Inbred mouse strains vary considerably in susceptibility to teratogen-induced cleft palate (CP). CP is readily induced in A/J mice but not in C57BL/6J mice. Although numerous biochemical differences exist between the strains, the specific basis for the strain differences in sensitivity to teratogens is unknown. One documented biochemical difference between mouse strains is variations in submandibular gland (SMG) levels of epidermal growth factor (EGF) whose synthesis and glandular level are regulated by androgen and thyroid hormone. Recent studies have shown that EGF can modulate development of the mammalian secondary palate. The hypothesis to be tested is that the availability of testosterone, established by the activity of steroid metabolic enzymes, determines androgen responsiveness of the SMG, and thus the levels of EGF and indirectly susceptibility to CP. Specifically, SMG from mouse strains known to differ markedly in their susceptibility to induced CP will be tested for: (a) the activity of androgen metabolizing enzymens, (b) the level of testosterone and its metabolites, (c) physiochemical properties of the androgen receptor, and (d) the concentration of EGF. Genetic studies using crosses of CP-sensitive and CP-resistant strains will validate if Delta4-3-ketosteroid-5alpha-oxidoreductase or other androgen metabolizing enzymes can serve as a marker for CP susceptibility. It will also be established if high SMG-EGF levels of the CP-sensitive A/J mouse strain are regulated by thyroid hormone either directly or indirectly through androgens. It will also be determined if progestins stimulate SMG-EGF levels and if so by what mechanism. These studies will provide important information on the role of androgen in the production of EGF and indirectly in the development of CP. In the long range this information is essential for the efficient design of experiments to determine if altering endogenous EGF levels modifies the resistance of high genetic risk individuals to CP.
