DISRUPTION OF EPIDERMAL GROWTH FACTOR SIGNALING IN THE MOUSE PALATE BY SECALONIC ADIC D: AN IN VIVO STUDY

Secalonic acid D (SAD) is a teratogenic mycotoxin of potential significance in human health and as a model compound for the induction and the study of cleft palate, the major malformation it produces in the offspring of treated mice. Recent evidence suggests that SAD-induced elevations in maternal corticosterone may mediate its cleft palatogenic effect. Since high levels of glucocorticoids are known to produce antiproliferative effect in a variety of cells via alterations in growth-factor pathways in which protein kinase C (PKC) plays a central role, these studies were designed to assess the role of epidermal growth factor (EGF) and PKC in SAD-induced cleft palate by studying (1) the effect of SAD administration \[on gestational day (GD) 11]on palatal EGF levels in CD 1 mouse embryos, and the influence of higher doses of suramin (anti-growthfactor effects) on palate development and SAD-induced cleft palate, and (2) the influence of suramin, a PKC stimulator (lower doses), on the incidence of SADinduced cleft palate. In addition, the role of glucocorticoids in SAD-induced cleft palate was further evaluated by studying the effect of protective doses of suramin on SAD-induced maternal corticosterone elevations and by evaluating whether hydrocortisone will itself produce alterations in EGF similar to SAD. A teratognic dose of SAD (30 mg/kg)significantly reduced palatal EGF levels at gestational ages during which palate development is continuing (GD 13.5 to 14.5) but not following palate closure (GD 15). Hydrocortisone also reduced palatal EGF levels significantly on GD 14. Palatal EGF levels were stable throughout this period in control palates. Suramin, at doses of up to 100 mg/kg body weight, neither induced deleterious effects nor enhanced SAD-induced adverse effects including cleft palate in mice. Higher doses, however, induced total resorptions and/or maternal deaths. In combination with SAD, lower doses of suramin either tended to reduce (50 mg/kg) or reduced (75 mg/kg) SAD-induced resorptions and cleft palate as well as SAD-induced maternal corticosterone elevation. Higher doses of suramin, on the other hand, increased SAD-induced resorptions (100 mg/kg) and lacked the protective effect against SAD-induced cleft palate (100 and 125 mg/kg) seen at lower doses of suramin. The results of these studies demonstrated that a cleft palatogenic dose of SAD is capable of disrupting the ontogeny of EGF in the palate. In addition, these data confirmed the involveme