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Increased susceptibility to retinoid-induced teratogenesis in TGF-beta2 knockout mice
Paul Nugent1, Michele M Pisano, Martin C Weinrich
1Birth Defects Center, University of Louisville School of Dentistry, 501 S Preston Street, Suite 301, Louisville, KY 40292, USA.
Abstract:
Transforming growth factor-beta (TGF-beta) and retinoic acid (RA) have been implicated in normal and abnormal embryonic development. The aim of this study was to investigate the effect of TGF-beta2 gene deletion on susceptibility to RA-induced teratogenesis in a mouse model. TGF-beta2 heterozygous or wild-type mice were mated and the dams dosed with a teratogenic dose of RA, or with control vehicle. The incidence of RA-induced cleft palate (CP) was 48% in wild-type embryos from wild-type dams, increasing to 71% in TGF-beta2 heterozygous littermates. Wild-type and TGF-beta2 heterozygous embryos from heterozygous dams exhibited a CP incidence of 74 and 77% respectively, following treatment with RA. Ninety-one percent of littermates nullizygous for TGF-beta2 were dead when examined; the remainder exhibited a CP. We conclude that the genotype of the dam and embryo with respect to TGF-beta2 affects the incidence of RA-induced teratogenesis.
Insights
Transforming growth factor-beta 2 (TGF-beta2) gene deletion increases susceptibility to retinoic acid (RA)-induced birth defects like cleft palate in mice. Dam and embryo genotypes significantly impact teratogenesis outcomes.
Area of Science:
- Developmental biology
- Teratology
- Genetics
Background:
- Transforming growth factor-beta (TGF-beta) and retinoic acid (RA) are crucial in embryonic development.
- Both factors are implicated in normal and abnormal embryonic development, including birth defects.
- Understanding their interplay is vital for preventing congenital abnormalities.
Purpose of the Study:
- To investigate the impact of TGF-beta2 gene deletion on susceptibility to RA-induced teratogenesis.
- To determine how maternal and embryonic TGF-beta2 genotypes influence RA-induced birth defects.
- To establish a mouse model for studying the genetic basis of teratogenesis.
Main Methods:
- Mating of TGF-beta2 heterozygous or wild-type mice.
- Administration of a teratogenic dose of RA or control vehicle to dams.
- Assessment of RA-induced cleft palate (CP) incidence in embryos based on maternal and embryonic genotypes.
Main Results:
- RA-induced CP incidence was 48% in wild-type embryos from wild-type dams.
- CP incidence increased to 71% in TGF-beta2 heterozygous embryos from wild-type dams.
- Embryos from TGF-beta2 heterozygous dams showed high CP rates (74-77%); 91% of nullizygous littermates were non-viable with CP.
Conclusions:
- Maternal and embryonic TGF-beta2 genotype significantly influences susceptibility to RA-induced teratogenesis.
- TGF-beta2 deficiency exacerbates RA-induced cleft palate formation.
- Genetic background is a critical determinant in the manifestation of drug-induced birth defects.