
he 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.