The role of multiple drug resistance proteins in fetal and/or placental protection against teratogen-induced orofacial clefting.

Previous studies have shown a role for multiple drug resistance proteins in protecting the fetus from a limited number of teratogens. We have expanded the number of proteins and teratogens examined by comparing the influence of the mdr1a and mdr2 proteins on teratogen-induced orofacial clefting using their respective knockouts in crosses with the A/J, high susceptibility strain. Western blots identified the presence of mdr1a and possibly mdr2 in the placenta and fetus. The mdr1a knockout, on its unique genetic background showed lower, similar, and higher incidences of clefting compared to A/J for Dilantin, hydrocortisone (HC), and 6-aminonicotinamide (6-AN), respectively. The mdr2 knockout did not affect 6-AN clefting when compared to A/J. In reciprocal crosses, when corrected for increased spontaneous clefting, maternally inherited A/J susceptibility genes predominated over the effects of the maternal absence of mdr1a (with 6-AN). Unlike mdr1a, which had a direct effect in the fetus as shown by genotyping of affected versus unaffected fetuses, an effect of mdr2 in the fetus was not found. The mdr1a knockout was backcrossed to the A/J inbred strain for 11 generations (congenics) to eliminate genetic background effects. Reciprocal crosses showed no maternal effect from the lack of mdr1a, confirming that mdr1a expression in the fetus, rather than the placenta, protects the fetus from teratogens. Mdr2 seems not to be involved in the protection of the fetus from teratogens.