Glucocorticoid-induced cleft palate in the mouse: two major histocompatibility complex, H-2, loci with different mechanisms.
Isolated cleft palate is induced in the progeny of pregnant mice that are given glucocorticoids. The incidence varies among inbred strains and with dose and stage of gestation when the drug is given. One chromosomal region responsible for strain-associated differences in sensitivity is the major histocompatibility complex, H-2. H-2a is associated with susceptibility, H-2b with resistance. There appear to be both maternal and embryonic genetic factors affecting the sensitivity to glucocorticoids. In experiments reported here congenic strains of mice with H-2a, H-2d and H-2k haplotypes on a C57BL/10 genomic background were used. This allowed the determination of the effect on sensitivity by two H-2 subregions; the subregions are H-2K to I-E and I-C to H-2D. Methods included dose-response analysis and reciprocal cross analysis using dexamethasone given on day 12 of pregnancy. Results show that each subregion affects the strain's sensitivity to dexamethasone-induced cleft palate. The regression coefficients for B10.A-H-2a (45.4 +/- 4.13) were different from those for B10.BR-H-2k (67.2 +/- 10.8) and B10.D2-H-2d (70.5 +/- 9.74). The estimated mean arcsine % cleft palate at 160 mg/kg was different for each strain: B10.A-H-2a, 53.1 +/- 2.19; B10.BR-H-2k, 33.1 +/- 2.27; B10.D2-H-2d, 25.0 +/- 2.75. Different patterns of change in sensitivity were observed among the reciprocal crosses. In summary, the H-2K to I-E subregion seemed to influence both maternal and embryonic factors, whereas only embryonic factors were influenced by the I-C to H-2D subregion. These data suggest that the mechanisms affecting glucocorticoid sensitivity which are genetically encoded within each H-2 subregion are different, and there is an interaction between the alleles. The mode of interaction can be either complementation or epistasis.
D000818:Animals; D002972:Cleft Palate / Q000139:chemically induced / Q000235:genetics*; D003433:Crosses, Genetic; D003907:Dexamethasone / Q000009:adverse effects; D004198:Disease Susceptibility; D004305:Dose-Response Relationship, Drug; D005260:Female; D005327:Fetal Resorption; D006183:H-2 Antigens / Q000235:genetics*; D008297:Male; D051379:Mice / Q000235:genetics*; D008810:Mice, Inbred C57BL; D011247:Pregnancy
D006183:H-2 Antigens; D003907:Dexamethasone